Abstract:
Method for in vitro diagnosis of susceptiblility of developing venous malformations i the extracranial segment of the cerebrospinal veins in a patient comprising the detection of copy number variations (CNVs) in chromosome 6p21 in a sample of genomic DNA of the patient, wherein the venous malformations are associated with the development of multiple sclerosis.

Description:
FIELD OF THE INVENTION 
       [0001]    This disclosure concerns a Array-based method for detection of Copy number variations in the HLA locus for the genetic determination of susceptibility of development of venous malformations in the extracranial segments of the cerebrospinal veins associated with multiple sclerosis. More specifically, the present disclosure concerns a genetic diagnostic method for the determination of the genotype-phenotype correlation risk of development of venous malformations associated with multiple sclerosis. 
       BACKGROUND OF THE INVENTION 
       [0002]    Multiple sclerosis is the most common neurological disease in young adult population catalogued into neurodegenerative disorders of unknown etiology. Inflammatory, infective, and autoimmune causes have been proposed to have a pathogenic role in this disease, although the link between these factors and the disease etiology remains to be elucidated. 
         [0003]    From the genetic point of view, studies on twins and siblings suggest that susceptibility genes may play a role in this disease. Multiple sclerosis has, in fact, a clinically significant heritable component. 
         [0004]    A genomewide association study was carried out in order to identify alleles associated with the risk of multiple sclerosis [7]. A transmission disequilibrium test of 334,923 single-nucleotide polymorphisms (SNPs) in 931 family trios revealed 49 SNPs having an association with multiple sclerosis. Alleles of IL2RA and IL7RA and those in the HLA locus are identified as heritable risk factors for multiple sclerosis. However, the detection of susceptibility loci is an important starting point, but does not clarify what are exactly the genes involved in the transmission of the disease and through what molecular mechanisms. Moreover, a correlation between genotype variation and phenotype phenomena has not been demonstrated. For such a reason, susceptibility loci need to be finely mapped and also correlated with the function of the component genes. 
         [0005]    Candidate-gene studies and whole genome association studies as well as copy number variations (CNVs) detection on single nucleotide polymorphisms (SNPs) based arrays involving more than hundred thousand markers have been performed and identified several susceptibility loci in the human genome, being the HLA locus on 6p21.32 the more confidently associated locus [1-6]. A few other possible susceptibility loci have been described although of uncertain statistical significance [7,8]. 
         [0006]    When using single nucleotide polymorphisms (SNPs) based arrays and even when controls are accurately randomised, undetectable errors may occur especially linked to the population geographical origins, to the known differences in SNPs density, depending on the various human chromosomes or even genomic regions involved. These errors may inflate the apparently significant differences between patients and controls (genomic inflation) generating false positive or false negative, and finally hampering a true recognition of the associated loci [8]. 
         [0007]    In order to overcome this “potential” trouble, an enormous number of individuals have to be analysed as recommend by the Wellcome Trust Case Control Consortium and as recently reported [8], to get unbiased data and to replicate the associations in the identified loci. However, the Authors themselves conclude that functional studies are required. 
       SUMMARY OF THE INVENTION 
       [0008]    Taking into account these premises, the need is therefore felt for improved solutions enabling reliable detection of genetic predisposition factors of patients to development of venous malformations associated with multiple sclerosis. 
         [0009]    The object of this disclosure is providing such improved solutions. 
         [0010]    According to the invention, the above object is achieved thanks to the subject matter recalled specifically in the ensuing claims, which are understood as forming an integral part of this disclosure. 
         [0011]    An embodiment of the present disclosure provides a method for in vitro diagnosis of risk of development of venous malformations comprising the step of detecting copy number variations (CNVs) in chromosome 6p21, wherein the venous malformations are associated with the development of multiple sclerosis. 
         [0012]    A further embodiment of the present disclosure concerns a kit for performing such a diagnostic method. More specifically, the kit comprises CGH probes covering the HLA-DRA locus region for the detection of CNVs in chromosome 6p21 in genomic DNA of patients. 
         [0013]    A still further embodiment of the present disclosure concerns a CGH array entirely covering the HLA-DRA locus region for the detection of CNVs in chromosome 6p21 in genomic DNA of patients. 
         [0014]    The data herein disclosed demonstrate a significant correlation between the number of CNVs found in the HLA-DRA region and the number of venous malformations, more specifically of chronic cerebrospinal venous malformations, identified in patients. This disclosure demonstrates that the number of multiple polymorphic CNVs in the HLA locus identified are determinants possibly involved in the phenotypic manifestation to this novel venous malformations/multiple sclerosis association. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0015]    The invention will now be described, by way of example only, with reference to the enclosed figures of drawing, wherein: 
           [0016]      FIGS. 1A and 1B : Genomic distribution of the Known CNVs among the patients studied along the HLA-DRA locus. In the graph are reported the starting nucleotide for each CNV. In white are highlighted the regions of the HLA genes. 
           [0017]      FIG. 2 : Exemplification of stenosing venous malformation associated to MS. A) Significant stenosis (arrow) of the left internal jugular vein (L IJV). B) Membranous obstruction of the outlet of the Azygous vein (o AZY) into the superior vena cave (SVC). 
           [0018]      FIGS. 3 to 5 : Linear regression analysis. A significant correlation between the number CNVs ( FIG. 3 ), intragenic CNVs ( FIG. 4 ) and extragenic CNVs ( FIG. 5 ) and the number of venous malformations detected by the means of selective venography was found (r=0.53, r=0.28, p&lt;0.05). 
           [0019]      FIG. 6 : Number of total (A), intragenic (B) and extragenic (C) known CNVs reported in the Database of Genomic Variants per patient. 
           [0020]      FIG. 7 : Functional links of the known genes within the HLA locus networking on neurodegeneration, multiple sclerosis and immunity disorders (A) and angiogenesis and venous formation pathways (B). 
           [0021]      FIG. 8 : The CGH profile identified in patient PF as example. The multiple perturbation of the genomic area is well apparent. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0022]    In the following description, numerous specific details are given to provide a thorough understanding of embodiments. The embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the embodiments. 
         [0023]    Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. 
         [0024]    The headings provided herein are for convenience only and do not interpret the scope or meaning of the embodiments. 
         [0025]    The present inventors to investigate the occurrence of copy number variations (CNVs) underlining genome unbalances in the major locus (HLA, chromosome 6p21) associated with multiple sclerosis (MS) recur to a comparative genomic hybridisation (CGH) array in order to overcome the inevitable errors associated with the SNPs-based arrays. 
         [0026]    It is now well recognised that copy number variations (CNVs) typically ranging from 1 kb to several Mb do contribute to genetic variations and disease susceptibility. CNVs account for more nucleotide variations between individuals; in addition, the functional meaning of CNVs might be more immediate, especially for those located within genes, regulatory regions or known imprinted regions, since the possible consequence of the genome unbalance(s) may be interpretable in a more straight forward way. 
         [0027]    The advantage to search for CNVs by the CGH technique is the possibility to directly correlate the known, validated CNVs with a possible function, both related to the specific gene unbalanced and to other genomic regions with copy variations. In fact, CGH approach allows to finely mapping the identified CNVs in non-genic regions, possibly correlated to genes regulatory function, epigenetic changes or other non-coding functions. 
         [0028]    The development of robust high throughput platforms based on comparative genomic hybridisation (CGH) capable of identifying thousand genomic variations has greatly improved the research in this direction, as recently demonstrated in a major neurodegenerative disorder, the amiotrophic lateral sclerosis, in which non-polymorphic sub-microscopic duplications and deletions seem to be frequent in sporadic cases. 
         [0029]    The present inventors designed a locus-specific CGH array in order to explore the occurrence of CNVs in the HLA-DRA locus region (6,899,999 bp; chromosome 6p21: 29,900,001-36,800,000 bp) in 15 patients with the peculiar association of chronic cerebrospinal venous insufficiency (CCSVI) and MS phenotype. 
         [0030]    The present inventors already described the peculiar association of chronic cerebrospinal venous insufficiency (CCSVI) in patients with MS in the international patent application No. PCT/IT2008/000129. In such an application the inventors demonstrated that CCSVI is due to stenosing venous malformations (VM) affecting the azygous and the jugular veins, leading to significant anomalies in cerebral venous outflow haemodynamics. The hampered cerebral venous return in consequence of the extracranial venous malformations is peculiar to MS, and was not found in a miscellaneous of patients affected by other neurodegenerative disorders, such as Parkinson&#39;s, Alzheimer&#39;s, amyotrophic lateral sclerosis. 
         [0031]    In total patients showed 322 CNVs of which 225 extragenic and 97 intragenic. The present inventors identified 234 known polymorphic CNVs in the 15 patients having such a “plus” phenotype (i.e. VM-CCSVI and MS phenotype). Looking at the distribution of the polymorphic CNVs identified in these patients, the present inventors observed a peak of CNVs number within the HLA region. Outside this specific region however, the number of CNVs per patients remains high, though with variable distribution. 
         [0032]    Interesting, the overall number of CNVs showed a correlation with the number of stenosing VM as demonstrated by venography in the extracranial segments of the cerebrospinal veins, with a trend toward significance. 
         [0033]    The contribution to the correlation is certainly due to the extragenic CNVs, being significantly correlated to the number of stenosing VM (r=0.53, r=0.28, p&lt;0.05). 
         [0034]    This result suggests that the contribution of extragenic CNVs in the development of the associated VM is related to their regulatory action in the process of angiogenesis. 
         [0035]    The region studied contains 211 known genes. Using the functional bioinformatics tool the present inventors identify many genes interacting in both neurodegenerative and angiogenesis circuits. Notably, HSPA1L, HSP1A and HSP1B and the HLADQ2 genes network on both pathways. Heat-shock proteins (HSPs) represent a group of regulatory proteins involved in a variety of processes, including immunity and angiogenesis. In particular, HSPA1L expression is modulated by ETS1 transcription factor and by SP100 a nuclear autoimmune antigen. Interestingly, genes negatively regulated by ETS1 and up-regulated by SP100, as HSPA1L, have anti-migratory or anti-angiogenic properties. 
         [0036]    MS has a very well known major heritable component since its susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLADQB1*0602 haplotypes, which dominate genetic contribution to MS risk [20]. Interestingly HLADQA2 is known to be involved with pro-inflammatory CD4(+) T-cell-mediated autoimmune diseases, such as MS and type 1 diabetes [21]. CD4 is also a very well known inhibitor of tumor angiogenesis [22], so supporting a link between the two pathways. The interpretation of the pathway interaction is obviously complex, but it suggests biological and functional links among these genes as well as, intriguingly, between angiogenesis and immunity. 
         [0037]    Consistently with the general meaning of extragenic CNVs, putatively involved in gene expression regulation, this finding is interesting, since it supports the possibility that the number of structural variations laying within regulatory regions may represent a genomic “perturbation” increasing susceptibility for VM phenotype associated with MS the present inventors described. 
         [0038]    Regarding specific candidate genes which expression could be potentially disturbed by genomic unbalances or “perturbation”, the pathways analysis suggests that genes involved in angiogenesis and immunity are the more interesting proteins. 
       Methods 
     Subjects 
       [0039]    Fifteen patients affected by the relapsing-remitting clinical course of MS diagnosed according to the revised Mc Donald criteria as disclosed in [11] entered the study. The present inventors determined the expanded disability disease score (EDSS) as disclosed in [12], as well as the multiple sclerosis severity score (MS-SS) as disclosed in [13,14]. 
         [0040]    The Kurtzke Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The EDSS categorizes a person&#39;s level of disability. EDSS scores range from 0-10, with higher scores indicating more severe disability. The MS-SS is a relationship between the EDSS and the disease duration, being the MS clinical course more aggressive in accordance with the time in which a certain score has been reached. 
         [0041]    In the present population MS was associated with CCSVI venous malformation documented by a sequential Colour-Doppler/selective venography protocol as disclosed in the international patent application No. PCT/IT2008/000129 as well as in [9]. The clinical and demographic characteristics of the selected patients are given in the Table 1. Patients signed an informed consent. Detailed information about each of the 15 patients is provided in table 2. 
         [0000]    
       
         
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                   
                 Multiple sclerosis 
               
               
                   
                   
                 relapsing remitting 
               
               
                   
                 Parameters 
                 n° 15 Median (IR) 
               
               
                   
                   
               
             
             
               
                   
                 Age, years 
                 36 (12) 
               
               
                   
                 Sex M/F 
                 7/8 
               
               
                   
                 Disease duration, years 
                 6 (9) 
               
               
                   
                 EDSS 
                 1.5 (1)   
               
               
                   
                 MS-SS 
                 2.6 (3.8) 
               
               
                   
                 Number of VM 
                 2 (1) 
               
               
                   
                 Total CNVs 
                 23 (13) 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                   
                   
                 MS 
                   
                   
                   
               
               
                   
                   
                   
                 N° 
                 DISEASE 
                   
                   
                 Number 
               
               
                 PATIENT 
                   
                   
                 OF 
                 DURATION 
                   
                 MS- 
                 of 
               
               
                 CODE 
                 SEX 
                 AGE 
                 VM 
                 YEARS 
                 EDSS 
                 SS 
                 CNVs 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 PB 
                 F 
                 36 
                 2 
                 15 
                 7 
                 8.17 
                 8 
               
               
                 RM 
                 M 
                 31 
                 3 
                 3 
                 1.5 
                 3.34 
                 31 
               
               
                 DD 
                 M 
                 46 
                 4 
                 3 
                 2 
                 4.82 
                 39 
               
               
                 GE 
                 M 
                 46 
                 2 
                 6 
                 1 
                 1.13 
                 20 
               
               
                 BL 
                 M 
                 40 
                 3 
                 14 
                 1.5 
                 1.03 
                 18 
               
               
                 CC 
                 M 
                 32 
                 3 
                 4 
                 1 
                 1.45 
                 14 
               
               
                 FR 
                 M 
                 46 
                 3 
                 12 
                 1 
                 0.64 
                 22 
               
               
                 PF 
                 F 
                 27 
                 2 
                 4 
                 1 
                 1.45 
                 12 
               
               
                 CM 
                 F 
                 46 
                 2 
                 15 
                 4 
                 5.09 
                 23 
               
               
                 MU 
                 M 
                 40 
                 2 
                 9 
                 1 
                 0.88 
                 10 
               
               
                 CF 
                 F 
                 30 
                 2 
                 5 
                 1.5 
                 2.6 
                 29 
               
               
                 HH 
                 F 
                 36 
                 3 
                 3 
                 1.5 
                 3.34 
                 15 
               
               
                 LS 
                 F 
                 25 
                 4 
                 3 
                 2 
                 4.82 
                 20 
               
               
                 VF 
                 F 
                 36 
                 2 
                 6 
                 0.5 
                 0.25 
                 12 
               
               
                 MC 
                 F 
                 37 
                 2 
                 3 
                 1.5 
                 3.34 
                 52 
               
               
                   
               
             
          
         
       
     
         [0042]    DNA from the 15 patients was extracted by protocol recommended by Agilent using the Qiagen DNeasy Blood &amp; Tissue Kit. DNA from the 15 patients was extracted by protocol recommended by Agilent. Highly concentrated DNA was checked with a Nanodrop for quality (260/280 ratio −1.8 and 260/230 ratio=2.0). DNA integrity was evaluated on agarose gel at 1% in TBE 1×. 
       Statistical Analysis 
       [0043]    Clinical data are given as median and interquartile range. Genotype-phenotype correlations were analyzed by the means of linear regression analysis, including evaluation of slope, X and Y Intercept, followed by Run Test. P values &lt;0.05 were considered to be significant. 
       Microarray Design, Hybridization and Data Analysis 
       [0044]    MS-CGH microarray design was carried out using the web based Agilent eArray database version 5.4 (Agilent Technologies, Santa Clara, Calif.) [16]. The high density aCGH search function within eArray was used to turn the genomic region chr6: 29,900,001-36,800,000 (March 2006 human reference sequence, NCBI Build 36.1, hg18;) into a probe set by selecting the maximum number of exonic, intronic and intragenic 60mer oligonucleotide CGH probes available in the database. This probe set included 43102 probes that were used to reach the array format of 4×44 K, creating four identical 44 K arrays on a single slide for simultaneous analysis of four different samples. 
         [0045]    This platform called MS-CGH is a High-Density microarray with a resolution of one probe every 160 bp which allow the rapid determination of the molecular profile identifying the presence of copy number variations (CNVs) in heterozygosity or in homozygosity in the genomic region studied. 
         [0046]    Labelling and hybridisation were performed following the protocols provided by Agilent (Agilent Oligonucleotide Array-Based CGH for Genomic DNA Analysis protocol v5.0) as described in [17]. Briefly, genomic DNA from a control and a patient in the same quantity were digested by restriction enzymes AluI and RsaI in separate tubes. The obtained fragments of DNA from each samples were amplified in presence of Cyanine 3-dUTP (control sample) and Cyanine 5-dUTP (patient sample). After a step of purification and quantitation of the incorporation of the Cyanines samples were combined and hybridized onto the microarray for 17 hours at 65° C. 
         [0047]    The array was analysed with the Agilent scanner and the Feature Extraction software (v9.1). A graphical overview and analysis of the data were obtained using the DNA analytics software (v4.0.36). For identifying duplications and deletions the present inventors used the standard set-up of the ADM-2 statistical analysis provided by DNA analytics software (Agilent genomic Workbench 5.0) freely available at Agilent Technologies website. 
         [0048]    According to this set-up and in the case of autosomal genes, heterozygous deletions are visualised with values of minus 1 and homozygous deletions as minus infinite (−4 in CGH analytics). The corresponding values for heterozygous and homozygous duplications are plus 0.5 and plus 1 respectively. At least 4 consecutive non-overlapping probes reaching these values were needed for a positive call, together with absence of known SNPs in the region covered by the significant probes. All the 15 patients were done in duplicate on the array in order to provide robustness and validity to the results. 
       Bioinformatics Analysis of Gene Networks 
       [0049]    Pathway analysis and literature mining was performed using Pathway Studio software from Ariadne Genomics Inc. Pathway Studio database contains millions of regulatory and interaction events from all Pubmed abstracts and more than 350,000 full-text articles extracted by MedScan natural language processing technology. The present inventors have used graph navigation tool in Pathway Studio called “Build pathway” to find literature evidence supporting functional association of measured genes with angiogenesis and other processes linked to blood vessel formation as well as immunity and neurodegeneration. 
       Results 
     CGH-ARRAY Data 
       [0050]    The present inventors identified 234 known polymorphic CNVs in the 15 patients by comparing with the CNVs database [18]. This finding confirmed that the HLA locus is highly polymorphic in terms of genomic unbalances as expected considering the known high density of SNPs. The distribution of the CNVs among patients both in terms of number and density of them is showed in  FIGS. 1A and 1B . 
         [0051]    Table 3 reports all the CNVs identified in patients. CNVs in the last column of the table are identified with same catalog number of the Database of Genomic Variants and can be searched either in UCSC Genome Browser and in the Database of Genomic Variants itself. 
         [0052]      FIG. 8  reports on the CGH profile identified in patient PF, as example. 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Patient 
                   
                   
                   
                   
                   
               
               
                 Code 
                 Chr. 
                 Start 
                 Stop 
                 genes 
                 Hs_hg18_CNV_20080404 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 BL 
                 chr6 
                 32536756 
                 32766992 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_32789, CNV_31279, 
               
               
                   
                   
                   
                   
                   
                 CNV_31280, CNV_4767, CNV_23237, CNV_32790, CNV_32791, 
               
               
                   
                   
                   
                   
                   
                 CNV_23801, CNV_1709, CNV_32792, CNV_23802, CNV_6759, 
               
               
                   
                   
                   
                   
                   
                 CNV_6761, CNV_32793, CNV_32794, CNV_7568, CNV_23283, 
               
               
                   
                   
                   
                   
                   
                 CNV_32795, CNV_6764, CNV_32796, CNV_7569 
               
               
                 BL 
                 chr6 
                 32564230 
                 32565022 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 BL 
                 chr6 
                 32595206 
                 32595421 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237 
               
               
                 BL 
                 chr6 
                 32596430 
                 32597048 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 BL 
                 chr6 
                 32600343 
                 32605108 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 BL 
                 chr6 
                 32630548 
                 32633760 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 BL 
                 chr6 
                 32644521 
                 32654562 
                 HLR-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_32792 
               
               
                 BL 
                 chr6 
                 32654143 
                 32654521 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 BL 
                 chr6 
                 32668385 
                 32668850 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 BL 
                 chr6 
                 32680250 
                 32680644 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 BL 
                 chr6 
                 32712472 
                 32712943 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 BL 
                 chr6 
                 32720046 
                 32720535 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 BL 
                 chr6 
                 32720570 
                 32721540 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 BL 
                 chr6 
                 32728265 
                 32728541 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 BL 
                 chr6 
                 32728938 
                 32731038 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 BL 
                 chr6 
                 32734749 
                 32734935 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 BL 
                 chr6 
                 32786798 
                 32787270 
                   
                 CNV_3603, CNV_4767, CBV_7569, CNV_31281 
               
               
                 BL 
                 chr6 
                 34425436 
                 34426875 
                 NUDT3 
                 CNV_7572 
               
               
                 CF 
                 chr6 
                 31387332 
                 31418253 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7563, CNV_7564, CNV_32780, 
               
               
                   
                   
                   
                   
                   
                 CNV_1708, CNV_10145, CNV_10146, CNV_6758, CNV_23799 
               
               
                 CF 
                 chr6 
                 32680250 
                 32680644 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 CM 
                 chr6 
                 29929774 
                 29935498 
                   
                 CNV_8209, CNV_3599 
               
               
                 CM 
                 chr6 
                 30761724 
                 30763025 
                 KIAA1949 
                 CNV_3600, CNV_31270 
               
               
                 CM 
                 chr6 
                 31311983 
                 31314021 
                   
                 CNV_3601, CNV_8131, CNV_7561 
               
               
                 CM 
                 chr6 
                 31384822 
                 31392869 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7563, CNV_7564, CNV_32780, 
               
               
                   
                   
                   
                   
                   
                 CNV_1708, CNV_10145, CNV_10146, CNV_6758 
               
               
                 CM 
                 chr6 
                 31390259 
                 31390381 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7564, CNV_32780, CNV_1708, 
               
               
                   
                   
                   
                   
                   
                 CNV_10146 
               
               
                 CM 
                 chr6 
                 31392907 
                 31418253 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7564, CNV_32780, CNV_10146, 
               
               
                   
                   
                   
                   
                   
                 CNV_23799 
               
               
                 CM 
                 chr6 
                 31456523 
                 31457088 
                   
                 CNV_3601, CNV_8131, CNV_7564 
               
               
                 CM 
                 chr6 
                 31457088 
                 31457425 
                   
                 CNV_3601, CNV_8131, CNV_7564 
               
               
                 CM 
                 chr6 
                 31646140 
                 31646463 
                   
                 CNV_2625 
               
               
                 CM 
                 chr6 
                 32229423 
                 32230350 
                 PPT2 
                 CNV_3602 
               
               
                 CM 
                 chr6 
                 32506490 
                 32506778 
                   
                 CNV_3603, CNV_4493 
               
               
                 CM 
                 chr6 
                 32536756 
                 32537232 
                   
                 CNV_3603, CNV_4493, CNV_7567 
               
               
                 CM 
                 chr6 
                 32563017 
                 32683706 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790, CNV_32791, CNV_23801, CNV_1709, 
               
               
                   
                   
                   
                   
                   
                 CNV_32792, CNV_23802, CNV_6759, CNV_6761 
               
               
                 CM 
                 chr6 
                 32564230 
                 32564724 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 CM 
                 chr6 
                 32596430 
                 32597048 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 CM 
                 chr6 
                 32600343 
                 32605108 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 CM 
                 chr6 
                 32672694 
                 32673267 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 CM 
                 chr6 
                 32680250 
                 32680644 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 CM 
                 chr6 
                 32737867 
                 32739304 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 CM 
                 chr6 
                 32742604 
                 32743626 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 CM 
                 chr6 
                 32767739 
                 32772277 
                   
                 CNV_3603, CNV_4767, CNV_7569, CNV_32797 
               
               
                 CM 
                 chr6 
                 32784811 
                 32785414 
                   
                 CNV_3603, CNV_4767, CNV_7569, CNV_31281 
               
               
                 CM 
                 chr6 
                 32786798 
                 32786971 
                   
                 CNV_3603, CNV_4767, CNV_7569, CNV_31281 
               
               
                 CM 
                 chr6 
                 32799007 
                 32799166 
                   
                 CNV_3603, CNV_32799 
               
               
                 CM 
                 chr6 
                 35586239 
                 35586376 
                 TULP1 
                 CNV_3607 
               
               
                 CM 
                 chr6 
                 35702110 
                 35704258 
                 FKBP5 
                 CNV_3607 
               
               
                 CM 
                 chr6 
                 35761904 
                 35762281 
                 FKBP5 
                 CNV_3607, CNV_0286 
               
               
                 CM 
                 chr6 
                 35785199 
                 35785703 
                 FKBP5 
                 CNV_3607, CNV_0286 
               
               
                 CM 
                 chr6 
                 35870799 
                 35870982 
                 CLPS 
                 CNV_3607, CNV_0286, CNV_31285, CNV_7575 
               
               
                 CC 
                 chr6 
                 31191344 
                 31191466 
                 PSORS1C1 
                 CNV_3601, CNV_8131 
               
               
                 CC 
                 chr6 
                 32605201 
                 32627687 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791, CNV_23801 
               
               
                 CC 
                 chr6 
                 32680250 
                 32680644 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31230, CNV_4767 
               
               
                 CC 
                 chr6 
                 32715940 
                 32716099 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 CC 
                 chr6 
                 32723584 
                 32723758 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 CC 
                 chr6 
                 32739728 
                 32740502 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 CC 
                 chr6 
                 32763291 
                 32763593 
                   
                 CNV_3603, CNV_4767, CNV_7568 
               
               
                 CC 
                 chr6 
                 32796711 
                 32797255 
                   
                 CNV_3603, CNV_32799 
               
               
                 CC 
                 chr6 
                 32799007 
                 32799166 
                   
                 CNV_3603, CNV_32799 
               
               
                 CC 
                 chr6 
                 32800626 
                 32800785 
                   
                 CNV_3603, CNV_32799, CNV_31282 
               
               
                 CC 
                 chr6 
                 32800937 
                 32801062 
                   
                 CNV_3603, CNV_32799, CNV_31282 
               
               
                 CC 
                 chr6 
                 32801490 
                 32801789 
                   
                 CNV_3603, CNV_32799, CNV_31282 
               
               
                 CC 
                 chr6 
                 32977765 
                 32979689 
                   
                 CNV_0076, CNV_3604 
               
               
                 CC 
                 chr6 
                 35761943 
                 35762129 
                 FKBP5 
                 CNV_3607, CNV_0286 
               
               
                 DD 
                 chr6 
                 29962127 
                 30021448 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_6756, CNV_6763, 
               
               
                   
                   
                   
                   
                   
                 CNV_6760, CNV_6757, CNV_6765, CNV_9031, CNV_7956, 
               
               
                   
                   
                   
                   
                   
                 CNV_1124, CNV_1126, CNV_23797, CNV_6486, CNV_32777 
               
               
                 DD 
                 chr6 
                 30053593 
                 30053867 
                 HLA-29.1 
                 CNV_3599, CNV_2622, CNV_31269, CNV_4669 
               
               
                 DD 
                 chr6 
                 30063205 
                 30063591 
                 HLA-29.1 
                 CNV_3599, CNV_2622, CNV_31269, CNV_4669 
               
               
                 DD 
                 chr6 
                 30761724 
                 30763025 
                 KIAA1949 
                 CNV_3600, CNV_31270 
               
               
                 DD 
                 chr6 
                 30844693 
                 30845056 
                   
                 CNV_3600 
               
               
                 DD 
                 chr6 
                 31157798 
                 31159289 
                   
                 CNV_3601, CNV_31271 
               
               
                 DD 
                 chr6 
                 31345211 
                 31345844 
                   
                 CNV_3601, CNV_8131, CNV_7561, CNV_31272, CNV_5387, 
               
               
                   
                   
                   
                   
                   
                 CNV_8508, CNV_32779 
               
               
                 DD 
                 chr6 
                 31360138 
                 31361802 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_7562, CNV_2624, CNV_31274 
               
               
                 DD 
                 chr6 
                 31387332 
                 31392906 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7563, CNV_7564, CNV_32780, 
               
               
                   
                   
                   
                   
                   
                 CNV_1708, CNV_10145, CNV_10146, CNV_6758 
               
               
                 DD 
                 chr6 
                 31393365 
                 31418253 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7564, CNV_32780, CNV_10146, 
               
               
                   
                   
                   
                   
                   
                 CNV_23799 
               
               
                 DD 
                 chr6 
                 31457088 
                 31457425 
                   
                 CNV_3601, CNV_8131, CNV_7564 
               
               
                 DD 
                 chr6 
                 32229423 
                 32230350 
                 PPT2 
                 CNV_3602 
               
               
                 DD 
                 chr6 
                 32507789 
                 32508030 
                   
                 CNV_3603, CNV_4493 
               
               
                 DD 
                 chr6 
                 32563017 
                 32733981 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790, CNV_32791, CNV_23801, CNV_1709, 
               
               
                   
                   
                   
                   
                   
                 CNV_32792, CNV_23802, CNV_6759, CNV_6761, CNV_32793, 
               
               
                   
                   
                   
                   
                   
                 CNV_32794, CNV_7568, CNV_23283 
               
               
                 DD 
                 chr6 
                 32564372 
                 32564724 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 DD 
                 chr6 
                 32587915 
                 32592942 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 DD 
                 chr6 
                 32591668 
                 32592671 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                   
                   
                   
                   
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                 DD 
                 chr6 
                 32596475 
                 32597048 
                 HLA-DRB5 
                 CNV_23237, CNV_32791 
               
               
                   
                   
                   
                   
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                 DD 
                 chr6 
                 32600343 
                 32605108 
                 HLA-DRB5 
                 CNV_23237, CNV_32791 
               
               
                 DD 
                 chr6 
                 32658647 
                 32659246 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 DD 
                 chr6 
                 32689971 
                 32716235 
                 HLA-DQA1 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_32793, CNV_32794, CNV_7568 
               
               
                 DD 
                 chr6 
                 32699139 
                 32699290 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_32793 
               
               
                 DD 
                 chr6 
                 32712472 
                 32712943 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 DD 
                 chr6 
                 32718420 
                 32731038 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 DD 
                 chr6 
                 32718654 
                 32718952 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 DD 
                 chr6 
                 32719432 
                 32720046 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 DD 
                 chr6 
                 32720611 
                 32721540 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 DD 
                 chr6 
                 32723425 
                 32728264 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 DD 
                 chr6 
                 32739094 
                 32739774 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 DD 
                 chr6 
                 32761602 
                 32762261 
                   
                 CNV_3603, CNV_31280, CNV_4767, CNV_7568 
               
               
                 DD 
                 chr6 
                 32763120 
                 32763367 
                   
                 CNV_3603, CNV_4767, CNV_7568 
               
               
                 DD 
                 chr6 
                 32786798 
                 32790418 
                   
                 CNV_3603, CNV_4767, CNV_7569, CNV_31281 
               
               
                 DD 
                 chr6 
                 32798813 
                 32800626 
                   
                 CNV_3603, CNV_32799, CNV_31282 
               
               
                 DD 
                 chr6 
                 32810657 
                 32810878 
                   
                 CNV_3603 
               
               
                 DD 
                 chr6 
                 32817895 
                 32818011 
                 HLA-DQA2 
                 CNV_7570 
               
               
                 DD 
                 chr6 
                 33069396 
                 33075621 
                   
                 CNV_0076, CNV_3604 
               
               
                 DD 
                 chr6 
                 34773702 
                 34779441 
                   
                 CNV_3605 
               
               
                 DD 
                 chr6 
                 35761943 
                 35762075 
                 FKBP5 
                 CNV_3607, CNV_0286 
               
               
                 DD 
                 chr6 
                 35862999 
                 35868527 
                 C6orf127 
                 CNV_3607, CNV_0286, CNV_31285, CNV_7575 
               
               
                 FR 
                 chr6 
                 29962649 
                 30017382 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_6756, CNV_6763, 
               
               
                   
                   
                   
                   
                   
                 CNV_6760, CNV_6757, CNV_6765, CNV_9031, CNV_7956, 
               
               
                   
                   
                   
                   
                   
                 CNV_1124, CNV_1126, CNV_23797, CNV_6486 
               
               
                 FR 
                 chr6 
                 31387332 
                 31418253 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7563, CNV_7564, CNV_32780, 
               
               
                   
                   
                   
                   
                   
                 CNV_1708, CNV_10145, CNV_10146, CNV_6758, CNV_23799 
               
               
                 FR 
                 chr6 
                 31457088 
                 31457425 
                   
                 CNV_3601, CNV_8131, CNV_7564 
               
               
                 FR 
                 chr6 
                 32563235 
                 32740502 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790, CNV_32791, CNV_23801, CNV_1709, 
               
               
                   
                   
                   
                   
                   
                 CNV_32792, CNV_23802, CNV_6759, CNV_6761, CNV_32793, 
               
               
                   
                   
                   
                   
                   
                 CNV_32794, CNV_7568, CNV_23283 
               
               
                 FR 
                 chr6 
                 32564230 
                 32565022 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 FR 
                 chr6 
                 32590368 
                 32592554 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 FR 
                 chr6 
                 32596475 
                 32597048 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 FR 
                 chr6 
                 32599429 
                 32600342 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 FR 
                 chr6 
                 32600917 
                 32605108 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 FR 
                 chr6 
                 32630548 
                 32631353 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 FR 
                 chr6 
                 32644521 
                 32650783 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_32792 
               
               
                 FR 
                 chr6 
                 32680250 
                 32680644 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 FR 
                 chr6 
                 32712300 
                 32712943 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 FR 
                 chr6 
                 32719305 
                 32719432 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 FR 
                 chr6 
                 32720046 
                 32720535 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 FR 
                 chr6 
                 32720570 
                 32721540 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                 HLA-DQA1 
                 CNV_23283 
               
               
                 FR 
                 chr6 
                 32728265 
                 32728737 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 FR 
                 chr6 
                 32734749 
                 32734935 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 FR 
                 chr6 
                 32743627 
                 32744515 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 FR 
                 chr6 
                 32760501 
                 32761273 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 FR 
                 chr6 
                 32786937 
                 32787270 
                   
                 CNV_3603, CNV_4767, CNV_7569, CNV_31281 
               
               
                 FR 
                 chr6 
                 35761943 
                 35762281 
                 FKBP5 
                 CNV_3607, CNV_0286 
               
               
                 GE 
                 chr6 
                 29940096 
                 30017382 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_23095, CNV_22632, CNV_23796, CNV_32776, 
               
               
                   
                   
                   
                   
                   
                 CNV_4669, CNV_6756, CNV_6763, CNV_6760, CNV_6757, 
               
               
                   
                   
                   
                   
                   
                 CNV_6765, CNV_9031, CNV_7956, CNV_1124, CNV_1126, 
               
               
                   
                   
                   
                   
                   
                 CNV_23797, CNV_6486 
               
               
                 GE 
                 chr6 
                 29981807 
                 29982868 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_9031, CNV_7956 
               
               
                 GE 
                 chr6 
                 31367445 
                 31367910 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274 
               
               
                 GE 
                 chr6 
                 31384717 
                 31418029 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7563, CNV_7564, CNV_32780, 
               
               
                   
                   
                   
                   
                   
                 CNV_1708, CNV_10145, CNV_10146, CNV_6758, CNV_23799 
               
               
                 GE 
                 chr6 
                 31390259 
                 31390381 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7564, CNV_32780, CNV_1708, 
               
               
                   
                   
                   
                   
                   
                 CNV_10146 
               
               
                 GE 
                 chr6 
                 31457088 
                 31457425 
                   
                 CNV_3601, CNV_8131, CNV_7564 
               
               
                 GE 
                 chr6 
                 32477682 
                 32477991 
                 BTNL2 
                 CNV_7566 
               
               
                 GE 
                 chr6 
                 32506490 
                 32506778 
                   
                 CNV_3603, CNV_4493 
               
               
                 GE 
                 chr6 
                 32507919 
                 32508030 
                   
                 CNV_3603, CNV_4493 
               
               
                 GE 
                 chr6 
                 32563017 
                 32744157 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790, CNV_32791, CNV_23801, CNV_1709, 
               
               
                   
                   
                   
                   
                   
                 CNV_32792, CNV_23802, CNV_6759, CNV_6761, CNV_32793, 
               
               
                   
                   
                   
                   
                   
                 CNV_32794, CNV_7568, CNV_23283 
               
               
                 GE 
                 chr6 
                 32587915 
                 32592942 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 GE 
                 chr6 
                 32600917 
                 32605108 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 GE 
                 chr6 
                 32658039 
                 32659542 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 GE 
                 chr6 
                 32699503 
                 32701186 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_32793 
               
               
                 GE 
                 chr6 
                 32718420 
                 32723425 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 GE 
                 chr6 
                 32719432 
                 32720268 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 GE 
                 chr6 
                 32720611 
                 32721540 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 GE 
                 chr6 
                 32738284 
                 32738429 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 GE 
                 chr6 
                 32739094 
                 32739452 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 GE 
                 chr6 
                 35761943 
                 35762281 
                 FKBP5 
                 CNV_3607, CNV_0286 
               
               
                 HH 
                 chr6 
                 31387332 
                 31418253 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7563, CNV_7564, CNV_32780, 
               
               
                   
                   
                   
                   
                   
                 CNV_1708, CNV_10145, CNV_10146, CNV_6758, CNV_23799 
               
               
                 LS 
                 chr6 
                 31387332 
                 31392974 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7563, CNV_7564, CNV_32780, 
               
               
                   
                   
                   
                   
                   
                 CNV_1708, CNV_10145, CNV_10146, CNV_6758 
               
               
                 LS 
                 chr6 
                 32563017 
                 32563369 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237 
               
               
                 MU 
                 chr6 
                 29995047 
                 29998209 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_9031, CNV_7956, 
               
               
                   
                   
                   
                   
                   
                 CNV_1124, CNV_1126 
               
               
                 MU 
                 chr6 
                 32600917 
                 32604580 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 MU 
                 chr6 
                 32605201 
                 32628505 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791, CNV_23801 
               
               
                 MU 
                 chr6 
                 32664486 
                 32667076 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 MU 
                 chr6 
                 32700842 
                 32700989 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_32793 
               
               
                 MU 
                 chr6 
                 32711745 
                 32712127 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_32794, 
               
               
                   
                   
                   
                   
                   
                 CNV_7568 
               
               
                 MU 
                 chr6 
                 32760784 
                 32761389 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 MU 
                 chr6 
                 32763120 
                 32763593 
                   
                 CNV_3603, CNV_4767, CNV_7568 
               
               
                 MU 
                 chr6 
                 32798352 
                 32802221 
                   
                 CNV_3603, CNV_32799, CNV_31282 
               
               
                 MU 
                 chr6 
                 35761943 
                 35762281 
                 FKBP5 
                 CNV_3607, CNV_0286 
               
               
                 MC 
                 chr6 
                 29950578 
                 30017155 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_23095, CNV_22632, CNV_23796, CNV_32776, 
               
               
                   
                   
                   
                   
                   
                 CNV_4669, CNV_6756, CNV_6763, CNV_6760, CNV_6757, 
               
               
                   
                   
                   
                   
                   
                 CNV_6765, CNV_9031, CNV_7956, CNV_1124, CNV_1126, 
               
               
                   
                   
                   
                   
                   
                 CNV_23797, CNV_6486 
               
               
                 MC 
                 chr6 
                 29982195 
                 29982333 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_9031, CNV_7956 
               
               
                 MC 
                 chr6 
                 29985562 
                 30001164 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_9031, CNV_7956, 
               
               
                   
                   
                   
                   
                   
                 CNV_1124, CNV_1126 
               
               
                 MC 
                 chr6 
                 29985909 
                 29986570 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_9031, CNV_7956 
               
               
                 MC 
                 chr6 
                 29988968 
                 29994086 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_9031, CNV_7956, 
               
               
                   
                   
                   
                   
                   
                 CNV_1124, CNV_1126 
               
               
                 MC 
                 chr6 
                 30006771 
                 30010434 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_9031, CNV_7956, 
               
               
                   
                   
                   
                   
                   
                 CNV_23797, CNV_6486 
               
               
                 MC 
                 chr6 
                 31387332 
                 31418029 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7563, CNV_7564, CNV_32780, 
               
               
                   
                   
                   
                   
                   
                 CNV_1708, CNV_10145, CNV_10146, CNV_6758, CNV_23799 
               
               
                 MC 
                 chr6 
                 32563017 
                 32567703 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 MC 
                 chr6 
                 32564548 
                 32565176 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 MC 
                 chr6 
                 32587803 
                 32588104 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 MC 
                 chr6 
                 32605201 
                 32605946 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 MC 
                 chr6 
                 32667923 
                 32668136 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 MC 
                 chr6 
                 32668136 
                 32668384 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 MC 
                 chr6 
                 32703944 
                 32707105 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_32793 
               
               
                 MC 
                 chr6 
                 32711745 
                 32712681 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_32794, 
               
               
                   
                   
                   
                   
                   
                 CNV_7568 
               
               
                 MC 
                 chr6 
                 32720611 
                 32721540 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 MC 
                 chr6 
                 32728386 
                 32728737 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 MC 
                 chr6 
                 32739606 
                 32740000 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 PF 
                 chr6 
                 30006771 
                 30010434 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_9031, CNV_7956, 
               
               
                   
                   
                   
                   
                   
                 CNV_23797, CNV_6486 
               
               
                 PF 
                 chr6 
                 31384822 
                 31386601 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_2624, CNV_31274, CNV_7563, CNV_7564, CNV_32780, 
               
               
                   
                   
                   
                   
                   
                 CNV_1708, CNV_10145 
               
               
                 PF 
                 chr6 
                 31457088 
                 31457425 
                   
                 CNV_3601, CNV_8131, CNV_7564 
               
               
                 PF 
                 chr6 
                 32506490 
                 32506778 
                   
                 CNV_3603, CNV_4493 
               
               
                 PF 
                 chr6 
                 32600343 
                 32605108 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 PF 
                 chr6 
                 32680250 
                 32680644 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 PF 
                 chr6 
                 32717273 
                 32717345 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 PF 
                 chr6 
                 32799007 
                 32799166 
                   
                 CNV_3603, CNV_32799 
               
               
                 PF 
                 chr6 
                 32800937 
                 32801062 
                   
                 CNV_3603, CNV_32799, CNV_31282 
               
               
                 PF 
                 chr6 
                 32801490 
                 32801789 
                   
                 CNV_3603, CNV_32799, CNV_31282 
               
               
                 PF 
                 chr6 
                 35586239 
                 35586376 
                 TULP1 
                 CNV_3607 
               
               
                 PF 
                 chr6 
                 35761943 
                 35762281 
                 FKBP5 
                 CNV_3607, CNV_0286 
               
               
                 PB 
                 chr6 
                 31456117 
                 31456849 
                   
                 CNV_3601, CNV_8131, CNV_7564 
               
               
                 PB 
                 chr6 
                 32563017 
                 32605362 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790, CNV_32791 
               
               
                 PB 
                 chr6 
                 32593105 
                 32598770 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 PB 
                 chr6 
                 32596367 
                 32597048 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 PB 
                 chr6 
                 32667523 
                 32668384 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 PB 
                 chr6 
                 32694846 
                 32696612 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767 
               
               
                 PB 
                 chr6 
                 32737298 
                 32739452 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 PB 
                 chr6 
                 32741720 
                 32741876 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 RM 
                 chr6 
                 29962127 
                 30017382 
                   
                 CNV_8209, CNV_3599, CNV_7558, CNV_2622, CNV_9032, 
               
               
                   
                   
                   
                   
                   
                 CNV_31269, CNV_32776, CNV_4669, CNV_6756, CNV_6763, 
               
               
                   
                   
                   
                   
                   
                 CNV_6760, CNV_6757, CNV_6765, CNV_9031, CNV_7956, 
               
               
                   
                   
                   
                   
                   
                 CNV_1124, CNV_1126, CNV_23797, CNV_6486 
               
               
                 RM 
                 chr6 
                 30761842 
                 30763025 
                 KIAA1949 
                 CNV_3600, CNV_31270 
               
               
                 RM 
                 chr6 
                 31361260 
                 31361802 
                   
                 CNV_3601, CNV_8131, CNV_5387, CNV_8508, CNV_5222, 
               
               
                   
                   
                   
                   
                   
                 CNV_7562, CNV_2624, CNV_31274 
               
               
                 RM 
                 chr6 
                 32226417 
                 32226779 
                 PRRT1 
                 CNV_3602 
               
               
                 RM 
                 chr6 
                 32229121 
                 32230350 
                 PPT2 
                 CNV_3602 
               
               
                 RM 
                 chr6 
                 32260717 
                 32261345 
                 PBX2 
                 CNV_3602 
               
               
                 RM 
                 chr6 
                 32507870 
                 32508030 
                   
                 CNV_3603, CNV_4493 
               
               
                 RM 
                 chr6 
                 32536756 
                 32537232 
                   
                 CNV_3603, CNV_4493, CNV_7567 
               
               
                 RM 
                 chr6 
                 32563017 
                 32763367 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790, CNV_32791, CNV_23801, CNV_1709, 
               
               
                   
                   
                   
                   
                   
                 CNV_32792, CNV_23802, CNV_6759, CNV_6761, CNV_32793, 
               
               
                   
                   
                   
                   
                   
                 CNV_32794, CNV_7568, CNV_23283, CNV_32795, CNV_6764 
               
               
                 RM 
                 chr6 
                 32563017 
                 32592942 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 RM 
                 chr6 
                 32564010 
                 32564512 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 RM 
                 chr6 
                 32587915 
                 32588033 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 RM 
                 chr6 
                 32596475 
                 32597048 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 RM 
                 chr6 
                 32600343 
                 32605946 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 RM 
                 chr6 
                 32613338 
                 32627232 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31230, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 RM 
                 chr6 
                 32667923 
                 32668136 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 RM 
                 chr6 
                 32679817 
                 32680250 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 RM 
                 chr6 
                 32682524 
                 32683273 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_6759, CNV_6761 
               
               
                 RM 
                 chr6 
                 32693553 
                 32703913 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_32793 
               
               
                 RM 
                 chr6 
                 32702660 
                 32702818 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_32793 
               
               
                 RM 
                 chr6 
                 32703944 
                 32707105 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_32793 
               
               
                 RM 
                 chr6 
                 32719403 
                 32719774 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 RM 
                 chr6 
                 32720611 
                 32721540 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 RM 
                 chr6 
                 32728265 
                 32731038 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 RM 
                 chr6 
                 32733982 
                 32759283 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_32795, CNV_6764 
               
               
                 RM 
                 chr6 
                 32735643 
                 32735978 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 RM 
                 chr6 
                 32739094 
                 32739452 
                 HLA-DQB1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568 
               
               
                 RM 
                 chr6 
                 32786937 
                 32790418 
                   
                 CNV_3603, CNV_4767, CNV_7569, CNV_31281 
               
               
                 RM 
                 chr6 
                 32798570 
                 32801825 
                   
                 CNV_3603, CNV_32799, CNV_31282 
               
               
                 RM 
                 chr6 
                 35761943 
                 35762281 
                 FKBP5 
                 CNV_3607, CNV_0286 
               
               
                 RM 
                 chr6 
                 35862999 
                 35868527 
                 C6orf127 
                 CNV_3607, CNV_0286, CNV_31285, CNV_7575 
               
               
                 VF 
                 chr6 
                 32563017 
                 32588104 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 VF 
                 chr6 
                 32564548 
                 32565176 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32790 
               
               
                 VF 
                 chr6 
                 32605201 
                 32605362 
                 HLA-DRB5 
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767, 
               
               
                   
                   
                   
                   
                   
                 CNV_23237, CNV_32791 
               
               
                 VF 
                 chr6 
                 32667923 
                 32668136 
                   
                 CNV_3603, CNV_4493, CNV_7567, CNV_31280, CNV_4767 
               
               
                 VF 
                 chr6 
                 32703944 
                 32707105 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_32793 
               
               
                 VF 
                 chr6 
                 32711745 
                 32712943 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_32794, 
               
               
                   
                   
                   
                   
                   
                 CNV_7568 
               
               
                 VF 
                 chr6 
                 32720611 
                 32721540 
                 HLA-DQA1 
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                 VF 
                 chr6 
                 32728265 
                 32728737 
                   
                 CNV_3603, CNV_7567, CNV_31280, CNV_4767, CNV_7568, 
               
               
                   
                   
                   
                   
                   
                 CNV_23283 
               
               
                   
               
             
          
         
       
     
       Genotype-Phenotype Correlation: Statistical Analysis 
       [0053]    The present inventors correlated the number of the CNVs, with the clinical parameters of the patients ( FIG. 2 , top panel, Table 1). For the oversized number of CNVs significantly affecting X and Y Intercept, Slope and Run Test the present inventors excluded from linear regression analysis the patient coded as MC (52 CNVs vs median (IR) 23 (13) of our patients population, Table 1). 
         [0054]    Linear regression analysis demonstrated that the overall number of CNVs is correlated with the number of extracranial VM demonstrated by venography in the extracranial segments of the cerebrospinal veins, with a trend toward significance (r=0.52, r=0.27, p=0.0545) ( FIG. 3  and  FIG. 6  panel A). By splitting the analysis correlating either the extragenic CNVs ( FIG. 5  and  FIG. 6  panel C) or the intragenic CNVs ( FIG. 4  and  FIG. 6  panel B) with the extracranial VM the present inventors found a robust and significant correlation with the former (r=0.53, r=0.28, p&lt;0.05). 
       Pathways and Genes Network Functional Bioinformatics Analysis 
       [0055]    211 genes are contained within the region the present inventors covered by the present CGH array. 
         [0056]    Since the phenotype in focus is characterised by multiple sclerosis and venous malformation, the present inventors applied a bioinformatics tool to select genes known to be involved in angiogenesis and venous development as well as linked to multiple sclerosis, immunity and neurodegeneration. Interestingly some genes are linked to these processes. HSPA1L and HSPA1A are linked to MS and diabetes and other immunity disorders, and regulatory functions as chromatin remodelling, neuroprotection, protein folding, and regenerative-degenerative tools as neurodegeneration, neuron toxicity, cell survival, neuroprotection, synaptic transmission or even aging factors (senescence and telomere maintenance). Also the gene GRM4 seems to interact with many proteins linked to MS ( FIG. 7A ) 
         [0057]    Focusing on specific functional pathways, as angiogenesis, obviously considering the plus phenotype of the present patients (venous malformation) the present inventors obtained a more selective puzzle of interactions ( FIG. 7B ). GRB2 and HSPA1A and B genes directly act on angiogenesis, TAF11 is known to be involved in artery passage and E2F1 transcription factor is known to be an angiogenesis positive inducer in hepatitis and cancer. Interesting HLA-DQA2 may also be implicated in angiogenesis by interacting with CD4. 
         [0058]    The correlation found between genotype (CNVs) and phenotype (VM/CCSVI) are further supported by the above reported regulatory functions in the angiogenic process. Both extragenic and intragenic CNVs with known interaction in human angiogenesis support the hypothesis that the identified genetic variants may determine disregulation in the embryological process of venous angiogenesis, possibly leading to the development of VM. VM in turn create overtime a status known as CCSVI which is strongly associated to MS. 
         [0059]    Naturally, while the principle of the invention remains the same, the details of construction and the embodiments may widely vary with respect to what has been described and illustrated purely by way of example, without departing from the scope of the present invention. 
       BIBLIOGRAPHY 
       [0000]    
       
         1. Comabella M, et al.  PLoS One  2008; 3:e3490. 
         2. Ramagopalan S V, et al.  BMC Med Genet  2009; 10:10. 
         3. Chao M J, et al.  Proc Natl Acad Sci USA  2008; 105:13069-74. 
         4. Aulchenko Y S, et al.  Nat Genet.  2008; 40:1402-3. 
         5. Cronin S, et al.  Hum Mol Genet.  2008; 17:3392-8. 
         6. Blauw H M, et al.  Lancet Neurol.  2008; 7:319-26. 
         7. International Multiple Sclerosis Genetics Consortium, Hailer DA, et al.  N Engl J Med.  2007; 357:851-62. 
         8. International Multiple Sclerosis Genetics Consortium (IMSGC).  Lancet Neurol.  2008; 7:567-9. 
         9. Zamboni P, et al.  J Neurol Neurosurg Psychiatry  2009; 80:392-9. 
         10. Zamboni P, et al.  J Neurol Sci.  2009; 282:21-7. 
         11. Polman C H, et al.  Ann Neurol.  2005; 58:840-6. 
         12. Kurtzke J R.  Neurology.  1983; 33:1444-52. 
         13. Roxburgh R H, et al.  Neurology.  2005; 64:1144-51. 
         14. Pachner A R, Steiner I.  J Neurol Sci.  2009; 278:66-70. 
         15. Menegatti E, Zamboni P.  Curr. Neurovasc. Res.  2008; 5:260-5. 
         16. Agilent Technologies eArray [https://earray.chem.agilent.com/earray] 
         17. Bovolenta M, et al.  BMC genomics.  2008, 9:572. 
         18. Database of Genomic Variants [http://projects.tcag.ca/variation] 
         19. Singh A V, Zamboni P.  J Cer Blood Flow Met  2009 
         20. Lincoln M R, at al.  Proc Natl Acad Sci USA.  2009; 106(18):7542-7. 
         21. Podojil J R, Miller S D.  Immunol Rev.  2009; 229(1):337-55. 
         22. Wieder T, et al.  Cell Cycle.  2008; 7(19):2974-7.