bluuebunny/crossref_metadata_2025 huggingface dataset:
New DNA markers with increased informativeness show diminished support for a chromosome 5q11–13 schizophrenia susceptibility locus and exclude linkage in two new cohorts of British and Icelandic families
Authors: KALSI G. , MANKOO B. , CURTIS D. , SHERRINGTON R. , MELMER G. , BRYNJOLFSSON J. , SIGMUNDSSON T. , READ T. , MURPHY P. , PETURSSON H. , GURLING H.
Published: March 2003

Genetic linkage of schizophrenia to markers at 5q11.2–13.3 had been reported previously in five Icelandic and two British families, but attempts at replication in independent samples have been unsuccessful. We report here an update on the diagnoses and results of linkage analyses using newer highly polymorphic microsatellite markers at or near the loci D5S76 and D5S39 in the original sample of pedigrees and in two new family samples from Iceland and from Britain. The new results show a reduction in evidence for linkage in the original sample and evidence against linkage in the two new family samples. Although it is possible that a rare locus is present, perhaps in the region 5p14.1–13.1 rather than 5q11.2–13.3, it appears most likely that the original positive lod scores represent an exaggeration of the ‘true’ lod scores due to random effects and that the small lod scores we now obtain could have arisen by chance.
A statistically robust variance‐components approach for quantitative trait linkage analysis
Authors: WANG J. , GUERRA R. , COHEN J.
Published: March 2003

Previously we showed (Wang, Guerra & Cohen 1998) that a statistically robust version of the Haseman & Elston (1972) sib‐pair method greatly increased power to detect linkage in the presence of outliers. In this paper we report on M‐estimation to accommodate outliers in the variance‐components approach to linkage analysis developed by Amos (1994). Simulations show that in the presence of outliers the robust variance‐components approach provides substantially greater power, more precise estimation of heritabilities, and better false–positive rates than the original Gaussian based approach. In the absence of outliers the performance of the robust variance‐components approach is similar to that of the Gaussian based approach. For illustration we apply the method to two well characterized lipoprotein systems.
Meta‐analysis of genome searches
Authors: WISE L. H. , LANCHBURY J. S. , LEWIS C. M.
Published: March 2003

We have developed a method for meta‐analysis of genome scans which allows systematic integration of data from published results. The Genome Search Meta‐analysis method (GSMA) uses a non‐parametric ranking method to identify genetic regions that show consistently increased sharing statistics or lod scores. The GSMA ranks genetic regions according to the lod score or p‐value achieved in each scan. The summed rank across studies is compared to its probability distribution assuming ranks are randomly assigned. The GSMA can confirm evidence for regions highlighted in the original genome scans, and identify novel regions, which did not reach significance in any scan. In this paper, the GSMA was applied to four genome screens in multiple sclerosis and across 11 screens from autoimmune disorders. The GSMA is appropriate for studies with different family ascertainment, markers, and statistical analysis methods. The method increases the power to detect individual linkages in a clinically homogeneous dataset and has the potential to detect susceptibility loci in clinically distinct diseases which show involvement of common pathogenetic pathways.
Search for the PARK3 founder haplotype in a large cohort of patients with Parkinson's disease from Northern Germany
Authors: KLEIN C. , VIEREGGE P. , HAGENAH J. , SIEBERER M. , DOYLE E. , JACOBS H. , GASSER T. , BREAKEFIELD X. O. , RISCH N. J. , OZELIUS L. J.
Published: March 2003

A founder haplotype on chromosome 2p for autosomal dominant Parkinson's disease (PD) has been postulated for two families of Northern European descent, and a new mutation in the α‐synuclein gene (Ala30Pro) has been found in a German PD family. We evaluated 85 German PD patients and 85 ethnically matched controls for shared markers on chromosome 2p and for the new α‐synuclein mutation. We found no evidence for linkage disequilibrium, suggesting that the putative founder mutation on chromosome 2p is not a common cause of PD in the local population. Furthermore, no patient carried the Ala30Pro change, supporting earlier findings that mutations in the α‐synuclein gene are extremely rare.
Evidence of a major gene effect for angiotensinogen among Nigerians
Authors: GUO X. , ROTIMI C. , COOPER R. , LUKE A. , ELSTON R. C. , OGUNBIYI O. , WARD R.
Published: March 2003

To dissect the genetic pathway of hypertension, we measured angiotensinogen in 685 members of 186 families recruited from a rural community in southwest Nigeria. Commingling and segregation analyses were carried out. A mixture of two and/or three distributions fits the data significantly better than a single distribution in commingling analysis, suggesting a major gene effect. Segregation analysis confirmed that a recessive major gene model for low values of angiotensinogen provides the best fit to the data and about 13% of the variance was due to the recessive gene segregation.
Influence of apolipoprotein E genotype variation on the means, variances, and correlations of plasma lipids and apolipoproteins in children
Authors: NELSON M. R. , KARDIA S. L. R. , FERRELL R. E. , SING C. F.
Published: March 2003

The impact of the three most common apolipoprotein E (APOE) genotypes (ε32, ε33, and ε43) on means, variances, and correlations of nine plasma lipid and apolipoprotein traits (total cholesterol, lnTriglycerides, HDL cholesterol, and apolipoproteins AI, AII, B, CII, CIII, and lnE) was studied in 212 unrelated female and 219 unrelated male children aged 5–21.5 years from 278 pedigrees ascertained without regard to health status from Rochester, Minnesota. There was significant heterogeneity (p≤ 0.05) among genotypes for the mean plasma levels of lnApo E, Apo CII, Apo CIII, and lnTriglycerides (lnTrig) in females, and for the means of lnApo E, Apo B, and total cholesterol (Total‐C) in males. Significant heterogeneity of intragenotypic variance was observed in males for Apo CII, lnTrig, and HDL‐C; no significant heterogeneity was observed in females. Pairwise correlations between traits differed significantly among APOE genotypes in both females (6 of 36 pairs) and males (5 of 36 pairs). These results differ from those obtained from studies of the parental generation from the same sample of pedigrees. Our study further demonstrates that, with the exception of mean lnApo E levels, the univariate and bivariate distributions of traits that are measures of lipoprotein metabolism are influenced by variation in the APOE gene in a gender‐ and generation‐dependent manner.
Molecular scanning for mutations in the melanocortin‐4 receptor gene in obese/diabetic Japanese
Authors: OHSHIRO Y. , SANKE T. , UEDA K. , SHIMAJIRI Y. , NAKAGAWA T. , TSUNODA K. , NISHI M. , SASAKI H. , TAKASU N. , NANJO K.
Published: March 2003

Decreased function of the melanocortin‐4 receptor (MC4R) was reported to cause late‐onset obesity and insulin resistance in rodents. Thus mutations in the MC4R gene drew strong attention as a possible cause of obesity and diabetes. We screened for mutations in the MC4R gene in extremely obese [body mass index (BMI) ≥ 35 kg/m2] Japanese with diabetes by direct sequencing. A heterozygous mutation (V103I) was detected in one case (2.0 %), however the frequency was not significantly different from that in non‐obese (BMI ≤ 24 kg/m2) and non‐diabetic subjects (2.7 %). No other mutations were detected. These results suggest that mutations including V103I in the MC4R gene are not a major cause of obesity or diabetes in Japanese.
Molecular instability of the mitochondrial haplogroup T sequences at nucleotide positions 16292 and 16296
Authors: MALYARCHUK B. A. , DERENKO M. V.
Published: March 2003

The mitochondrial haplogroup T, characterized by the nucleotide motif 16126C–16294T in the hypervariable segment I (HVS I), is one of the most frequent among Europeans. It has been shown that this haplogroup includes the only well‐resolved subgroup, T1, but that other HVS I sequences cannot be differentiated into subgroups due to possible homoplasies at nucleotide positions 16292, 16296 and 16304, leading to the reticulations in the topology of phylogenetic networks. To study the problem of molecular instability at these positions, we have performed an analysis of 159 previously published West Eurasian HVS I sequences belonging to haplogroup T, together with 12 new HVS I sequences of Eastern Slavs. These 12 sequences represent 16.9% of a total of 71 samples analysed and identified as haplogroup T mtDNAs by RFLP analysis in this study. A search for rare point mutations associated with different combinations of nucleotides 16292T, 16296T and 16304C within the haplogroup T sequences, and specific to certain populations or a group of closely related‐by‐descent populations, was performed. This analysis revealed 11 marker mutations, each of which was characteristic for a certain group of linguistically or geographically close individuals – the Adygei, Germans, Kazakhs and linguistic isolates of the Eastern Italian Alps. The occurrence of these rare population‐specific polymorphisms in association with various combinations of mutations at positions 16292 and 16296 on the haplogroup T background provides evidence of molecular instability at these nucleotide positions. Molecular instability in the haplogroup T HVS I sequences is also suggested by multiple independent losses of the haplogroup T diagnostic nucleotide variants in different populations. The results of the present study suggest that identical haplogroup T HVS I sequence types might have arisen independently in different human populations.
Linking genotype to aorto‐coronary atherosclerosis: a model using familial hypercholesterolemia and aorto‐coronary calcification
Authors: JENSEN J. M. , KRUSE T. A. , BRORHOLT‐PETERSEN J. U. , CHRISTIANSEN T. M. , JENSEN H. K. , KOLVRAA S. , FAERGEMAN O.
Published: March 2003

Most studies of the pathogenesis of coronary heart disease occur between gene variants and biochemical or physiological variables known to be atherogenic. In many situations, however, the gene products are not necessarily known. We studied 17 families (n= 122) with mutations in the low density lipoprotein (LDL) receptor gene as a model in which to test formally for linkage directly between an atherogenic genotype and ischemic heart disease (IHD) or aorto‐coronary calcified atherosclerosis. In each family one of three different mutations was found: the Trp66–Gly mutation, the Trp23–Stop mutation, or a ten kilobase deletion removing exons 3–6 of the LDL receptor gene. Genomic DNA was used to determine these mutations by either enzymatic cleavage assays or Southern blotting. Aorto‐coronary calcification was significantly associated with age and plasma cholesterol. Sex, hypertension, BMI and smoking were not associated with aorto‐coronary calcification. Nonparametric analysis indicated significant linkage of the LDL receptor gene locus to aortic (p < 0.00005) and to aorto‐coronary calcified atherosclerosis (p < 0.00001). Assuming a dominant mode of inheritance, significant linkage was detected for aortic (LOD = 3.89) and aorto‐coronary calcified atherosclerosis (LOD = 4.10). We suggest that the atherogenicity of variations in other genes could be assessed by a similar approach.
Skewed secondary sex ratio in the offspring of carriers of the 214G > A mutation of the RS1 gene
Authors: HUOPANIEMI L. , FELLMAN J. , RANTALA A. , ERIKSSON A. , FORSIUS H. , DE LA CHAPELLE A. , ALITALO T.
Published: March 2003

Carriers of X‐linked juvenile retinoschisis (RS) were previously suggested to give birth to an excess of boys. We determined the carrier status for the 214G > A mutation of the RS1 gene in 202 females belonging to a large RS founder pedigree. The secondary sex ratio (SSR) in the offspring of 149 carriers was 129.8 (z= 2.25), which differed significantly from that of the Finnish population (SSR 106) but not from that of 53 non‐carrier females belonging to the same pedigree (SSR 116.7; z= 0.51). Since possible causes for the skewed SSR include factors affecting fertilisation, implantation and embryonic death, we searched for expression of RS1 in various placental and uterine cells and found that, in addition to the retina, RS1 is expressed in the uterus. We hypothesize that the RS1 protein has a role in implantation or embryonic survival.
Hardy–Weinberg quality control
Authors: GOMES I. , COLLINS A. , LONJOU C. , THOMAS N. S. , WILKINSON J. , WATSON M. , MORTON N.
Published: March 2003

An efficient test of deviation from Hardy–Weinberg frequencies with one degree of freedom was applied to 44 marker loci in a genome scan, and 7 loci had a significant excess of apparent homozygotes (χ2(1) > 6) suggestive of typing error. In this example evidence for linkage did not increase when outliers were censored. Statistical quality control is an essential part of genotyping, and the effect of mistyping and map error should be considered in evaluating any genome scan.
Four novel mutations in the Tyrosine Hydroxylase gene in patients with infantile parkinsonism
Authors: SWAANS R. J. M. , RONDOT P. , RENIER W. O. , VAN DEN HEUVEL L. P. W. J. , STEENBERGEN‐SPANJERS G. C. H. , WEVERS R. A.
Published: March 2003

Mutation detection in the Tyrosine Hydroxylase gene (TH) was performed in patients from two families. DNA sequencing revealed the presence of four novel missense mutations (exon 9 and 14 in family A, exon 8 and 9 in family B); the mutations were confirmed with restriction enzyme analysis, and did not occur in control alleles. Three mutations are in the catalytic domain of the enzyme and one may disturb tetramerization. At the moment, all patients are in the fourth decade of life. For more than 30 years they have been able to live a normal life with low‐dose l‐DOPA medication.
Deletion pattern in the dystrophin gene in Turks and a comparison with Europeans and Indians
Authors: ÖNENGÜT S. , KAVASLAR G. N. , BATTALOĞLU E. , SERDAROĞLU P. , DEYMEER F. , ÖZDEMİR C. , CALAFELL F. , TOLUN A.
Published: March 2003

Patterns of dystrophin gene deletions in DMD/BMD patients were compared in four populations: Turks (n= 146 deletions), Europeans (n= 838), North Indians (n= 89), and Indians from all over India (n= 103). Statistical tests revealed that there are differences in the proportions of small deletions. In contrast, the distribution of deletion breakpoints and the frequencies of specific deletions commonly observed in the four populations are not significantly different. The variations strongly suggest that sequence differences exist in the introns, and the differences are in agreement with genetic distances among populations. The similarities suggest that some intronic sequences have been conserved and that those will trigger recurrent deletions, since it is unlikely that gene flow would disperse the deleted chromosomes, which vanish from the gene pool in a few generations.
A genome‐based study of consanguinity in three co‐resident endogamous Pakistan communities
Authors: WANG W. , SULLIVAN S. G. , AHMED S. , CHANDLER D. , ZHIVOTOVSKY L. A. , BITTLES A. H.
Published: March 2003

In a study based on 173 individuals drawn from three endogamous, co‐resident communities in the province of Punjab, the Awan, Khattar and Rajpoot, an analysis of 10 autosomal single tandem repeats on chromosomes 13 and 15 revealed distinctive genetic profiles in each community. A total of 99 different alleles were detected, with 28 alleles (28.3%) shared by all three communities. The mean private allele frequency was 7.7%. There was a reduction in heterozygosity and high average inbreeding effects (FIS and/or HS), particularly in the Awan, indicating genetic isolation and a high cumulative level of autozygosity. Genotyping with eight Y‐chromosome STRs resulted in the construction of six haplotypes, one each for the Awan and the Khattar but four for the Rajpoot, suggesting marked variation in the patterns of male founder effects in the history of each community. The lower than expected levels of homozygosity observed at a number of loci may be indicative of cosegregation of the STRs with nearby early development genes subject to selection.
Equivalence by descent: pedigree analysis with inbreeding and gametic phase disequilibrium
Authors: DENNISTON C.
Published: March 2003

In the presence of gametic phase disequilibrium and inbreeding, multiple locus genotype frequencies cannot be written solely in terms of identity by descent (IBD) probabilities. Following Cockerham & Weir (1973) we introduce the concept of ‘equivalence by descent’ (EBD), an extension of the concept of IBD to include non‐allelic genes. Two genes are said to be EBD if they derive ultimately from the same founding gamete of a pedigree. Allelic genes that are EBD are also IBD. For two loci 11 EBD probabilities, the ‘J‐coefficients,’ are required and for three loci 117 J‐coefficients are required to write genotype probabilities. It is shown how the 117 J‐coefficients for three loci can be reduced to a basic set of 37. Computer programs, written in the algebraic programming language, MAPLE™, are described which are capable of calculating the two‐ and three‐locus J‐coefficients for any pedigree, subject only to size limitations. The MAPLE™ packages are available from the author upon request.
Cloning and characterization of the TATA‐less promoter from the human GFI1 Proto‐oncogene
Authors: LIU S. , COWELL J. K.
Published: March 2003

The growth factor independent 1 (GFI1) gene encodes a zinc finger protein which acts as a transcriptional repressor and confers growth factor independence on tumor cells, as suggested by the study of its mouse ortholog, Gfi1. We previously isolated the human GFI1 gene but no information about the structure and location of the promotor of this gene has been reported. In this study we have cloned and characterized the human GFI1 promoter. The nucleotide sequence of the promoter region is GC‐rich and does not contain a typical TATA or CAAT box. Several Sp1 sites are present and computer predictions indicate that either of the two Sp1 sites might serve as the sites for transcription initiation. Analysis of various lengths of the promoter region using the luciferase reporter assay identifies a functional promoter that is active in NIH3T3 cells. The strongest activity lies within a region 312–602 basepairs upstream from the translation start site.
Microsatellite evolution in modern humans: a comparison of two data sets from the same populations
Authors: JIN L. , BASKETT M. L. , CAVALLI‐SFORZA L. L. , ZHIVOTOVSKY L. A. , FELDMAN M. W. , ROSENBERG N. A.
Published: March 2003

We genotyped 64 dinucleotide microsatellite repeats in individuals from populations that represent all inhabited continents. Microsatellite summary statistics are reported for these data, as well as for a data set that includes 28 out of 30 loci studied by Bowcock et al. (1994) in the same individuals. For both data sets, diversity statistics such as heterozygosity, number of alleles per locus, and number of private alleles per locus produced the highest values in Africans, intermediate values in Europeans and Asians, and low values in Americans. Evolutionary trees of populations based on genetic distances separated groups from different continents. Corresponding trees were topologically similar for the two data sets, with the exception that the (δμ)2 genetic distance reliably distinguished groups from different continents for the larger data set, but not for the smaller one. Consistent with our results from diversity statistics and from evolutionary trees, population growth statistics Sk and β, which seem particularly useful for indicating recent and ancient population size changes, confirm a model of human evolution in which human populations expand in size and through space following the departure of a small group from Africa.
2E4/Kaptin (KPTN) – a candidate gene for the hearing loss locus, DFNA4
Authors: BEARER E. L. , CHEN A. F. , CHEN A. H. , LI Z. , MARK H.‐F. , SMITH R. J. H. , JACKSON C. L.
Published: March 2003

Stereocilia of the inner ear play an integral role in the mechanotransduction of sound. Their structural support is derived from actin filaments and actin‐binding proteins. We have identified a novel actin‐binding protein, 2E4‐kaptin (KPTN), which appears to be involved in this structural network. Using double label immunofluorescence, we now show that KPTN extends beyond the barbed ends of actin filaments at the tips of stereocilia, and using cloned human cDNA, we mapped KPTN to chromosome 19q13.4. A combination of FISH, radiation hybrid mapping and YAC screening localized KPTN between markers D19S412 and NIB1805, making this gene an excellent functional and positional candidate for DFNA4, a form of autosomal dominant non‐syndromic hearing loss. We identified a second family with inherited deafness that also maps to the DFNA4 region. To screen KPTN for deafness‐causing mutations, we first determined its genomic structure and then completed a mutational analysis by direct sequencing and SSCP in affected family members. Although no deafness‐causing mutations were identified in the coding region, KPTN remains an excellent candidate gene for hearing loss; by synteny, its murine orthologue also remains a candidate gene for the Nijmegan waltzer (nv) mouse mutant, which has vestibular defects and a variable sensorineural hearing loss.
Adaptation of the extended transmission/disequilibrium test to distinguish disease associations of multiple loci: the Conditional Extended Transmission/Disequilibrium Test
Authors: KOELEMAN B. P. C. , DUDBRIDGE F. , CORDELL H. J. , TODD J. A.
Published: March 2003

Linkage and association studies in complex diseases are used to identify and fine map disease loci. The process of identifying the aetiological polymorphism, the molecular variant responsible for the linkage and association of the chromosome region with disease, is complicated by the low penetrance of the disease variant, the linkage disequilibrium between physically‐linked polymorphic markers flanking the disease variant, and the possibility that more than one polymorphism in the most associated region is aetiological. It is important to be able to detect additional disease determinants in a region containing a cluster of genes, such as the major histocompatibility complex (MHC) region on chromosome 6p21. Some methods have been developed for detection of additional variants, such as the Haplotype Method, Marker Association Segregation Chi‐squares (MASC) Method, and the Homozygous Parent Test. Here, the Extended Transmission/Disequilibrium Test is adapted to test for association conditional on a previously associated locus. This test is referred to as the Conditional Extended TDT (CETDT). We discuss the advantages of the CETDT compared to existing methods and, using simulated data, investigate the effect of polymorphism, inheritance, and linkage disequilibrium on the CETDT.
Conditional ETDT analysis of the Human Leukocyte Antigen region in type 1 diabetes
Authors: KOELEMAN B. P. C. , HERR M. H. , ZAVATTARI P. , DUDBRIDGE F. , MARCH R. , CAMPBELL D. , BARNETT A. H. , BAIN S. C. , MULARGIA A. P. , LODDO M. , AMOS W. , CUCCA F. , TODD J. A.
Published: March 2003

Several studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA‐DQB1 and ‐DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non‐ DR/DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA‐DQB1 and ‐DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1‐DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1‐DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA‐DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA‐DQB1‐DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1.
Search for multifactorial disease susceptibility genes in founder populations
Authors: BOURGAIN C. , GENIN E. , QUESNEVILLE H. , CLERGET‐DARPOUX F.
Published: March 2003

The current challenge in biomedical research is to detect genetic risk factors involved in common complex diseases. The power to detect their role is generally poor in populations that have been large for a long time. It has been suggested that the power may be increased by taking advantage of the specificity of founder populations; linkage disequilibrium spanning larger regions and kinship coefficients being stronger than in large populations. A new method is proposed here, the Maximum Identity Length Contrast (MILC) which, in contrast with other existing methods, does not make the assumption of unique ancestry for the genetic risk factors. It is thus appropriate for a search for common genetic risk factors for complex diseases. Statistical properties of the method are discussed in realistic contexts.
Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1)
Authors: HAYER M. , BÖNISCH H. , BRÜSS M.
Published: March 2003

In this study we report the cloning of four human OCT1 (hOCT1/SLC22A1) isoforms: a long form, hOCT1G/L554, and three shorter forms (hOCT1G/L506, hOCT1G483 and hOCT1G353). All four variants could be identified in the human glioma cell line SK‐MG‐1, whereas only two isoforms (hOCT1G/L554 and hOCT1G/L506) were found in human liver cDNA. The hOCT1G/L554 represents the full length hOCT1 since the sequence of this clone is more than 99% identical to previously cloned hOCT1 cDNAs. Elucidation of the gene structure of human OCT1 demonstrated that the other isolated isoforms are alternatively spliced variants. The hOCT1 gene consists of 7 exons and 6 introns. When stably expressed in human embryonic kidney (HEK293) cells, only the full length hOCT1 cDNA mediated decynium‐22 (D22)‐sensitive uptake of tritiated 1‐methyl‐4‐phenylpyridinium ([3H]‐MPP+).
Multiple interacting gene products may influence susceptibility to malignant hyperthermia
Authors: ROBINSON R. L. , CURRAN J. L. , ELLIS F. R. , HALSALL P. J. , HALL W. J. , HOPKINS P. M. , ILES D. E. , WEST S. P. , SHAW M‐A.
Published: March 2003

Malignant hyperthermia (MH) is a potentially lethal disorder triggered in susceptible individuals on exposure to common anaesthetic agents. Crises reflect the consequences of disturbed skeletal muscle calcium homeostasis. MH is an autosomal dominant, genetically heterogeneous trait. Defects in a single major gene have been assumed to determine susceptibility status in individual families. However, in some pedigrees phenotypic and genotypic data are discordant. One explanation, in contrast to the current genetic model, is that susceptibility is dependent upon the effects of more than one gene. Using the transmission disequilibrium test we assessed the involvement of 8 MH candidate loci (RYR1, CACNA1S, CACNA2D1, MHS4 at 3q13.1, MHS6 at 5p, LIPE, DM1, dystrophin) by analysis of data from 130 MH nuclear families. Results suggested that variations in more than one gene may influence MH susceptibility in single families.
Northwest African distribution of the CD4/Alu microsatellite haplotypes
Authors: FLORES C. , MACA‐MEYER N. , GONZÁLEZ A. M. , CABRERA V. M.
Published: March 2003

We have analysed a linked microsatellite/Alu polymorphism at the CD4 locus (CD4/Alu) in 666 chromosomes from samples of the Iberian Peninsula, Northwest Africa, and West sub‐Saharan Africa. The Iberian Peninsula differs from other European populations by its higher levels of haplotype diversity (0.75), and weaker association between the microsatellite allele 90 and Alu(−) chromosomes. These results are explainable by a substantial gene flow from Northwest Africa. Significant geographic clines for the five major haplotypes suggest a south to north migration from sub‐Saharan Africa into Northwest Africa. In spite of this, the consistent presence of haplotype 110(−) in this area is congruent with an ancient and autochthonous human presence in Northwest Africa.
An EM algorithm for obtaining maximum likelihood estimates in the multi‐phenotype variance components linkage model
Authors: ITURRIA S. J. , BLANGERO J.
Published: March 2003

In recent years variance components models have been developed for localising genes that contribute to human quantitative variation. In typical applications one assumes a multivariate normal model for phenotypes and estimates model parameters by maximum likelihood. For the joint analysis of several correlated phenotypes, however, finding the maximum likelihood estimates for an appropriate multivariate normal model can be a difficult computational task due to complex constraints among the model parameters. We propose an algorithm for computing maximum likelihood estimates in a multi‐phenotype variance components linkage model that readily accommodates these parameter constraints. Data simulated for Genetic Analysis Workshop 10 are used to demonstrate the potential increase in power to detect linkage that can be obtained if correlated phenotypes are analysed jointly rather than individually.
Selecting SNPs in two‐stage analysis of disease association data: a model‐free approach
Authors: HOH J. , WILLE A. , ZEE R. , CHENG S. , REYNOLDS R. , LINDPAINTNER K. , OTT J.
Published: March 2003

For large numbers of marker loci in a genomic scan for disease loci, we propose a novel 2‐stage approach for linkage or association analysis. The two stages are (1) selection of a subset of markers that are ‘important’ for the trait studied, and (2) modelling interactions among markers and between markers and trait. Here we focus on stage 1 and develop a selection method based on a 2‐level nested bootstrap procedure. The method is applied to single nucleotide polymorphisms (SNPs) data in a cohort study of heart disease patients. Out of the 89 original SNPs the method selects 11 markers as being ‘important’. Conventional backward stepwise logistic regression on the 89 SNPs selects 7 markers, which are a subset of the 11 markers chosen by our method.
Allelic association in the FRAX region
Authors: ENNIS S. , COLLINS A. , MURRAY A. , MACPHERSON J. N. , MORTON N. E.
Published: March 2003

The sex chromosomes enable direct determination of haplotypes, and the analysis of 8 microsatellite markers from the FRAX region on Xq27‐q28 contributes 7219 independent haplotypes from our study in Wessex. Allelic association increases with frequency of alleles, and is less for trinucleotide than dinucleotide repeats. The estimate of ε, the exponential decline of association with distance in kb, is 0.0023. The swept radius 1/ε estimates the distance at which disequilibrium falls to e−1≈ .37 of its initial value. The current study estimates the swept radius of association to be 433 kb, which is surprisingly close to estimates for SNPs, and suggests that a marker density of 1/100 kb should be powerful in regions such as FRAX. An explanation for these results is offered, and some speculations made about what will be found when SNPs are subjected to an equally intensive study in multiple regions.
The consistency of the posterior probability of linkage
Authors: WANG K. , HUANG J. , VIELAND V. J.
Published: March 2003

When searching for trait loci along the genome, properly incorporating prior genomic information into the analysis will almost certainly increase the chance of success. Recently, we devised a method that utilizes such prior information in the mapping of trait genes for complex disorders (Vieland, 1998; Wang et al. 1999; Vieland et al. 2000). This method uses the posterior probability of linkage (PPL) based on the admixture model as a measure of linkage information. In this paper, we study the consistency of the PPL. It is shown that, as the number of pedigrees increases, the PPL converges in probability to 1 when there is linkage between the marker and a trait locus, and converges to 0 otherwise. This conclusion is shown to be true for general pedigrees and trait models, even when the likelihood functions are based on misspecified trait models. As part of the effort to prove this conclusion, it is shown that when there is no linkage, the maximum likelihood estimator of the recombination fraction in the admixture model is asymptotically 0.5, even when the admixture model misrepresents the true model.
Transmission/disequilibrium tests for quantitative traits
Authors: SUN F. Z. , FLANDERS W. D. , YANG Q. H. , ZHAO H. Y.
Published: March 2003

The transmission/disequilibrium test (TDT) is a powerful method of locating disease genes. The TDT was originally proposed for use in studies of qualitative traits in families with both parents available. Recently, the TDT has been extended to studies of qualitative traits in sibships without parents available and in families with one parent available. It has also been extended for use in studies of quantitative traits in families with both parents available and in sibships with multiple offspring. In this paper, we first propose a new class of TDT‐type tests for linkage in the presence of linkage disequilibrium for use in studies of families with both parents available. The TDT of Spielman et al. (1993) for qualitative traits and the TDT of Rabinowitz (1997) for quantitative traits are special cases of the new tests. Second, we propose a new class of TDT‐type tests for linkage for use in studies of families with one parent available. Third, we study the validity and the power of the tests using simulations. Finally, we propose a method of combining data from different types of families. The combined test is valuable and allows researchers full use of the available data in detecting linkage between a marker locus and an unobservable quantitative trait locus. An important feature of the tests proposed in this paper is that no assumptions on the distribution of the quantitative traits are needed.
Simple approximations for the maximal transmission/disequilibrium test with a multi‐allelic marker
Authors: BETENSKY R. A. , RABINOWITZ D.
Published: March 2003

Spielman et al. (1993) popularized the transmission/disequilibrium test (TDT) to test for linkage between disease and marker loci that show a population association. Several authors have proposed extensions to the TDT for multi‐allelic markers. Many of these approaches exhibit a ‘swamping’ effect in which a marker with a strong effect is not detected by a global test that includes many markers with no effect. To avoid this effect, Schaid (1996) proposed using the maximum of the bi‐allelic TDT statistics computed for each allele versus all others combined. The maximal TDT statistic, however, no longer follows a chi‐square distribution. Here, a refinement to Bonferroni's correction for multiple testing provided by Worsley (1982) based on maximal spanning trees is applied to calculate accurate upper bounds for the type I error and p‐values for the maximal TDT. In addition, an accurate lower Bonferroni bound is applied to calculate power. This approach does not require any simulation‐based analysis and is less conservative than the standard Bonferroni correction. The bounds are given for both the exact probability calculations and for those based on the normal approximation. The results are assessed through simulations.
Mitochondrial DNA variability in Russians and Ukrainians: Implication to the origin of the Eastern Slavs
Authors: MALYARCHUK B. A. , DERENKO M. V.
Published: March 2003

In order to investigate the origin of the Eastern Slavs, mitochondrial DNA (mtDNA) sequence variation was examined in Russians and Ukrainians by hypervariable segment I (HVS I) sequencing and restriction analysis of the haplogroup‐specific sites. No significant differences were found for Russians and Ukrainians when compared to other Europeans – in fact, they fall within the range of gene diversity seen throughout Europe and exhibit the unimodal pattern of pairwise sequence differences. Moreover, HVS I sequences in the Russians and Ukrainians are similar or identical to those found in eastern and western European populations. Despite the small genetic distances between Europeans, phylogenetic analysis reveals a considerable heterogeneity of Eastern Slavonic populations – they do not cluster together onto a phylogenetic tree. Analysis of distribution of rare HVS I types shared between populations of Eastern Slavs and other West Eurasians has shown that Russians share rare haplotypes mainly with Germans and Finno–Ugric populations. Of these, subhaplogroup H1 sequence types, which are defined by different combinations of nucleotides 16192T, 16294T, 16304C, 16311C and 16320T, are found predominantly in common between Russians and German‐speaking populations. The data obtained allow us to conclude that the Slavonic migrations in early Middle Ages from their putative homeland in central Europe to the east of Europe were accompanied mostly by the same mtDNA types characteristic for the pre‐Slavonic populations of eastern Europe.
MtDNA from extinct Tainos and the peopling of the Caribbean
Authors: LALUEZA‐FOX C. , CALDERÓN F. LUNA , CALAFELL F. , MORERA B , BERTRANPETIT J.
Published: March 2003

Tainos and Caribs were the inhabitants of the Caribbean when Columbus reached the Americas; both human groups became extinct soon after contact, decimated by the Spaniards and the diseases they brought. Samples belonging to pre‐Columbian Taino Indians from the La Caleta site (Dominican Republic) have been analyzed, in order to ascertain the genetic affinities of these groups in relation to present‐day Amerinds, and to reconstruct the genetic and demographic events that took place during the peopling of the Caribbean.

Twenty‐seven bone samples were extracted and analyzed for mtDNA variation. The four major Amerindian mtDNA lineages were screened through amplification of the specific marker regions and restriction enzymatic digestion, when needed. The HVRI of the control region was amplified with four sets of overlapping primers and sequenced in 19 of the samples. Both restriction enzyme and sequencing results suggest that only two (C and D) of the major mtDNA lineages were present in the sample: 18 individuals (75%) belonged to the C haplogroup, and 6 (25%) to the D haplogroup. Sequences display specific substitutions that are known to correlate with each haplogroup, a fact that helped to reject the possibility of European DNA contamination. A low rate of Taq misincorporations due to template damage was estimated from the cloning and sequencing of different PCR products of one of the samples. High frequencies of C and D haplogroups are more common in South American populations, a fact that points to that sub‐continent as the homeland of the Taino ancestors, as previously suggested by linguistic and archaeological evidence. Sequence and haplogroup data show that the Tainos had a substantially reduced mtDNA diversity, which is indicative of an important founder effect during the colonization of the Caribbean Islands, assumed to have been a linear migratory movement from mainland South America following the chain configuration of the Antilles.
Mortality and cancer incidence in persons with Down's syndrome, their parents and siblings
Authors: HERMON C. , ALBERMAN E. , BERAL V. , SWERDLOW A. J. ,   FOR THE COLLABORATIVE STUDY GROUP OF GENETIC DISORDERS
Published: March 2003

A cohort study of 1425 persons with Down's syndrome (DS), and of their parents (447 mothers, 435 fathers) and siblings (1176), was set up to investigate death rates from various causes and cancer incidence patterns. In individuals with DS the all‐cause death rate was six times that of the national population (SMR = 622: 95% CI 559–693), the excess being attributable to many different causes. These included: leukaemia (SMR = 1304: 95% CI 651–2334); diabetes mellitus (SMR = 982: 95% CI 267–2515); Alzheimer's disease (SMR = 22028: 95% CI 7137–51326); epilepsy (SMR = 1727: 95% CI 744–3403); and congenital anomalies (SMR = 4987: 95% CI 4175–5955). The overall survival showed marked improvements for successive birth cohorts, particularly at young ages. For mothers and fathers of persons with DS, all‐cause death rates were 20% lower than national rates and there were no significant excesses from any specific cause. For siblings, all‐cause death rates were similar to national rates; the only condition with a significantly raised mortality ratio was colo‐rectal cancer (SMR = 793: 95% CI 216–2031), but this may well be a chance finding.
Novel mutations in the 7‐dehydrocholesterol reductase gene of 13 patients with Smith–Lemli–Opitz syndrome
Authors: JIRA P. E. , WANDERS R. J. A. , SMEITINK J. A. M. , DE JONG J. , WEVERS R. A. , OOSTHEIM W. , TUERLINGS J. H. A. M. , HENNEKAM R. C. M. , SENGERS R. C. A. , WATERHAM H. R.
Published: March 2003

Smith–Lemli–Opitz syndrome (SLOS) is caused by mutations in the DHCR7 gene leading to deficient activity of 7‐dehydrocholesterol reductase (DHCR7; EC 1.3.1.21), the final enzyme of the cholesterol biosynthetic pathway, resulting in low cholesterol and high concentrations of its direct precursor 7‐dehydrocholesterol in plasma and tissues. We here report mutations identified in the DHCR7 gene of 13 children diagnosed with SLOS by clinical and biochemical criteria. We found a high frequency of the previously described IVS8–1 G > C splice acceptor site mutation (two homozygotes, eight compound heterozygotes). In addition, 13 missense mutations and one splice acceptor mutation were detected in eleven patients with a mild to moderate SLOS‐phenotype. The mutations include three novel missense mutations (W182L, C183Y, F255L) and one novel splice acceptor site mutation (IVS8–1 G > T).

Two patients, homozygous for the IVS8–1 G > C mutation, presented with a severe clinical phenotype and died shortly after birth. Seven patients with a mild to moderate SLOS‐phenotype disclosed compound heterozygosity of the IVS8–1 G > C mutation in combination with different novel and known missense mutations.
Interaction of the common apolipoprotein C‐III (APOC3 ‐482C > T) and hepatic lipase (LIPC ‐514C > T) promoter variants affects glucose tolerance in young adults. European Atherosclerosis Research Study II (EARS‐II)
Authors: JANSEN H. , WATERWORTH D. M. , NICAUD V. , EHNHOLM C. , TALMUD P. J.
Published: March 2003

Both hepatic lipase (HL) and apolipoprotein C‐III (apoC‐III) influence lipid metabolism. Common variation in promoters of both genes, LIPC ‐514C > T and APOC3 ‐482C > T, respectively, have been shown to affect plasma lipids and lipoproteins and glucose tolerance. We studied the interaction between both variants on parameters of glucose tolerance and lipid metabolism in 714 healthy young males participating in the second European Atherosclerosis Research Study (EARS‐II). Approximately 18% of the subjects were carriers of at least one rare LIPC and APOC3 allele. These subjects exhibited, after fasting and oral fat loading, the highest values of triglyceride‐rich lipoproteins, but there was no significant interactive effect on any lipid variable. However, interaction occurred on basal diastolic blood pressure (p=0.036) and, during oral glucose tolerance testing, on peak (p= 0.0065) and area under the curve for glucose (p=0.049), and insulin (p= 0.035). This resulted in the highest diastolic blood pressure and lowest glucose tolerance in carriers of at least one rare allele of both genes. Thus gene:gene interaction between LIPC and APOC3, even in these healthy young males, leads to changes in parameters that are typically characteristic of Syndrome‐X.
Evidence for population sub‐structuring in São Tomé e Príncipe as inferred from Y‐chromosome STR analysis
Authors: TROVOADA M. J. , ALVES C. , GUSMÃO L. , ABADE A. , AMORIM A. , PRATA M. J.
Published: March 2003

Seven Y‐chromosome STR loci, DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392 and DYS393 have been analysed in population samples of Angolares, Forros and Tongas, three ethnic groups from the African archipelago of São Tomé e Príncipe (Gulf of Guinea). Complete typings were obtained for 103 chromosomes, which belonged to 79 different haplotypes. The mean heterozygosity per locus in the overall São Tomean sample was 0.566, with the highest value found among Forros and the lowest among Angolares. Angolares also showed the lowest level of haplotype diversity. On average, the mean pairwise difference between two random haplotypes from Angolares, Forros and Tongas was 4.69, 6.74 and 6.23 repeats, respectively. The genetic distances were found to be statistically significant between Angolares and Forros or Tongas. In accordance, AMOVA revealed that the percentage of variation attributable to differences among groups was only significant when we distinguished between Angolares and non‐Angolares. Globally, these results indicate that, with respect to the pool of male lineages of São Tomé e Príncipe, some genetic sub‐structuring does exist, basically determined by the Angolares ethnic group.
Sample size calculations for classical association and TDT‐type methods using family data
Authors: TREGOUET D. A. , PALLAUD C. , SASS C. , VISVIKIS S. , TIRET L.
Published: March 2003

Transmission Disequilibrium Test (TDT)‐based methods have been advocated by several authors for testing that a marker‐phenotype association is actually due to linkage and not to uncontrolled stratification. As a pre‐requisite of TDT‐type methods is the presence of an association between marker and phenotype, one may wish to first investigate the association using a classical association study, and then to check by a TDT approach whether this association is actually due to linkage. We propose an estimating equation (EE) procedure, to compute analytically the minimum sample size of sibship data required to detect the association between a marker and a quantitative phenotype, and that required to confirm it by two TDT methods. We show that, when the marker allele frequency is low or high, the number of informative sibs needed in TDT‐type methods can be lower than the number required in an association analysis, and even more so when the familial clustering is strong. However, in all cases, the number of sibs that need to be sampled to get the appropriate number of informative sibs for analysis is always larger for TDT methods than for an association study. In a phenotype‐first strategy, this number may be critical when investigating costly phenotypes.