pinecone/core-2020-05-10-deduplication huggingface dataset:
Common Gene Variants in Schizophrenia Susceptibility with Focus on Neurodevelopment

Schizophrenia is a severe multifactorial mental disorder with an important and complex genetic component, and the understanding of the underlying biological mechanisms is limited. Several lines of evidence support that abnormal neurodevelopment is involved, such as cognitive deficits in children who later develop schizophrenia, abnormalities in brain structure in the early phase of disease, and aberrant neuronal distributions. Also, glutamatergic dysfunctions are suggested in the schizophrenia etiology, and glutamate signalling is important during neurodevelopment. Perineuronal nets are extracellular matrix structures involved in brain maturation, which includes the characteristic neural epitope Human Natural Killer-1 (HNK-1).  <br>
To investigate if common gene variants important for neurodevelopment are involved in schizophrenia etiology, we used candidate gene-based association studies of tagSNPs spanning thirty genes, genotyped in a large Scandinavian case-control sample (SCOPE).  Nineteen, out of the 289 tagSNPs in 18 neuronal migration genes, were nominally significant, and the strongest finding was a tagSNP located in MAM domain containing glycosylphosphatidylinositol anchor 1 (MDGA1), but no findings were significant after correction.  
Phosphodiesterase 4B (PDE4B) is a Disrupted-in-Schizophrenia-1 (DISC1) interactor, with previously reported genetic associations only in women. Six and 16, out of 40 and 72 PDE4B tagSNPs, were nominally associated with schizophrenia and bipolar disorder, respectively, in the combined samples or in gender-specific subgroups. No findings were significant after correction. However, two of the tagSNPs nominally associated in schizophrenia females had proxies which were nominally associated in the total bipolar disorder sample, and the four SNPs were located in the same block, surrounding the splice site for the PDE4B3 isoform.  <br>
Five out of 104 tagSNPs in ten genes involved in perineuronal net formation and HNK-1 biosynthesis, located in beta-1,3-glucuronyltransferase 2 (B3GAT2), were nominally associated with schizophrenia. The association signal for tagSNPs in one of the LD blocks was replicated by proxy SNPs in a much larger European sample (SGENE-plus).  <br>
Six out of 30 tagSNPs in glutamate receptor ionotrophic kainate 3 (GRIK3) were nominally associated, and the best tagSNP were significant after correction, with increased significance in the Swedish subsample, as well as when the risk allele was combined with another tagSNP risk allele.  
When investigating clinical characteristics, including positive and negative symptom scores, age at onset, and cognitive measures of learning, memory and IQ, for association with a subset of the tagSNPs and genes included in the thesis studies, there were no significant associations after correction.  
The current results indicate that gene variants involved in neurodevelopment are associated with schizophrenia, which further supports the neurodevelopmental hypothesis
Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders

The gastrin-releasing peptide receptor (GRPR) was implicated for the first time in the pathogenesis of Autism spectrum disorders (ASD) by Ishikawa-Brush et al. [Ishikawa-Brush et al. (1997): Hum Mol Genet 6: 1241-1250]. Since this original observation, only one association study [Marui et al. (2004): Brain Dev 26: 5-7] has further investigated, though unsuccessfully, the involvement of the GRPR gene in ASD. With the aim of contributing further information to this topic we have sequenced the entire coding region and the intron/exon junctions of the GRPR gene in 149 Italian autistic patients. The results of this study led to the identification of four novel point mutations, two of which, that is, C6S and L181F, involve amino acid changes identified in two patients with ASD and Rett syndrome, respectively. Both the leucine at position 181 and the cysteine at position 6 are strongly conserved in vertebrates. C6S and L181F mutant proteins were expressed in COS-7 and BALB/3T3 cells, but they did not affect either GRP's binding affinity or its potency for stimulating phospholipase C-mediated production of inositol 1,4,5-trisphosphate. In summary, our results do not provide support for a major role of the GRPR gene in ASD in the population of patients we have studied. However, there is a potential role of C6S and L181F mutations on GRPR function, and possibly in the pathogenesis of the autistic disorders in the two patient
Functional characterization of three single–nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA– protein interactions.

Variations in levels of apolipoprotein E (ApoE) have been tied to the risk and progression of\ud
Alzheimer’s disease (AD). Our group has previously compared and contrasted the promoters of\ud
the mouse and human ApoE gene (APOE) promoter sequences and found notable similarities\ud
and significant differences that suggest the importance of the APOE promoter’s role in the\ud
human disease. We examine here three specific single–nucleotide polymorphisms within the\ud
human APOE promoter region, specifically at −219 (G/T), −427 (T/C), and at −491 (A/T)\ud
upstream from the +1 transcription start site. The −219 and −491 polymorphic variations have\ud
significant association with instance of AD, and −491AA has significant risk even when\ud
stratified for the APOEε4 allele. We also show significant effects on reporter gene expression in\ud
neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The\ud
−491 and −219 polymorphisms may have an interactive effect in addition to any independent\ud
activity. DNA–protein interactions differ between each polymorphic state. We propose SP1 and\ud
GATA as candidates for regulatory control of the −491 and −219 polymorphic sites. This work’s\ud
significance lies in drawing connection among APOE promoter polymorphisms’ associations\ud
with AD to functional promoter activity differences and specific changes in DNA–protein\ud
interactions with cell culture-based assays. Taken together, these results suggest that APOE\ud
expression levels are a risk factor for AD irrespective of APOEε4 allele status.This work was supported by the Alzheimer’s Association [to DKL];\ud
National Institutes of Health [grant numbers AG18379, AG18884 to DKL]; and the Ministerio\ud
de Educación y Ciencia [grant number SAF2006-00724 to JP–T].Peer reviewe
Non-Replication of Association for Six Polymorphisms From Meta-Analysis of Genome-Wide Association Studies of Parkinson?s Disease: Large-Scale Collaborative Study

Early genome-wide association (GWA) studies on Parkinson's disease (PD) have not been able to yield conclusive, replicable signals of association, perhaps due to limited sample size. We aimed to investigate whether association signals derived from the meta-analysis of the first two GWA investigations might be replicable in different populations. We examined six single-nucleotide polymorphisms (SNPs) (rs1000291, rs1865997, rs2241743, rs2282048, rs2313982, and rs3018626) that had reached nominal significance with at least two of three different strategies proposed in a previous analysis of the original GWA studies. Investigators from the "Genetic Epidemiology of Parkinson's Disease" (GEOPD) consortium were invited to join in this study. Ten teams contributed replication data from 3,458 PD cases and 3,719 controls. The data from the two previously published GWAs (599 PD cases, 592 controls and 443 sibling pairs) were considered as well. All data were synthesized using both fixed and random effects models. The summary allelic odds ratios were ranging from 0.97 to 1.09 by random effects, when all data were included. The summary estimates of the replication data sets (excluding the original GWA data) were very close to 1.00 (range 0.98-1.09) and none of the effects were nominally statistically significant. The replication data sets had significantly different results than the GWA data. Our data do not support evidence that any of these six SNPs reflect susceptibility markers for PD. Much stronger signals of statistical significance in GWA platforms are needed to have substantial chances of replication. Specifically in PD genetics, this would require much larger GWA studies and perhaps novel analytical techniques
Reduced 3-O-methyl-dopa levels in OCD patients and their unaffected parents is associated with the low activity M158 COMT allele.

International audienceThe catechol-O-methyltransferase (COMT) gene is considered as a candidate gene in obsessive-compulsive disorder (OCD). Specifically, the COMT low-activity M158 allele has been suggested to be associated with OCD. However, there is no study reporting that COMT activity is decreased in OCD patients and that the decrease is mediated by the V158M polymorphism. Therefore, the purpose of our study was to assess COMT activity in OCD by measuring plasma levels of 3-O-methyl-dopa (3-OMD), which result from the methylation of levodopa by COMT, and to investigate the relationship between 3-OMD levels and the V158M polymorphism. We also examined whether 3-OMD levels represented an endophenotype, associated with the genetic liability to OCD, by assessing unaffected relatives of OCD patients. We assessed plasma 3-OMD levels in a sample of drug-free OCD probands (n = 34) and their unaffected parents (n = 63), and compared them with controls (n = 85). The COMT V158M polymorphism was genotyped in all participants. Lower plasma 3-OMD levels were found in OCD probands and their unaffected parents compared to controls. The COMT M158 allele was associated with reduced plasma 3-OMD levels in a co-dominant manner, both in OCD probands and their relatives, but not in controls. Our results suggest that COMT activity could act as a limiting factor for the production of 3-OMD in OCD patients and in their relatives. These findings further support a role of COMT in the susceptibility to OCD and provide evidence that 3-OMD levels could represent an endophenotype in OCD
Association study of 182 candidate genes in anorexia nervosa.

We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case-control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathway-based analysis in order to make up for deficiencies in traditional candidate gene approaches to AN
Polymorphisms of the steroid sulfatase (STS) gene are associated with attention deficit hyperactivity disorder and influence brain tissue mRNA expression

Supported by Wellcome Trust fundingPrevious studies in animals and humans have implicated the X-chromosome STS gene in the etiology of attentional difficulties and attention deficit hyperactivity disorder (ADHD). This family based association study has fine mapped a region of the STS gene across intron 1 and 2 previously associated with ADHD, in an extended sample of 450 ADHD probands and their parents. Significant association across this region is demonstrated individually with 7 of the 12 genotyped SNPs, as well as an allele specific haplotype of the 12 SNPs. The over transmitted risk allele of rs12861247 was also associated with reduced STS mRNA expression in normal human post-mortem frontal cortex brain tissue compared to the non-risk allele (P = 0.01). These results are consistent with the hypothesis arising from previous literature demonstrating that boys with deletions of the STS gene, and hence no STS protein are at a significantly increased risk of developing ADHD. Furthermore, this study has established the brain tissue transcript of STS, which except from adipose tissue, differs from that seen in all other tissues investigated. © 2010 Wiley-Liss, Inc.Publisher PDFPeer reviewe
Selected rapporteur summaries from the XX world congress of psychiatric genetics, Hamburg, Germany, October 14-18, 2012

The XXth World Congress of Psychiatric Genetics (WCPG), sponsored by The International Society of Psychiatric Genetics (ISPG) took place in Hamburg, Germany on October 14–18, 2012. Approximately 600 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned sessions as rapporteurs. This manuscript represents topics covered in most, but not all, oral presentations during the conference, and some of the major notable new findings reported at this 2012 WCPG
A genome-wide association study of sleep habits and insomnia

Several aspects of sleep behavior such as timing, duration and quality have been demonstrated to be heritable. To identify common variants that influence sleep traits in the population, we conducted a genome-wide association study of six sleep phenotypes assessed by questionnaire in a sample of 2,323 individuals from the Australian Twin Registry. Genotyping was performed on the Illumina 317, 370, and 610K arrays and the SNPs in common between platforms were used to impute non-genotyped SNPs. We tested for association with more than 2,000,000 common polymorphisms across the genome. While no SNPs reached the genome-wide significance threshold, we identified a number of associations in plausible candidate genes. Most notably, a group of SNPs in the third intron of the CACNA1C gene ranked as most significant in the analysis of sleep latency (P=1.3×10-6). We attempted to replicate this association in an independent sample from the Chronogen Consortium (n=2,034), but found no evidence of association (P=0.73). We have identified several other suggestive associations that await replication in an independent sample. We did not replicate the results from previous genome-wide analyses of self-reported sleep phenotypes after correction for multiple testing
Epigenetic studies in Alzheimer's disease: Current findings, caveats, and considerations for future studies

This is the peer reviewed version of the article, which has been published in final form at DOI: 10.1002/ajmg.b.32201. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Alzheimer's disease (AD) is a sporadic, chronic neurodegenerative disease, usually occurring late in life. The last decade has witnessed tremendous advances in our understanding about the genetic basis of AD, but a large amount of the variance in disease risk remains to be explained. Epigenetic mechanisms, which developmentally regulate gene expression via modifications to DNA, histone proteins, and chromatin, have been hypothesized to play a role in other complex neurobiological diseases, and studies to identify genome-wide epigenetic changes in AD are currently under way. However, the simple brute-force approach that has been successfully employed in genome-wide association studies is unlikely to be successful in epigenome-wide association studies of neurodegeneration. A more academic approach to understanding the role of epigenetic variation in AD is required, with careful consideration of study design, methodological approaches, tissue-specificity, and causal inference. In this article, we review the empirical literature supporting a role for epigenetic processes in AD, and discuss important considerations and future directions for this new and emerging field of research. © 2013 Wiley Periodicals, Inc.NI
A recessive genetic model and runs of homozygosity in major depressive disorder

Genome-wide association studies (GWASs) of major depressive disorder (MDD) have yet to identify variants that surpass the threshold for genome-wide significance. A recent study reported that runs of homozygosity (ROH) are associated with schizophrenia, reflecting a novel genetic risk factor resulting from increased parental relatedness and recessive genetic effects. Here, we explore the possibility of such a recessive model in MDD. In a sample of 9,238 cases and 9,521 controls reported in a recent mega-analysis of 9 GWAS we perform an analysis of ROH and common variants under a recessive model. Since evidence for association with ROH could reflect a recessive mode of action at loci, we also conducted a genome-wide association analyses under a recessive model. The genome-wide association analysis using a recessive model found no significant associations. Our analysis of ROH suggested that there was significant heterogeneity of effect across studies in effect (P=0.001), and it was associated with genotyping platform and country of origin. The results of the ROH analysis show that differences across studies can lead to conflicting systematic genome-wide differences between cases and controls that are unaccounted for by traditional covariates. They highlight the sensitivity of the ROH method to spurious associations, and the need to carefully control for potential confounds in such analyses. We found no strong evidence for a recessive model underlying MDD
Testing the role of circadian genes in conferring risk for psychiatric disorders

Disturbed sleep and disrupted circadian rhythms are a common feature of psychiatric disorders, and many groups have postulated an association between genetic variants in circadian clock genes and psychiatric disorders. Using summary data from the association analyses of the Psychiatric Genomics Consortia (PGC) for schizophrenia, bipolar disorder and major depressive disorder, we evaluated the evidence that common SNPs in genes encoding components of the molecular clock influence risk to psychiatric disorders. Initially, gene-based and SNP P-values were analyzed for 21 core circadian genes. Subsequently, an expanded list of genes linked to control of circadian rhythms was analyzed. After correcting for multiple comparisons, none of the circadian genes were significantly associated with any of the three disorders. Several genes previously implicated in the etiology of psychiatric disorders harbored no SNPs significant at the nominal level of
Language and traits of autism spectrum conditions: evidence of limited phenotypic and etiological overlap

Language difficulties have historically been viewed as integral to autism spectrum conditions (ASC), leading molecular genetic studies to consider whether ASC and language difficulties have overlapping genetic bases. The extent of genetic, and also environmental, overlap between ASC and language is, however, unclear. We hence conducted a twin study of the concurrent association between autistic traits and receptive language abilities. Internet-based language tests were completed by ∼3,000 pairs of twins, while autistic traits were assessed via parent ratings. Twin model fitting explored the association between these measures in the full sample, while DeFries-Fulker analysis tested these associations at the extremes of the sample. Phenotypic associations between language ability and autistic traits were modest and negative. The degree of genetic overlap was also negative, indicating that genetic influences on autistic traits lowered language scores in the full sample (mean genetic correlation = −0.13). Genetic overlap was also low at the extremes of the sample (mean genetic correlation = 0.14), indicating that genetic influences on quantitatively defined language difficulties were largely distinct from those on extreme autistic traits. Variation in language ability and autistic traits were also associated with largely different nonshared environmental influences. Language and autistic traits are influenced by largely distinct etiological factors. This has implications for molecular genetic studies of ASC and understanding the etiology of ASC. Additionally, these findings lend support to forthcoming DSM-5 changes to ASC diagnostic criteria that will see language difficulties separated from the core ASC communication symptoms, and instead listed as a clinical specifier. © 2014 Wiley Periodicals, Inc
The effect of ANK3 bipolar-risk polymorphisms on the working memory circuitry differs between loci and according to risk-status for bipolar disorder

Polymorphisms at the rs10994336 and rs9804190 loci of the Ankyrin 3 (ANK3) gene have been strongly associated with increased risk for bipolar disorder (BD). However, their potential pathogenetic effect on BD-relevant neural circuits remains unknown. We examined the effect of BD-risk polymorphisms at rs10994336 and rs9804190 on the working memory (WM) circuit using functional magnetic resonance imaging (fMRI) data obtained from euthymic patients with BD (n = 41), their psychiatrically healthy first-degree relatives (n = 25) and unrelated individuals without personal or family history of psychiatric disorders (n = 46) while performing the N-back task. In unrelated healthy individuals, the rs10994336-risk-allele was associated with reduced activation of the ventral visual cortical components of the WM circuit while the rs9804190-risk-allele was associated with inefficient hyperactivation of the prefrontal cortical components of the WM. In patients and their healthy relatives, risk alleles at either loci were associated with hyperactivation in the ventral anterior cingulate cortex. Additionally, Rs9804190-risk-allele carriers with BD evidenced abnormal hyperactivation within the posterior cingulate cortex. This study provides new insights on the neurogenetic correlates of allelic variation at different genome-wide supported BD-risk associated ANK3 loci that support their involvement in BD and highlight the modulatory influence of increased background genetic risk for BD