Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia
Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus(1,2). This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQ beta 1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P = 1.73 x 10(-19)). In addition, two amino acid substitutions in the. extracellular …
Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation
Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci.
Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis
To access publisher's full text version of this article click on the hyperlink at the bottom of the page Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci sh…
Trans-ancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders
AbstractLiability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM - IV diagnosed AD. Genome - wide data on 14,904 individuals with AD and 37,944 controls from 28 case / control and family - based studies were meta - analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome - wide significant effects of different ADH1B variants were identified in European (rs1229984; p = …
Genetic contribution to alcohol dependence: Investigation of a heterogeneous german sample of individuals with alcohol dependence, chronic alcoholic pancreatitis, and alcohol-related cirrhosis
The present study investigated the genetic contribution to alcohol dependence (AD) using genome-wide association data from three German samples. These comprised patients with: (i) AD; (ii) chronic alcoholic pancreatitis (ACP); and (iii) alcohol-related liver cirrhosis (ALC). Single marker, gene-based, and pathway analyses were conducted. A significant association was detected for the ADH1B locus in a gene-based approach (puncorrected = 1.2 × 10-6; pcorrected = 0.020). This was driven by the AD subsample. No association with ADH1B was found in the combined ACP + ALC sample. On first inspection, this seems surprising, since ADH1B is a robustly replicated risk gene for AD and may therefore be …
Genome-wide association data provide further support for an association between 5-HTTLPR and major depressive disorder.
Abstract Background Dysfunctions of serotonergic neurotransmission are supposed to be involved in the pathogenesis of psychiatric disorders such as major depressive disorder (MDD). The concentration of serotonin (5-hydroxytryptamine, 5-HT) in the synaptic cleft is essentially regulated by the 5-HT transporter (5-HTT). A length polymorphism repeat in the 5-HTT promoter region, termed 5-HTTLPR, has been commonly investigated for an association with psychiatric disorders. Methods Genotyping of the 5-HTTLPR is time-consuming and technically challenging. Recently, a two-SNP haplotype was identified that tags the 5-HTTLPR at r 2 =0.775. This allows extraction of 5-HTTLPR genotype information from…
Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array
Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been repor…
XRCC5 as a Risk Gene for Alcohol Dependence : Evidence from a Genome-Wide Gene-Set-Based Analysis and Follow-up Studies in Drosophila and Humans
Genetic factors play as large a role as environmental factors in the etiology of alcohol dependence. Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of alcohol dependence, many true findings may be missed due to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets of which five could be replicated in an independent sample. Clustered in these ge…
Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster
Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome-wide association study (GWAS). The sample comprised 1333 male in-patients with severe AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 2168 controls. These included 487 patients and 1358 controls from a previous GWAS study by our group. All individuals were of German descent. Single-marker tests and a polygenic score-based analysis to assess the …
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68…
Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
AbstractEating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use (genetic correlation [rg], twin-based=0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge-eating, AN without binge-eating, and a BN factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], …
Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region
Background: Classic bladder exstrophy (CBE) is the most common form of the bladder exstrophy and epispadias complex. Previously, we and others have identified four patients with a duplication of 22q11.21 among a total of 96 unrelated CBE patients. Methods: Here, we investigated whether this chromosomal aberration was commonly associated with CBE/bladder exstrophy and epispadias complex in an extended case-control sample. Multiplex ligation-dependent probe amplification and microarray-based analysis were used to identify 22q11.21 duplications in 244 unrelated bladder exstrophy and epispadias complex patients (including 217 CBE patients) and 665 healthy controls. Results: New duplications of …
Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs
AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in …
Shared genetic etiology between alcohol dependence and major depressive disorder
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Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways
G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an an…
Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder
Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generat…