Genotype-stratified GWAS meta-analysis reveals novel loci associated with alcohol consumption

An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis in up to 40,679 individuals from Japanese populations to uncover additional loci associated with alcohol consumption in an rs671-dependent manner. No loci satisfied the genome-wide significance threshold in wild-type homozygotes (GG), but six loci (ADH1B, ALDH1B1, ALDH1A1, ALDH2, GOT2, and MYOM1- MYL12A) did so in heterozygotes (GA). Of these, three loci (ALDH2, GOT2, and MYOM1- MYL12A) were novel, and two (ADH1B and ALDH1B1) showed genome-wide significant interaction with rs671. Our results identify a new genetic architecture associated with alcohol consumption, and shed additional light on the genetic characteristics of alcohol consumption among East Asians.

Download Full-text

Genome-wide association studies of antidepressant class response and treatment-resistant depression

Translational Psychiatry ◽

10.1038/s41398-020-01035-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Qingqin S. Li ◽

◽

Chao Tian ◽

David Hinds

Keyword(s):

Reuptake Inhibitor ◽

Meta Analysis ◽

Genomic Region ◽

Genome Wide Association Studies ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Significance Threshold ◽

Genome Wide ◽

Resistant Depression ◽

Genome Wide Significance

Abstract The “antidepressant efficacy” survey (AES) was deployed to > 50,000 23andMe, Inc. research participants to investigate the genetic basis of treatment-resistant depression (TRD) and non-treatment-resistant depression (NTRD). Genome-wide association studies (GWAS) were performed, including TRD vs. NTRD, selective serotonin reuptake inhibitor (SSRI) responders vs. non-responders, serotonin-norepinephrine reuptake inhibitor (SNRI) responders vs. non-responders, and norepinephrine-dopamine reuptake inhibitor responders vs. non-responders. Only the SSRI association reached the genome-wide significance threshold (p < 5 × 10−8): one genomic region in RNF219-AS1 (SNP rs4884091, p = 2.42 × 10−8, OR = 1.21); this association was also observed in the meta-analysis (13,130 responders vs. 6,610 non-responders) of AES and an earlier “antidepressant efficacy and side effects” survey (AESES) cohort. Meta-analysis for SNRI response phenotype derived from AES and AESES (4030 responders vs. 3049 non-responders) identified another genomic region (lead SNP rs4955665, p = 1.62 × 10−9, OR = 1.25) in an intronic region of MECOM passing the genome-wide significance threshold. Meta-analysis for the TRD phenotype (31,068 NTRD vs 5,714 TRD) identified one additional genomic region (lead SNP rs150245813, p = 8.07 × 10−9, OR = 0.80) in 10p11.1 passing the genome-wide significance threshold. A stronger association for rs150245813 was observed in current study (p = 7.35 × 10−7, OR = 0.79) than the previous study (p = 1.40 × 10−3, OR = 0.81), and for rs4955665, a stronger association in previous study (p = 1.21 × 10−6, OR = 1.27) than the current study (p = 2.64 × 10−4, OR = 1.21). In total, three novel loci associated with SSRI or SNRI (responders vs. non-responders), and NTRD vs TRD were identified; gene level association and gene set enrichment analyses implicate enrichment of genes involved in immune process.

Download Full-text

Meta-analysis of Genome-wide Association Study Identifies FBN2 as a Novel Locus Associated With Systemic Lupus Erythematosus in Thai Population

10.21203/rs.3.rs-33445/v1 ◽

2020 ◽

Author(s):

Pattarin Tangtanatakul ◽

Chisanu Thumarat ◽

Nusara Satproedprai ◽

Punna Kunhapan ◽

Tassamonwan Chaiyasung ◽

...

Keyword(s):

Lupus Erythematosus ◽

Chinese Population ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Disease Risk ◽

Meta Analysis ◽

Genome Wide Association ◽

Systemic Lupus ◽

Thai Population ◽

Genome Wide

Abstract Background: Differences in the expression of variants across ethnic groups in the Systemic Lupus Erythematosus (SLE) patients have been well documented. However, the genetic architecture in the Thai population has not been thoroughly examined. In this study, we carried out genome-wide association study (GWAS) in Thai population.Methods: Two GWAS cohorts were independently collected and genotyped: discovery dataset (487 SLE cases and 1,606 healthy controls) and replication dataset (405 SLE cases and 1,590 unrelated-disease controls). Data were imputed to the density of the 1,000 Genomes Project Phase 3. Association studies were performed based on different genetic models, and pathway enrichment analysis was further examined. In addition, the performance of disease risk estimation for individuals in Thai GWAS was assessed based on the polygenic risk score (PRS) model trained by other Asian populations.Results: Previous findings on SLE susceptible alleles were well replicated in the two GWAS. The SNPs on HLA-class II (rs9270970, A>G, OR=1.82, p-value = 3.61E-26), STAT4 (rs7582694, C>G, OR=1.57, p-value = 8.21E-16), GTF2I (rs73366469, A>G, OR=1.73, p-value = 2.42E-11) and FAM167A-BLK allele (rs13277113, A>G, OR=0.68, p-value = 1.58E-09) were also significantly associated with SLE in Thai population. Meta-analysis of the two GWAS identified a novel locus at the FBN2 that was specifically associated with SLE in the Thai population (rs74989671, A>G, OR=1.54, p-value = 1.61E-08). Functional analysis showed that rs74989671 resided in a peak of H3K36me3 derived from CD14+ monocytes and H3K4me1 from T-lymphocytes. In addition, we showed that the PRS model trained from the Chinese population could be applied in individuals of Thai ancestry, with the area under the receiver-operator curve (AUC) achieving 0.76 for this predictor.Conclusions: We demonstrated the genetic architecture of SLE in the Thai population and identified a novel locus associated with SLE. Also, our study suggested a potential use of the PRS model from Chinese population to estimate the disease risk for individuals of Thai ancestry.

Download Full-text

Genetic variation in RCOR1 is associated with tinnitus in UK Biobank

10.1101/2020.09.11.20192583 ◽

2020 ◽

Author(s):

Helena Rose Rees Wells ◽

Fatin N Zainul Abidin ◽

Maxim Freydin ◽

Frances MK Williams ◽

Sally J Dawson

Keyword(s):

Molecular Mechanisms ◽

Genome Wide Association Study ◽

Uk Biobank ◽

Genetic Studies ◽

Significance Threshold ◽

Genome Wide ◽

Neuronal Gene ◽

Close Proximity ◽

Repressor Complex ◽

Genome Wide Significance

Tinnitus is a prevalent condition in which perception of sound occurs without an external stimulus. It is often associated with pre-existing hearing loss or noise-induced damage to the auditory system. In some individuals it occurs frequently or even continuously and leads to considerable distress and difficulty sleeping. There is little knowledge of the molecular mechanisms involved in tinnitus which has hindered the development of treatments. Evidence suggests that tinnitus has a heritable component although previous genetic studies have not established specific risk factors. We performed a case-control genome-wide association study for self-reported tinnitus in 172,608 UK Biobank volunteers. Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p=1.7E-08), rs4900545 (p=1.8E-08) and 14:103042287_CT_C (p=3.50E-08). RCOR1 encodes REST Corepressor 1, a component of a co-repressor complex involved in repressing neuronal gene expression in non-neuronal cells. Eleven other independent genetic loci reached a suggestive significance threshold of p<1E-06.

Download Full-text

Revisiting the genome-wide significance threshold for common variant GWAS

G3 Genes|Genome|Genetics ◽

10.1093/g3journal/jkaa056 ◽

2021 ◽

Vol 11 (2) ◽

Author(s):

Zhongsheng Chen ◽

Michael Boehnke ◽

Xiaoquan Wen ◽

Bhramar Mukherjee

Keyword(s):

False Positive ◽

Multiple Testing ◽

Meta Analysis ◽

False Positive Rate ◽

P Value ◽

Sample Sizes ◽

Replication Studies ◽

Significance Threshold ◽

Genome Wide ◽

Genome Wide Significance

Abstract Over the last decade, GWAS meta-analyses have used a strict P-value threshold of 5 × 10−8 to classify associations as significant. Here, we use our current understanding of frequently studied traits including lipid levels, height, and BMI to revisit this genome-wide significance threshold. We compare the performance of studies using the P = 5 × 10−8 threshold in terms of true and false positive rate to other multiple testing strategies: (1) less stringent P-value thresholds, (2) controlling the FDR with the Benjamini–Hochberg and Benjamini–Yekutieli procedure, and (3) controlling the Bayesian FDR with posterior probabilities. We applied these procedures to re-analyze results from the Global Lipids and GIANT GWAS meta-analysis consortia and supported them with extensive simulation that mimics the empirical data. We observe in simulated studies with sample sizes ∼20,000 and >120,000 that relaxing the P-value threshold to 5 × 10−7 increased discovery at the cost of 18% and 8% of additional loci being false positive results, respectively. FDR and Bayesian FDR are well controlled for both sample sizes with a few exceptions that disappear under a less stringent definition of true positives and the two approaches yield similar results. Our work quantifies the value of using a relaxed P-value threshold in large studies to increase their true positive discovery but also show the excess false positive rates due to such actions in modest-sized studies. These results may guide investigators considering different thresholds in replication studies and downstream work such as gene-set enrichment or pathway analysis. Finally, we demonstrate the viability of FDR-controlling procedures in GWAS.

Download Full-text

Association of the RPA3-UMAD1 locus with interstitial lung diseases complicated with rheumatoid arthritis in Japanese

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-217256 ◽

2020 ◽

Vol 79 (10) ◽

pp. 1305-1309

Author(s):

Yuya Shirai ◽

Suguru Honda ◽

Katsunori Ikari ◽

Masahiro Kanai ◽

Yoshito Takeda ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Genome Wide Association Study ◽

Risk Allele ◽

Meta Analysis ◽

Interstitial Lung Diseases ◽

Ct Image ◽

Significance Threshold ◽

Genome Wide ◽

Stratified Analysis ◽

Image Pattern

ObjectivesThe genetic background of rheumatoid arthritis–interstitial lung disease (RA-ILD) has been evaluated in Europeans, but little knowledge has been obtained in non-Europeans. This study aimed to elucidate genome-wide risk of RA-ILD in non-Europeans.MethodsWe performed an initial genome-wide association study (GWAS) of RA-ILD in the Japanese population. By conducting the meta-analysis of the three GWAS datasets of the RA cohorts and biobank of Japanese, our study included 358 RA-ILD cases and 4550 RA subjects without ILD. We then conducted the stratified analysis of the effect of the GWAS risk allele in each CT image pattern.ResultsWe identified one novel RA-ILD risk locus at 7p21 that satisfied the genome-wide significance threshold (rs12702634 at RPA3-UMAD1, OR=2.04, 95% CI 1.59 to 2.60, p=1.5×10−8). Subsequent stratified analysis based on the CT image patterns demonstrated that the effect size of the RA-ILD risk allele (rs12702634-C) was large with the UIP pattern (OR=1.86, 95% CI 0.97 to 3.58, p=0.062) and the probable UIP pattern (OR=2.26, 95% CI 1.36 to 3.73, p=0.0015).ConclusionWe revealed one novel genetic association with RA-ILD in Japanese. The RA-ILD risk of the identified variant at RPA3-UMAD1 was relatively high in the CT image patterns related to fibrosis. Our study should contribute to elucidation of the complicated aetiology of RA-ILD.

Download Full-text

Meta-analysis of genome-wide association study identifies FBN2 as a novel locus associated with Systemic Lupus Erythematosus in Thai population

10.21203/rs.3.rs-33445/v2 ◽

2020 ◽

Author(s):

Pattarin Tangtanatakul ◽

Chisanu Thumarat ◽

Nusara Satproedprai ◽

Punna Kunhapan ◽

Tassamonwan Chaiyasung ◽

...

Keyword(s):

Lupus Erythematosus ◽

Chinese Population ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Disease Risk ◽

Meta Analysis ◽

Genome Wide Association ◽

Systemic Lupus ◽

Thai Population ◽

Genome Wide

Abstract Background: Differences in the expression of variants across ethnic groups in the Systemic Lupus Erythematosus (SLE) patients have been well documented. However, the genetic architecture in the Thai population has not been thoroughly examined. In this study, we carried out genome-wide association study (GWAS) in the Thai population. Methods: Two GWAS cohorts were independently collected and genotyped: discovery dataset (487 SLE cases and 1,606 healthy controls) and replication dataset (405 SLE cases and 1,590 unrelated-disease controls). Data were imputed to the density of the 1,000 Genomes Project Phase 3. Association studies were performed based on different genetic models, and pathway enrichment analysis was further examined. In addition, the performance of disease risk estimation for individuals in Thai GWAS was assessed based on the polygenic risk score (PRS) model trained by other Asian populations. Results: Previous findings on SLE susceptible alleles were well replicated in the two GWAS. The SNPs on HLA-class II (rs9270970, A>G, OR=1.82, p-value = 3.61E-26), STAT4 (rs7582694, C>G, OR=1.57, p-value = 8.21E-16), GTF2I (rs73366469, A>G, OR=1.73, p-value = 2.42E-11) and FAM167A-BLK allele (rs13277113, A>G, OR=0.68, p-value = 1.58E-09) were significantly associated with SLE in Thai population. Meta-analysis of the two GWAS identified a novel locus at the FBN2 that was specifically associated with SLE in the Thai population (rs74989671, A>G, OR=1.54, p-value = 1.61E-08). Functional analysis showed that rs74989671 resided in a peak of H3K36me3 derived from CD14+ monocytes and H3K4me1 from T-lymphocytes. In addition, we showed that the PRS model trained from the Chinese population could be applied in individuals of Thai ancestry, with the area under the receiver-operator curve (AUC) achieving 0.76 for this predictor. Conclusions: We demonstrated the genetic architecture of SLE in the Thai population and identified a novel locus associated with SLE. Also, our study suggested a potential use of the PRS model from the Chinese population to estimate the disease risk for individuals of Thai ancestry.

Download Full-text

Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis

PLoS ONE ◽

10.1371/journal.pone.0053830 ◽

2013 ◽

Vol 8 (1) ◽

pp. e53830 ◽

Cited By ~ 66

Author(s):

Elizabeth G. Holliday ◽

Albert V. Smith ◽

Belinda K. Cornes ◽

Gabriëlle H. S. Buitendijk ◽

Richard A. Jensen ◽

...

Keyword(s):

Association Study ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Early Stage ◽

Meta Analysis ◽

Age Related Macular Degeneration ◽

Genome Wide Association ◽

Age Related ◽

Genome Wide ◽

A Genome

Download Full-text

Myasthenia gravis genome-wide association study implicates AGRN as a risk locus

Journal of Medical Genetics ◽

10.1136/jmedgenet-2021-107953 ◽

2021 ◽

pp. jmedgenet-2021-107953

Author(s):

Apostolia Topaloudi ◽

Zoi Zagoriti ◽

Alyssa Camille Flint ◽

Melanie Belle Martinez ◽

Zhiyu Yang ◽

...

Keyword(s):

Myasthenia Gravis ◽

Association Study ◽

Fine Mapping ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Late Onset ◽

Meta Analysis ◽

Susceptibility Gene ◽

Genome Wide Association ◽

Genome Wide

BackgroundMyasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date.MethodsWe performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders.ResultsWe confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10−13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders.DiscussionOur gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms.

Download Full-text

Genetic risk of clozapine-induced leukopenia and neutropenia: a genome-wide association study

Translational Psychiatry ◽

10.1038/s41398-021-01470-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jianhua Chen ◽

Ping Yang ◽

Qian Zhang ◽

Ruirui Chen ◽

Peng Wang ◽

...

Keyword(s):

Association Study ◽

Molecular Mechanisms ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Significance Level ◽

Genome Wide ◽

A Genome ◽

Genome Wide Significance

Abstract Background Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). Methods A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). Results The authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10−8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10−8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. Conclusions The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.

Download Full-text