scholarly journals What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations

2011 ◽  
Vol 41 (1) ◽  
pp. 273-286 ◽  
Author(s):  
Orestis A Panagiotou ◽  
John P A Ioannidis ◽  
Keyword(s):  
Genetic Associations ◽  
Significance Threshold ◽  
Genome Wide ◽  
Genome Wide Significance

scholarly journals Genetic Associations with Subjective Well-Being Also Implicate Depression and Neuroticism

2015 ◽  
Author(s):  
Aysu Okbay ◽  
Bart M. L. Baselmans ◽  
Jan-Emmanuel De Neve ◽  
Patrick Turley ◽  
Michel G. Nivard ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Genome Wide Association Study ◽  
Well Being ◽  
Genome Wide Association ◽  
Subjective Well Being ◽  
Genetic Associations ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

We conducted a genome-wide association study of subjective well-being (SWB) in 298,420 individuals. We also performed auxiliary analyses of depressive symptoms ("DS";N= 161,460) and neuroticism (N= 170,910), both of which have a substantial genetic correlation with SWB (ρ≈-0.8). We identify three SNPs associated with SWB at genome-wide significance. Two of them are significantly associated with DS in an independent sample. In our auxiliary analyses, we identify 13 additional genome-wide-significant associations: two with DS and eleven with neuroticism, including two inversion polymorphisms. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are enriched. The discovery of genetic loci associated with the three phenotypes we study has proven elusive; our findings illustrate the payoffs from studying them jointly.

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

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.

scholarly journals Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

2021 ◽  
Vol 11 (11) ◽  
pp. 1233
Author(s):  
Zulfan Zazuli ◽  
Corine de de Jong ◽  
Wei Xu ◽  
Susanne J. H. Vijverberg ◽  
Rosalinde Masereeuw ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Genetic Risk ◽  
Validation Cohort ◽  
Genotype Imputation ◽  
Candidate Gene Approach ◽  
Genetic Associations ◽  
Discovery Cohort ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

scholarly journals Genetic variation in RCOR1 is associated with tinnitus in UK Biobank

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.

scholarly journals Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255402
Author(s):  
Irene V. van Blokland ◽  
Pauline Lanting ◽  
Anil P. S. Ori ◽  
Judith M. Vonk ◽  
Robert C. A. Warmerdam ◽  
...  
Keyword(s):  
Prediction Model ◽  
Genetic Associations ◽  
Cross Sectional ◽  
Genetic Studies ◽  
Genome Wide ◽  
Host Genetic ◽  
Consistent Performance ◽  
Testing Policies ◽  
Genome Wide Significance ◽  
Limited Testing

Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict COVID-19 cases using cross-sectional self-reported disease-related symptoms. Here, we demonstrate that this COVID-19 prediction model has reasonable and consistent performance across multiple independent cohorts and that our attempt to improve upon this model did not result in improved predictions. Using the existing COVID-19 prediction model, we then conducted a GWAS on the predicted phenotype using a total of 1,865 predicted cases and 29,174 controls. While we did not find any common, large-effect variants that reached genome-wide significance, we do observe suggestive genetic associations at two SNPs (rs11844522, p = 1.9x10-7; rs5798227, p = 2.2x10-7). Explorative analyses furthermore suggest that genetic variants associated with other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. This study represents a first effort that uses a symptom-based predicted phenotype as a proxy for COVID-19 in our pursuit of understanding the genetic susceptibility of the disease. We conclude that the inclusion of symptom-based predicted cases could be a useful strategy in a scenario of limited testing, either during the current COVID-19 pandemic or any future viral outbreak.

scholarly journals Revisiting the genome-wide significance threshold for common variant GWAS

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 &gt;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.

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

2021 ◽  
Author(s):  
Yuriko N. Koyanagi ◽  
Masahiro Nakatochi ◽  
Hidemi Ito ◽  
Yumiko Kasugai ◽  
Akira Narita ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Genetic Architecture ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Dependent Manner ◽  
Wild Type ◽  
Genetic Characteristics ◽  
Significance Threshold ◽  
Genome Wide ◽  
Genome Wide Significance

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.

scholarly journals Genome-Wide Analysis of Sex Disparities in the Genetic Architecture of Lung and Colorectal Cancers

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 686
Author(s):  
Alireza Nazarian ◽  
Alexander M. Kulminski
Keyword(s):  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Significance Level ◽  
Association Analyses ◽  
Complex Disorders ◽  
Specific Effects ◽  
Genome Wide ◽  
Genetic Mechanisms ◽  
Sex Disparities ◽  
Almost All

Almost all complex disorders have manifested epidemiological and clinical sex disparities which might partially arise from sex-specific genetic mechanisms. Addressing such differences can be important from a precision medicine perspective which aims to make medical interventions more personalized and effective. We investigated sex-specific genetic associations with colorectal (CRCa) and lung (LCa) cancers using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent datasets. The genome-wide association analyses revealed that 33 SNPs were associated with CRCa/LCa at P < 5.0 × 10−6 neither males or females. Of these, 26 SNPs had sex-specific effects as their effect sizes were statistically different between the two sexes at a Bonferroni-adjusted significance level of 0.0015. None had proxy SNPs within their ±1 Mb regions and the closest genes to 32 SNPs were not previously associated with the corresponding cancers. The pathway enrichment analyses demonstrated the associations of 35 pathways with CRCa or LCa which were mostly implicated in immune system responses, cell cycle, and chromosome stability. The significant pathways were mostly enriched in either males or females. Our findings provided novel insights into the potential sex-specific genetic heterogeneity of CRCa and LCa at SNP and pathway levels.

scholarly journals Genome-wide association study suggests that variation at the RCOR1 locus is associated with tinnitus in UK Biobank

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Helena R. R. Wells ◽  
Fatin N. Zainul Abidin ◽  
Maxim B. Freidin ◽  
Frances M. K. Williams ◽  
Sally J. Dawson
Keyword(s):  
Association Study ◽  
Molecular Mechanisms ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Significance Threshold ◽  
Genome Wide ◽  
Final Sample ◽  
Close Proximity ◽  
Repressor Complex

AbstractTinnitus 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. From a total of 172,608 UK Biobank participants who answered questions on tinnitus we performed a case–control genome-wide association study for self-reported tinnitus. Final sample size used in association analysis was N = 91,424. 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.

scholarly journals Genome-wide association analysis of metabolic syndrome quantitative traits in the GENNID multiethnic family study

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jia Y. Wan ◽  
Deborah L. Goodman ◽  
Emileigh L. Willems ◽  
Alexis R. Freedland ◽  
Trina M. Norden-Krichmar ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Family Study ◽  
Genome Wide Association ◽  
European American ◽  
Japanese American ◽  
Genetic Associations ◽  
Chromosome 11 ◽  
Genome Wide ◽  
American Families

Abstract Background To identify genetic associations of quantitative metabolic syndrome (MetS) traits and characterize heterogeneity across ethnic groups. Methods Data was collected from GENetics of Noninsulin dependent Diabetes Mellitus (GENNID), a multiethnic resource of Type 2 diabetic families and included 1520 subjects in 259 African-American, European-American, Japanese-Americans, and Mexican-American families. We focused on eight MetS traits: weight, waist circumference, systolic and diastolic blood pressure, high-density lipoprotein, triglycerides, fasting glucose, and insulin. Using genotyped and imputed data from Illumina’s Multiethnic array, we conducted genome-wide association analyses with linear mixed models for all ethnicities, except for the smaller Japanese-American group, where we used additive genetic models with gene-dropping. Results Findings included ethnic-specific genetic associations and heterogeneity across ethnicities. Most significant associations were outside our candidate linkage regions and were coincident within a gene or intergenic region, with two exceptions in European-American families: (a) within previously identified linkage region on chromosome 2, two significant GLI2-TFCP2L1 associations with weight, and (b) one chromosome 11 variant near CADM1-LINC00900 with pleiotropic blood pressure effects. Conclusions This multiethnic family study found genetic heterogeneity and coincident associations (with one case of pleiotropy), highlighting the importance of including diverse populations in genetic research and illustrating the complex genetic architecture underlying MetS.

Sign in / Sign up

Export Citation Format

Share Document