HapBoost: A Fast Approach to Boosting Haplotype Association Analyses in Genome-Wide Association Studies

AbstractGenome-wide association studies (GWAS) have now been conducted for hundreds of phenotypes of relevance to human health. Many such GWAS involve multiple closely-related phenotypes collected on the same samples. However, the vast majority of these GWAS have been analyzed using simple univariate analyses, which consider one phenotype at a time. This is de-spite the fact that, at least in simulation experiments, multivariate analyses have been shown to be more powerful at detecting associations. Here, we conduct multivariate association analyses on 13 different publicly-available GWAS datasets that involve multiple closely-related phenotypes. These data include large studies of anthropometric traits (GIANT), plasma lipid traits (GlobalLipids), and red blood cell traits (HaemgenRBC). Our analyses identify many new associations (433 in total across the 13 studies), many of which replicate when follow-up samples are available. Overall, our results demonstrate that multivariate analyses can help make more effective use of data from both existing and future GWAS.1Author SummaryGenome-wide association studies (GWAS) have become a common and powerful tool for identifying significant correlations between markers of genetic variation and physical traits of interest. Often these studies are conducted by comparing genetic variation against single traits one at a time (‘univariate’); however, it has previously been shown that it is possible to increase your power to detect significant associations by comparing genetic variation against multiple traits simultaneously (‘multivariate’). Despite this apparent increase in power though, researchers still rarely conduct multivariate GWAS, even when studies have multiple traits readily available. Here, we reanalyze 13 previously published GWAS using a multivariate method and find >400 additional associations. Our method makes use of univariate GWAS summary statistics and is available as a software package, thus making it accessible to other researchers interested in conducting the same analyses. We also show, using studies that have multiple releases, that our new associations have high rates of replication. Overall, we argue multivariate approaches in GWAS should no longer be overlooked and how, often, there is low-hanging fruit in the form of new associations by running these methods on data already collected.

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Genome-wide association analyses in >119,000 individuals identifies thirteen morningness and two sleep duration loci

10.1101/031369 ◽

2016 ◽

Cited By ~ 4

Author(s):

Samuel E Jones ◽

Jessica Tyrrell ◽

Andrew R Wood ◽

Robin N Beaumont ◽

Katherine S Ruth ◽

...

Keyword(s):

Type 2 Diabetes ◽

Circadian Rhythms ◽

Sleep Duration ◽

Association Studies ◽

Genome Wide Association ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Association Analyses ◽

Genome Wide

Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but little is known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 White British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness [95%CI 1.15, 1.27], P=3x10-12) and PER2 (1.09 odds of morningness [95%CI 1.06, 1.12], P=4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self-reported data from 89,823 23andMe participants; thirteen of the chronotype signals remained significant at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. For sleep duration, we replicated one known signal in PAX8 (2.6 [95%CIs 1.9, 3.2] minutes per allele P=5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 [95% CI: 1.3, 2.7] minutes per allele, P=1.2x10-9; and 1.6 [95% CI: 1.1, 2.2] minutes per allele, P=7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG=0.056, P=0.048); undersleeping and BMI (rG=0.147, P=1x10-5) and oversleeping and BMI (rG=0.097, P=0.039), Mendelian Randomisation analyses provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study provides new insights into the biology of sleep and circadian rhythms in humans.

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A Genome Wide Association Study Identifies Novel Susceptibility Genes for Pediatric Venous Thrombosis,

Blood ◽

10.1182/blood.v118.21.3336.3336 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3336-3336 ◽

Cited By ~ 1

Author(s):

Astrid Arning ◽

Milan Hiersche ◽

Christoph Bidlingmaier ◽

Monika Stoll ◽

Ulrike Nowak-Gottl

Keyword(s):

Venous Thrombosis ◽

Association Studies ◽

Snp Array ◽

Independent Study ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Permutation Testing ◽

Haplotype Association ◽

Genome Wide ◽

A Genome

Abstract Abstract 3336 Background: Genome wide association studies (GWAS) are the current method of choice to dissect the genetic basis of common complex diseases. Up-to-date, studies in families with a known first onset of symptomatic arterial or venous thrombosis (VT) in early childhood are lacking. Methods: Here, we performed a GWAS in a large family-based study sample comprising 241 nuclear families with pediatric VT using the Illumina 660W Infinium SNP array. The average genotype call rate was >99.5%, and the genomic inflation factor was a= 1.012. Single point and haplotype association was assessed using the Transmission Disequilibrium Test (TDT) as implemented in PLINK and FBAT, respectively, and corrected for multiple testing using permutation testing. In addition, associations were corrected for age, gender, and in a subsequent analysis for Factor VLeiden. Results and Conclusion: Four SNPs exceeded the threshold for genome wide significance in this dataset as determined by permutation testing using 100.000 bootstrap permutations (p<10−5), and are likely true associations. Among these, 2 SNPs reside in a region on chromosome 6q13 comprising the gene for beta-1,3-glucoronyltransferase 2 (B3GAT2), a member of the human natural killer 1 (HNK1) carbohydrate pathway are associated with pediatric VT with p-values for rs1304029 (p=3.42×10−6) and rs2748331 (p=6.92×10−6). The corresponding haplotype association test resulted in a p=5.37×10−6 for the GA-haplotype, further underlining the robustness of the association. The SNPs rs636434 on chromosome 6q12 and rs1565242 on chromosome 15 both reside within hypothetical genes and are associated with VT with a p=2.70×10−6 and p=8.24×10−6, respectively. Additional SNPs exceeding a p<10−5 are included in subsequent analyses looking at gene networks and replication in independent study samples including our second GWAS on pediatric thromboembolic stroke (TS). Future studies using larger study samples are warranted to validate these findings and to characterize the genetic architecture underlying VT and TS in children. Disclosures: No relevant conflicts of interest to declare.

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A genome-wide association study for gut metagenome in Chinese adults illuminates complex diseases

Cell Discovery ◽

10.1038/s41421-020-00239-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Xiaomin Liu ◽

Shanmei Tang ◽

Huanzi Zhong ◽

Xin Tong ◽

Zhuye Jie ◽

...

Keyword(s):

Gut Microbiome ◽

Genome Wide Association Study ◽

Association Studies ◽

Copy Number Variations ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Association Analyses ◽

Genome Wide ◽

A Genome

AbstractThe gut microbiome has been established as a key environmental factor to health. Genetic influences on the gut microbiome have been reported, yet, doubts remain as to the significance of genetic associations. Here, we provide shotgun data for whole genome and whole metagenome from a Chinese cohort, identifying no <20% genetic contribution to the gut microbiota. Using common variants-, rare variants-, and copy number variations-based association analyses, we identified abundant signals associated with the gut microbiome especially in metabolic, neurological, and immunological functions. The controversial concept of enterotypes may have a genetic attribute, with the top two loci explaining 11% of the Prevotella–Bacteroides variances. Stratification according to gender led to the identification of differential associations in males and females. Our two-stage metagenome genome-wide association studies on a total of 1295 individuals unequivocally illustrates that neither microbiome nor GWAS studies could overlook one another in our quest for a better understanding of human health and diseases.

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Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences1

10.1101/261081 ◽

2018 ◽

Cited By ~ 1

Author(s):

Richard Karlsson Linnér ◽

Pietro Biroli ◽

Edward Kong ◽

S Fleur W Meddens ◽

Robbee Wedow ◽

...

Keyword(s):

Association Studies ◽

Risky Behaviors ◽

Risk Tolerance ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Bioinformatics Analyses ◽

Association Analyses ◽

Gabaergic Neurotransmission ◽

Genome Wide ◽

Shared Genetic

AbstractHumans vary substantially in their willingness to take risks. In a combined sample of over one million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. We identified 611 approximately independent genetic loci associated with at least one of our phenotypes, including 124 with general risk tolerance. We report evidence of substantial shared genetic influences across general risk tolerance and risky behaviors: 72 of the 124 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is moderately to strongly genetically correlated ( to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near general-risk-tolerance-associated SNPs are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We find no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.

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Glycosaminoglycan biosynthesis pathway in host genome is associated with Helicobacter pylori infection

Scientific Reports ◽

10.1038/s41598-021-97790-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Dingxue Hu ◽

Yueqi Lu ◽

Daoming Wang ◽

Chao Nie ◽

Yan Li

Keyword(s):

Helicobacter Pylori ◽

Chinese Population ◽

Association Studies ◽

Host Susceptibility ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Gastric Diseases ◽

Association Analyses ◽

Genome Wide ◽

H Pylori

AbstractHelicobacter pylori is a causative pathogen of many gastric and extra-gastric diseases. It has infected about half of the global population. There were no genome-wide association studies (GWAS) for H. pylori infection conducted in Chinese population, who carried different and relatively homogenous strain of H. pylori. In this work, we performed SNP (single nucleotide polymorphism)-based, gene-based and pathway-based genome-wide association analyses to investigate the genetic basis of host susceptibility to H. pylori infection in 480 Chinese individuals. We also profiled the composition and function of the gut microbiota between H. pylori infection cases and controls. We found several genes and pathways associated with H. pylori infection (P < 0.05), replicated one previously reported SNP rs10004195 in TLR1 gene region (P = 0.02). We also found that glycosaminoglycan biosynthesis related pathway was associated with both onset and progression of H. pylori infection. In the gut microbiome association study, we identified 2 species, 3 genera and several pathways had differential abundance between H. pylori infected cases and controls. This paper is the first GWAS for H. pylori infection in Chinese population, and we combined the genetic and microbial data to comprehensively discuss the basis of host susceptibility to H. pylori infection.

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Multi-ethnic genome-wide association analyses of white blood cell and platelet traits in the Population Architecture using Genomics and Epidemiology (PAGE) study

BMC Genomics ◽

10.1186/s12864-021-07745-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yao Hu ◽

Stephanie A. Bien ◽

Katherine K. Nishimura ◽

Jeffrey Haessler ◽

Chani J. Hodonsky ◽

...

Keyword(s):

Blood Cell ◽

White Blood Cell ◽

Complex Traits ◽

Association Studies ◽

Genetic Association Studies ◽

Genome Wide Association ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Association Analyses ◽

Genome Wide

Abstract Background Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. Results We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations. Conclusions Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.

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