Power, false discovery rate and Winner’s Curse in eQTL studies

Huang, Qin; Ritchie, Scott C.; Brożyńska, Marta; Inouye, Michael

doi:10.1093/nar/gky780

Cited by 104 publications

(100 citation statements)

References 51 publications

(60 reference statements)

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“…We used the hierarchical correction method to call significant eQTLs as previously described [69,70]. Firstly, p values of all cis SNPs are adjusted for multiple testing for each gene using Benjamini and Yekutieli (BY) method [71] as the locally adjusted p values.…”

Section: Eqtl Mapping Using Matrix Eqtlmentioning

confidence: 99%

Discovery of novel hepatocyte eQTLs in African Americans

Zhong

Alarcón

et al. 2020

PLoS Genet

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African Americans (AAs) are disproportionately affected by metabolic diseases and adverse drug events, with limited publicly available genomic and transcriptomic data to advance the knowledge of the molecular underpinnings or genetic associations to these diseases or drug response phenotypes. To fill this gap, we obtained 60 primary hepatocyte cultures from AA liver donors for genome-wide mapping of expression quantitative trait loci (eQTL) using LAMatrix. We identified 277 eGenes and 19,770 eQTLs, of which 67 eGenes and 7,415 eQTLs are not observed in the Genotype-Tissue Expression Project (GTEx) liver eQTL analysis. Of the eGenes found in GTEx only 25 share the same lead eQTL. These AA-specific eQTLs are less correlated to GTEx eQTLs. in effect sizes and have larger Fst values compared to eQTLs found in both cohorts (overlapping eQTLs). We assessed the overlap between GWAS variants and their tagging variants with AA hepatocyte eQTLs and demonstrated that AA hepatocyte eQTLs can decrease the number of potential causal variants at GWAS loci. Additionally, we identified 75,002 exon QTLs of which 48.8% are not eQTLs in AA hepatocytes. Our analysis provides the first comprehensive characterization of AA hepatocyte eQTLs and highlights the unique discoveries that are made possible due to the increased genetic diversity within the African ancestry genome.

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Section: Eqtl Mapping Using Matrix Eqtlmentioning

confidence: 99%

Discovery of novel hepatocyte eQTLs in African Americans

Zhong

Alarcón

et al. 2020

PLoS Genet

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“…This method was demonstrated to produce a lower FDR and greater true positive rate than the method that applies correction over all association tests. 37 We first used the Benjamini and Yekutieli (BY) procedure 38 to adjust p values for all association tests by each gene. We then pooled the minimum BY-adjusted p value of every tested gene to obtain its best associations.…”

Section: Cis-eqtl Mapping In Nigms and Gtexmentioning

confidence: 99%

On Using Local Ancestry to Characterize the Genetic Architecture of Human Traits: Genetic Regulation of Gene Expression in Multiethnic or Admixed Populations

Zhong

Perera

Gamazon

2019

The American Journal of Human Genetics

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Understanding the nature of the genetic regulation of gene expression promises to advance our understanding of the genetic basis of disease. However, the methodological impact of the use of local ancestry on high-dimensional omics analyses, including, most prominently, expression quantitative trait loci (eQTL) mapping and trait heritability estimation, in admixed populations remains critically underexplored. Here, we develop a statistical framework that characterizes the relationships among the determinants of the genetic architecture of an important class of molecular traits. We provide a computationally efficient approach to local ancestry analysis in eQTL mapping while increasing control of type I and type II error over traditional approaches. Applying our method to National Institute of General Medical Sciences (NIGMS) and Genotype-Tissue Expression (GTEx) datasets, we show that the use of local ancestry can improve eQTL mapping in admixed and multiethnic populations, respectively. We estimate the trait variance explained by ancestry by using local admixture relatedness between individuals. By using simulations of diverse genetic architectures and degrees of confounding, we show improved accuracy in estimating heritability when accounting for local ancestry similarity. Furthermore, we characterize the sparse versus polygenic components of gene expression in admixed individuals. Our study has important methodological implications for genetic analysis of omics traits across a range of genomic contexts, from a single variant to a prioritized region to the entire genome. Our findings highlight the importance of using local ancestry to better characterize the heritability of complex traits and to more accurately map genetic associations.

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“…Third, cis-pQTLs in linkage equilibrium that did not meet the trans-pQTL significance threshold in Sun et al were identified in a step-forward procedure. To identify additional cis-pQTLs we applied a hierarchical multiple testing correction procedure that has been shown to control the false discovery rate at 5% in expression quantitative trait loci (eQTL) studies 72,73 to the pQTL summary statistics from Sun et al 2018 15 . For each aptamer, P-values within each 1MB of any gene encoding the targeted protein or protein complex were first Bonferroni corrected for the number of tests within that cis window(s) to obtain locally corrected P-values.…”

Section: Mendelian Randomisation Analysesmentioning

confidence: 99%

Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases

Ritchie

Liu

Teo

et al. 2019

Preprint

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Polygenic risk scores (PRSs) capture the polygenic architecture of common diseases by aggregating genome-wide genetic variation into a single score that reflects individual's disease risk, affording a new opportunity to identify downstream molecular pathways involved in disease pathogenesis. We performed an integrative analysis to characterise associations of PRSs of five cardiometabolic diseases with 3,442 plasma proteins in 3,175 healthy individuals. Through polygenic association scans we identified 48 plasma proteins whose levels were associated with PRSs for coronary artery disease (CAD), chronic kidney disease (CKD), or type 2 diabetes (T2D). This approach identified both well-known disease-associated proteins as well as those with previously no known link to these diseases. We found that PRSs to protein associations were largely truly polygenic; independent of single loci and genomic regions expected to have strong effects on protein levels. Our integrative analysis and laboratory experiments revealed a role for polygenic effects on several well-known disease proteins and identified several promising novel targets for follow-up studies, including genes which through Mendelian randomization analysis displayed causal evidence for effects on disease risk. Mouse studies highlighted specific tissues and phenotypes for PRSassociated human proteins. We found that implicated genes were responsive to dietary intervention in mice and showed strong evidence of druggability in humans, consistent with PRS-associated proteins having therapeutic potential. Overall, our study provides a framework for polygenic association studies, and demonstrates the power of polygenic scores to unravel novel disease biology. Research (NIHR), the NIHR BioResource

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Power, false discovery rate and Winner’s Curse in eQTL studies

Cited by 104 publications

References 51 publications

Discovery of novel hepatocyte eQTLs in African Americans

Discovery of novel hepatocyte eQTLs in African Americans

On Using Local Ancestry to Characterize the Genetic Architecture of Human Traits: Genetic Regulation of Gene Expression in Multiethnic or Admixed Populations

Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases

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