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Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS.

ABSTRACT: Although genome-wide association studies (GWAS) of complex traits have yielded more reproducible associations than had been discovered using any other approach, the loci characterized to date do not account for much of the heritability to such traits and, in general, have not led to improved understanding of the biology underlying complex phenotypes. Using a web site we developed to serve results of expression quantitative trait locus (eQTL) studies in lymphoblastoid cell lines from HapMap samples (http://www.scandb.org), we show that single nucleotide polymorphisms (SNPs) associated with complex traits (from http://www.genome.gov/gwastudies/) are significantly more likely to be eQTLs than minor-allele-frequency-matched SNPs chosen from high-throughput GWAS platforms. These findings are robust across a range of thresholds for establishing eQTLs (p-values from 10(-4)-10(-8)), and a broad spectrum of human complex traits. Analyses of GWAS data from the Wellcome Trust studies confirm that annotating SNPs with a score reflecting the strength of the evidence that the SNP is an eQTL can improve the ability to discover true associations and clarify the nature of the mechanism driving the associations. Our results showing that trait-associated SNPs are more likely to be eQTLs and that application of this information can enhance discovery of trait-associated SNPs for complex phenotypes raise the possibility that we can utilize this information both to increase the heritability explained by identifiable genetic factors and to gain a better understanding of the biology underlying complex traits.

SUBMITTER: Nicolae DL

PROVIDER: S-EPMC2848547 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS.

Nicolae Dan L DL Gamazon Eric E Zhang Wei W Duan Shiwei S Dolan M Eileen ME Cox Nancy J NJ

PLoS genetics 20100401 4

Although genome-wide association studies (GWAS) of complex traits have yielded more reproducible associations than had been discovered using any other approach, the loci characterized to date do not account for much of the heritability to such traits and, in general, have not led to improved understanding of the biology underlying complex phenotypes. Using a web site we developed to serve results of expression quantitative trait locus (eQTL) studies in lymphoblastoid cell lines from HapMap sampl ...[more]

PMID: 20369019

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Project description:Understanding the genetic architecture of beef cattle growth cannot be limited simply to the genome-wide association study (GWAS) for body weight at any specific ages, but should be extended to a more general purpose by considering the whole growth trajectory over time using a growth curve approach. For such an approach, the parameters that are used to describe growth curves were treated as phenotypes under a GWAS model. Data from 1,255 Brahman cattle that were weighed at birth, 6, 12, 15, 18, and 24 months of age were analyzed. Parameter estimates, such as mature weight (A) and maturity rate (K) from nonlinear models are utilized as substitutes for the original body weights for the GWAS analysis. We chose the best nonlinear model to describe the weight-age data, and the estimated parameters were used as phenotypes in a multi-trait GWAS. Our aims were to identify and characterize associated SNP markers to indicate SNP-derived candidate genes and annotate their function as related to growth processes in beef cattle. The Brody model presented the best goodness of fit, and the heritability values for the parameter estimates for mature weight (A) and maturity rate (K) were 0.23 and 0.32, respectively, proving that these traits can be a feasible alternative when the objective is to change the shape of growth curves within genetic improvement programs. The genetic correlation between A and K was -0.84, indicating that animals with lower mature body weights reached that weight at younger ages. One hundred and sixty seven (167) and two hundred and sixty two (262) significant SNPs were associated with A and K, respectively. The annotated genes closest to the most significant SNPs for A had direct biological functions related to muscle development (RAB28), myogenic induction (BTG1), fetal growth (IL2), and body weights (APEX2); K genes were functionally associated with body weight, body height, average daily gain (TMEM18), and skeletal muscle development (SMN1). Candidate genes emerging from this GWAS may inform the search for causative mutations that could underpin genomic breeding for improved growth rates.

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Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS.

Publications

Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS.

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