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Explicating heterogeneity of complex traits has strong potential for improving GWAS efficiency.

ABSTRACT: Common strategy of genome-wide association studies (GWAS) relying on large samples faces difficulties, which raise concerns that GWAS have exhausted their potential, particularly for complex traits. Here, we examine the efficiency of the traditional sample-size-centered strategy in GWAS of these traits, and its potential for improvement. The paper focuses on the results of the four largest GWAS meta-analyses of body mass index (BMI) and lipids. We show that just increasing sample size may not make p-values of genetic effects in large (N?>?100,000) samples smaller but can make them larger. The efficiency of these GWAS, defined as ratio of the log-transformed p-value to the sample size, in larger samples was larger than in smaller samples for a small fraction of loci. These results emphasize the important role of heterogeneity in genetic associations with complex traits such as BMI and lipids. They highlight the substantial potential for improving GWAS by explicating this role (affecting 11-79% of loci in the selected GWAS), especially the effects of biodemographic processes, which are heavily underexplored in current GWAS and which are important sources of heterogeneity in the various study populations. Further progress in this direction is crucial for efficient use of genetic discoveries in health care.

SUBMITTER: Kulminski AM

PROVIDER: S-EPMC5064392 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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Explicating heterogeneity of complex traits has strong potential for improving GWAS efficiency.

Kulminski Alexander M AM Loika Yury Y Culminskaya Irina I Arbeev Konstantin G KG Ukraintseva Svetlana V SV Stallard Eric E Yashin Anatoliy I AI

Scientific reports 20161014

Common strategy of genome-wide association studies (GWAS) relying on large samples faces difficulties, which raise concerns that GWAS have exhausted their potential, particularly for complex traits. Here, we examine the efficiency of the traditional sample-size-centered strategy in GWAS of these traits, and its potential for improvement. The paper focuses on the results of the four largest GWAS meta-analyses of body mass index (BMI) and lipids. We show that just increasing sample size may not ma ...[more]

PMID: 27739495

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Project description:Aeromonas sobria is a mesophilic motile aeromonad currently depicted as an opportunistic pathogen, despite increasing evidence of mutualistic interactions in salmonid fish. However, the determinants of its host-microbe associations, either mutualistic or pathogenic, remain less understood than for other aeromonad species. On one side, there is an over-representation of pathogenic interactions in the A. sobria literature, of which only three articles to date report mutualistic interactions; on the other side, genomic characterization of this species is still fairly incomplete as only two draft genomes were published prior to the present work. Consequently, no study specifically investigated the biodiversity of A. sobria. In fact, the investigation of A. sobria as a species complex may have been clouded by: (i) confusion with A. veronii biovar sobria because of their similar biochemical profiles, and (ii) the intrinsic low resolution of previous studies based on 16S rRNA gene sequences and multilocus sequence typing. So far, the only high-resolution, phylogenomic studies of the genus Aeromonas included one A. sobria strain (CECT 4245 / Popoff 208), making it impossible to robustly conclude on the phylogenetic intra-species diversity and the positioning among other Aeromonas species. To further understand the biodiversity and the spectrum of host-microbe interactions in A. sobria as well as its potential genomic diversity, we assessed the genomic and phenotypic heterogeneity among five A. sobria strains: two clinical isolates recovered from infected fish (JF2635 and CECT 4245), one from an infected amphibian (08005) and two recently isolated brook charr probionts (TM12 and TM18) which inhibit in vitro growth of A. salmonicida subsp. salmonicida (a salmonid fish pathogen). A phylogenomic assessment including 2,154 softcore genes corresponding to 946,687 variable sites from 33 Aeromonas genomes confirms the status of A. sobria as a distinct species divided in two subclades, with 100% bootstrap support. The phylogenomic split of A. sobria in two subclades is corroborated by a deep dichotomy between all five A. sobria strains in terms of inhibitory effect against A. salmonicida subsp. salmonicida, gene contents and codon usage. Finally, the antagonistic effect of A. sobria strains TM12 and TM18 suggests novel control methods against A. salmonicida subsp. salmonicida.

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Explicating heterogeneity of complex traits has strong potential for improving GWAS efficiency.

Publications

Explicating heterogeneity of complex traits has strong potential for improving GWAS efficiency.

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