Re-sequencing expands our understanding of the phenotypic impact of variants at GWAS loci.

PLoS Genet
Authors
Keywords
Abstract

Genome-wide association studies (GWAS) have identified >500 common variants associated with quantitative metabolic traits, but in aggregate such variants explain at most 20-30% of the heritable component of population variation in these traits. To further investigate the impact of genotypic variation on metabolic traits, we conducted re-sequencing studies in >6,000 members of a Finnish population cohort (The Northern Finland Birth Cohort of 1966 [NFBC]) and a type 2 diabetes case-control sample (The Finland-United States Investigation of NIDDM Genetics [FUSION] study). By sequencing the coding sequence and 5' and 3' untranslated regions of 78 genes at 17 GWAS loci associated with one or more of six metabolic traits (serum levels of fasting HDL-C, LDL-C, total cholesterol, triglycerides, plasma glucose, and insulin), and conducting both single-variant and gene-level association tests, we obtained a more complete understanding of phenotype-genotype associations at eight of these loci. At all eight of these loci, the identification of new associations provides significant evidence for multiple genetic signals to one or more phenotypes, and at two loci, in the genes ABCA1 and CETP, we found significant gene-level evidence of association to non-synonymous variants with MAF

Year of Publication
2014
Journal
PLoS Genet
Volume
10
Issue
1
Pages
e1004147
Date Published
2014 Jan
ISSN
1553-7404
URL
DOI
10.1371/journal.pgen.1004147
PubMed ID
24497850
PubMed Central ID
PMC3907339
Links
Grant list
G0801056 / Medical Research Council / United Kingdom
HL087679 / HL / NHLBI NIH HHS / United States
G0500539 / Medical Research Council / United Kingdom
U54HG003079 / HG / NHGRI NIH HHS / United States
HG006695 / HG / NHGRI NIH HHS / United States
MH083268 / MH / NIMH NIH HHS / United States
090532 / Wellcome Trust / United Kingdom
R01 HL113315 / HL / NHLBI NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
U54 HG003079 / HG / NHGRI NIH HHS / United States
DK062370 / DK / NIDDK NIH HHS / United States
098381 / Wellcome Trust / United Kingdom
HL113315 / HL / NHLBI NIH HHS / United States
MH63706 / MH / NIMH NIH HHS / United States
R01 HG006695 / HG / NHGRI NIH HHS / United States
G0601261 / Medical Research Council / United Kingdom
G0600705 / Medical Research Council / United Kingdom