학술논문
Re-sequencing expands our understanding of the phenotypic impact of variants at GWAS loci.
Document Type
article
Author
Susan K Service; Tanya M Teslovich; Christian Fuchsberger; Vasily Ramensky; Pranav Yajnik; Daniel C Koboldt; David E Larson; Qunyuan Zhang; Ling Lin; Ryan Welch; Li Ding; Michael D McLellan; Michele O'Laughlin; Catrina Fronick; Lucinda L Fulton; Vincent Magrini; Amy Swift; Paul Elliott; Marjo-Riitta Jarvelin; Marika Kaakinen; Mark I McCarthy; Leena Peltonen; Anneli Pouta; Lori L Bonnycastle; Francis S Collins; Narisu Narisu; Heather M Stringham; Jaakko Tuomilehto; Samuli Ripatti; Robert S Fulton; Chiara Sabatti; Richard K Wilson; Michael Boehnke; Nelson B Freimer
Source
PLoS Genetics, Vol 10, Iss 1, p e1004147 (2014)
Subject
Language
English
ISSN
1553-7390
1553-7404
1553-7404
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