@article{3ab0e19f8acd4c86bf7923949248a564,
title = "Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes",
abstract = "Initial results from sequencing studies suggest that there are relatively few low-frequency (<5%) variants associated with large effects on common phenotypes. We performed low-pass whole-genome sequencing in 680 individuals from the InCHIANTI study to test two primary hypotheses: (i) that sequencing would detect single low-frequency-large effect variants that explained similar amounts of phenotypic variance as single common variants, and (ii) that some common variant associations could be explained by low-frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant-common phenotype associations-11 132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11 657 229 high-quality variants of which 6 129 221 and 5 528 008were common and lowfrequency (<5%), respectively, lowfrequency-large effect associations comprised 7% of detectable cis-gene expression traits [89 of 1314 cis-eQTLs at P < 1 × 10-06 (false discovery rate ~5%)] and one of eight biomarker associations at P <8× 10-10. Very few (30 of 1232; 2%) common variant associations were fully explained by lowfrequency variants. Our data show that whole-genome sequencing can identify low-frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low-frequency variants of large effect.",
author = "Wood, {Andrew R.} and Tuke, {Marcus A.} and Mike Nalls and Dena Hernandez and {Raphael Gibbs}, J. and Haoxiang Lin and Xu, {Christopher S.} and Qibin Li and Juan Shen and Goo Jun and Marcio Almeida and Toshiko Tanaka and Perry, {John R.B.} and Kyle Gaulton and Manny Rivas and Richard Pearson and Curran, {Joanne E.} and Johnson, {Matthew P.} and G{\"o}ring, {Harald H.H.} and Ravindranath Duggirala and John Blangero and Mccarthy, {Mark I.} and Stefania Bandinelli and Anna Murray and Weedon, {Michael N.} and Andrew Singleton and David Melzer and Luigi Ferrucci and Frayling, {Timothy M.}",
note = "Funding Information: This work was supported by Wellcome Trust grants: 083270/Z/07/ Z and 090367/Z/09/Z. A.W. and T.F. are supported by the European Research Council grant: SZ-50371-GLUCOSEGENES-FP7-IDEAS-ERC. M.T., M.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). M.T. is also supported through the Wellcome Trust grant WT090367MA. M.M. is a Wellcome Trust Senior Investigator and is supported by the Wellcome Trust grant 098381. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (ZO1-AG000947 and Z01-AG000185) and in part by the UK Medical Research Council. The InCHIANTI study baseline (1998–2000) was supported as a {\textquoteleft}targeted project{\textquoteright} (ICS110.1/ RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (contracts: 263 MD 9164 and 263 MD 821336). A portion of this study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih. gov). We thank the T2D-GENES consortium for whole-genome sequencing in the San Antonio Family Heart Study. Sequence data were generated by the T2D-GENES consortium with support from NIH/NIDDK U01{\textquoteright}s DK085501, DK085524, DK085526, DK085545 and DK085584. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. Publisher Copyright: {\textcopyright} The Author 2014.",
year = "2015",
month = mar,
day = "1",
doi = "10.1093/hmg/ddu560",
language = "English (US)",
volume = "24",
pages = "1504--1512",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "5",
}