@article{a1e3cf1c90f14b549e47f2b927290cf5,
title = "Association of structural variation with cardiometabolic traits in Finns",
abstract = "The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including 2 loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p = 1.47 × 10−54) and is also associated with increased levels of total cholesterol (p = 1.22 × 10−28) and 14 additional cholesterol-related traits, and (2) a multi-allelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p = 4.81 × 10−21) and alanine (p = 6.14 × 10−12) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs) and one linking recurrent HP gene deletion and cholesterol levels (p = 6.24 × 10−10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53 × 10−35). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.",
keywords = "Finnish population, cardiometabolic traits, genome-wide association study, structural variation",
author = "Lei Chen and Abel, {Haley J.} and Indraniel Das and Larson, {David E.} and Liron Ganel and Kanchi, {Krishna L.} and Regier, {Allison A.} and Young, {Erica P.} and Kang, {Chul Joo} and Scott, {Alexandra J.} and Colby Chiang and Xinxin Wang and Shuangjia Lu and Ryan Christ and Service, {Susan K.} and Chiang, {Charleston W.K.} and Havulinna, {Aki S.} and Johanna Kuusisto and Michael Boehnke and Markku Laakso and Aarno Palotie and Samuli Ripatti and Freimer, {Nelson B.} and Locke, {Adam E.} and Stitziel, {Nathan O.} and Hall, {Ira M.}",
note = "Funding Information: We thank D. Ray from Johns Hopkins University for her comments to the manuscript. This work was funded by an NHGRI CCDG award to I.M.H. and N.O.S. (UM1 HG008853) and DK U01 DK062370, the NHGRI large-scale sequencing grant (grant number 5U54HG003079), the Sigrid Jus{\'e}lius Foundation (to S.R.), the University of Helsinki HiLIFE Fellow grants 2017-2020 (to S.R.), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant number 312062 to S.R. grant number 312074 to S.R. and A.P.), the Academy of Finland (grant number 285380 to S.R.), the National Heart, Lung, and Blood Institute (grant number T32HL007081 to E.P.Y.), and the National Center for Advancing Translational Sciences (grant number UL1TR002345 to E.P.Y.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the MGI administration and data production team, in particular R. Fulton, L. Fulton, C. Fronick, A. Wollam, S.K. Dutcher, and J. Milbrandt. The FINRISK samples used for the research were obtained from THL Biobank. We thank all study participants for their generous participation in the THL Biobank, FINRISK study, and METSIM study. A.S.H. was supported by the Academy of Finland (grant no. 321356). L.C. was supported by the McDonnell International Scholars Academy Fellowship. A.J.S. was supported by the Mr. and Mrs. Spencer T. Olin Fellowship for Women in Graduate Study. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = apr,
day = "1",
doi = "10.1016/j.ajhg.2021.03.008",
language = "English",
volume = "108",
pages = "583--596",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
number = "4",
}