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Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Lookup NU author(s): Professor Mark Walker


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Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) > 1% with common metabolic phenotypes. The study comprised three stages. We performed medium-depth (8x) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI > 27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. Exome sequencing identified 70,182 polymorphisms with MAF > 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 x 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 x 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 x 10(-10)). We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

Publication metadata

Author(s): Albrechtsen A, Grarup N, Li Y, Sparso T, Tian G, Cao H, Jiang T, Kim SY, Korneliussen T, Li Q, Nie C, Wu R, Skotte L, Morris AP, Ladenvall C, Cauchi S, Stancakova A, Andersen G, Astrup A, Banasik K, Bennett AJ, Bolund L, Charpentier G, Chen Y, Dekker JM, Doney ASF, Dorkhan M, Forsen T, Frayling TM, Groves CJ, Gui Y, Hallmans G, Hattersley AT, He K, Hitman GA, Holmkvist J, Huang S, Jiang H, Jin X, Justesen JM, Kristiansen K, Kuusisto J, Lajer M, Lantieri O, Li W, Liang H, Liao Q, Liu X, Ma T, Ma X, Manijak MP, Marre M, Mokrosinski J, Morris AD, Mu B, Nielsen AA, Nijpels G, Nilsson P, Palmer CNA, Rayner NW, Renstrom F, Ribel-Madsen R, Robertson N, Rolandsson O, Rossing P, Schwartz TW, Slagboom PE, Sterner M, Tang M, Tarnow L, Tuomi T, van't Riet E, van Leeuwen N, Varga TV, Vestmar MA, Walker M, Wang B, Wang Y, Wu H, Xi F, Yengo L, Yu C, Zhang X, Zhang J, Zhang Q, Zhang W, Zheng H, Zhou Y, Altshuler D, 't Hart LM, Franks PW, Balkau B, Froguel P, McCarthy MI, Laakso M, Groop L, Christensen C, Brandslund I, Lauritzen T, Witte DR, Linneberg A, Jorgensen T, Hansen T, Wang J, Nielsen R, Pedersen O, DESIR Study Grp, DIAGRAM Consortium

Publication type: Article

Publication status: Published

Journal: Diabetologia

Year: 2013

Volume: 56

Issue: 2

Pages: 298-310

Print publication date: 01/02/2013

ISSN (print): 0012-186X

ISSN (electronic): 1432-0428

Publisher: Springer


DOI: 10.1007/s00125-012-2756-1


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Funder referenceFunder name
Aase and Ejner Danielsens Foundation
Academy of Finland
Ardix Medical
Association Diabete Risque Vasculaire
Bayer Diagnostics
BDA Research
Becket Foundation
Becton Dickinson
Bio-banking and Biomolecular Research Infrastructure the Netherlands (BBMRI-NL)
Danish Centre for Health Technology Assessment
Danish Medical Research Council
Danish Pharmaceutical Association
Diabetes UK
Federation Francaise de Cardiologie, La Fondation de France
Finnish Diabetes Research Foundation
Finnish Medical Society
Folkhalsan Research Foundation
Ib Henriksen Foundation
Inserm (Reseaux en Sante Publique, Interactions entre les determinants de la sante, Cohortes Sante TGIR)
Lundbeck Foundation
Ministry of Internal Affairs and Health
Oxford NIHR Biomedical Research Centre
Pahlssons Foundation
Pierre Fabre
Research Foundation of Copenhagen County
Sigrid Juselius Foundation
Umea University
Velux Foundation
ALK-Abello, (Horsholm, Denmark)
Augustinus Foundation
Danish Agency for Science, Technology and Innovation
Danish Council for Independent Research (Medical Sciences)
Danish Diabetes Association
Danish Heart Foundation
Danish Research Council
Finnish Cardiovascular Research Foundation
Heart Foundation of Northern Sweden
Knut & Alice Wallenberg Foundation
Merck Sante
Novo Nordisk
Novo Nordisk Foundation
Novo Nordisk Inc.
Research Centre for Prevention and Health (the Capital Region of Denmark)
Societe Francophone du Diabete
Swedish Diabetes Association
Swedish Heart-Lung Foundation
Swedish Research Council
06854/Z/02/ZWellcome Trust
076113/C/04/ZWellcome Trust
081682/Z/06/ZWellcome Trust
083270Wellcome Trust
5263EVO grant from the Kuopio University Hospital
2006.00.060Dutch Diabetes Research Foundation
2009-1039Swedish Research Foundation
521-2010-3490Swedish Research Foundation
Dnr-349-2006-6589Swedish Research Foundation
ENGAGE: HEALTH-F4-2007-201413EU
G0000649UK Medical Research Council
G0000934Medical Research Council
GR072960Wellcome Trust