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Lessard, S.* ; Manning, A.K.* ; Low-Kam, C.* ; Auer, P.L.* ; Giri, A.K.* ; Graff, M.* ; Schurmann, C.* ; Yaghootkar, H.* ; Luan, J.* ; Esko, T.* ; Karaderi, T.* ; NHLBI Grand Opportunity Exome Sequencing Project (*) ; GoT2D Consortium (Gieger, C. ; Grallert, H. ; Hrabě de Angelis, M. ; Huth, C. ; Meisinger, C. ; Meitinger, T. ; Müller-Nurasyid, M. ; Peters, A. ; Rathmann, W. ; Ried, J.S. ; Strauch, K. ; Strom, T.M.) ; T2D-GENES Consortium (*) ; Bottinger, E.P.* ; Lu, Y.* ; Carlson, C.S.* ; Caulfield, M.* ; Dubé, M.-P.* ; Jackson, R.D.* ; Kooperberg, C.* ; McKnight, B.* ; Mongrain, I.* ; Peters, U.* ; Reiner, A.P.* ; Rhainds, D.* ; Sotoodehnia, N.* ; Hirschhorn, J.N.* ; Scott, R.* ; Munroe, P.B.* ; Frayling, T.M.* ; Loos, R.J.* ; North, K.E.* ; Edwards, T.L.* ; Tardif, J.-C.* ; Lindgren, C.M.* ; Lettre, G.* ; GIANT Consortium (Albrecht, E. ; Heid, I.M. ; Illig, T. ; Klopp, N. ; Lichtner, P. ; Waldenberger, M. ; Wichmann, H.-E.)

Testing the role of predicted gene knockouts in human anthropometric trait variation.

Hum. Mol. Genet. 25, 2082-2092 (2016)
Publ. Version/Full Text Postprint Supplement DOI PMC
Open Access Green
Although the role of complete gene inactivation by two loss-of-function mutations inherited in trans is well-established in recessive Mendelian diseases, we have not yet explored how such gene knockouts (KOs) could influence complex human phenotypes. Here, we developed a statistical framework to test the association between gene KOs and quantitative human traits. Our method is flexible, publicly available, and compatible with common genotype format files (e.g. PLINK and vcf). We characterized gene KOs in 4,498 participants from the NHLBI Exome Sequence Project (ESP) sequenced at high coverage (>100X), 1,976 French Canadians from the Montreal Heart Institute Biobank sequenced at low coverage (5.7X), and >100,000 participants from the GIANT Consortium genotyped on an exome array. We tested associations between gene KOs and three anthropometric traits: body mass index (BMI), height and BMI-adjusted waist-to-hip ratio (WHR). Despite our large sample size and multiple datasets available, we could not detect robust associations between specific gene KOs and quantitative anthropometric traits. Our results highlight several limitations and challenges for future gene KO studies in humans, in particular when there is no prior knowledge on the phenotypes that might be affected by the tested gene KOs. They also suggest that gene KOs identified with current DNA sequencing methodologies probably do not strongly influence normal variation in BMI, height, and WHR in the general human population.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Of-function Variants; Primary Hyperoxaluria; Receptor Gene; Association; Disease; Dysfunction; Disorders; Database; Growth; Exomes
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Journal Human Molecular Genetics
Quellenangaben Volume: 25, Issue: 10, Pages: 2082-2092 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Experimental Genetics (IEG)
Institute of Human Genetics (IHG)
Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)