TY - JOUR

T1 - Testing the role of predicted gene knockouts in human anthropometric trait variation

AU - Lessard, Samuel

AU - Manning, Alisa K.

AU - Low-Kam, Cécile

AU - Auer, Paul L.

AU - Giri, Ayush

AU - Graff, Mariaelisa

AU - Schurmann, Claudia

AU - Yaghootkar, Hanieh

AU - Luan, Jian'an

AU - Esko, Tonu

AU - Karaderi, Tugce

AU - Bottinger, Erwin P.

AU - Lu, Yingchang

AU - Carlson, Chris

AU - Caulfield, Mark

AU - Dubé, Marie Pierre

AU - Jackson, Rebecca D.

AU - Kooperberg, Charles

AU - McKnight, Barbara

AU - Mongrain, Ian

AU - Peters, Ulrike

AU - Reiner, Alex P.

AU - Rhainds, David

AU - Sotoodehnia, Nona

AU - Hirschhorn, Joel N.

AU - Scott, Robert A.

AU - Munroe, Patricia B.

AU - Frayling, Timothy M.

AU - Loos, Ruth J.F.

AU - North, Kari E.

AU - Edwards, Todd L.

AU - Tardif, Jean Claude

AU - Lindgren, Cecilia M.

AU - Lettre, Guillaume

AU - NHLBI GO Exome Sequence Project

AU - GOT2D

AU - T2D-GENES

AU - GIANT Consortium

PY - 2016/5/15

Y1 - 2016/5/15

N2 - 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 4498 participants from the NHLBI Exome Sequence Project (ESP) sequenced at high coverage (>100×), 1976 French Canadians from the Montreal Heart Institute Biobank sequenced at low coverage (5.7×), and >100 000 participants from the Genetic Investigation of ANthropometric Traits (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.

AB - 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 4498 participants from the NHLBI Exome Sequence Project (ESP) sequenced at high coverage (>100×), 1976 French Canadians from the Montreal Heart Institute Biobank sequenced at low coverage (5.7×), and >100 000 participants from the Genetic Investigation of ANthropometric Traits (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.

UR - http://www.scopus.com/inward/record.url?scp=84992207024&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddw055

DO - 10.1093/hmg/ddw055

M3 - Journal article

C2 - 26908616

AN - SCOPUS:84992207024

VL - 25

SP - 2082

EP - 2092

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 10

ER -