Faculty Collaboration Database

Testing the role of predicted gene knockouts in human anthropometric trait variation. Hum Mol Genet 2016 May 15;25(10):2082-2092

Date

02/26/2016

Pubmed ID

26908616

Pubmed Central ID

PMC5062577

DOI

10.1093/hmg/ddw055

Scopus ID

2-s2.0-84992207024 (requires institutional sign-in at Scopus site)   8 Citations

Abstract

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.

Author List

Lessard S, Manning AK, Low-Kam C, Auer PL, Giri A, Graff M, Schurmann C, Yaghootkar H, Luan J, Esko T, Karaderi T, NHLBI GO Exome Sequence Project, GOT2D, T2D-GENES, GIANT Consortium, Bottinger EP, Lu Y, Carlson C, Caulfield M, Dubé MP, Jackson RD, Kooperberg C, McKnight B, Mongrain I, Peters U, Reiner AP, Rhainds D, Sotoodehnia N, Hirschhorn JN, Scott RA, Munroe PB, Frayling TM, Loos RJ, North KE, Edwards TL, Tardif JC, Lindgren CM, Lettre G

Author

Paul L. Auer PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anthropometry
Body Height
Body Mass Index
Canada
Exome
Female
Gene Knockout Techniques
Genotype
Humans
Male
Mutation
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Waist-Hip Ratio