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

Hum Mol Genet
Authors
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.

Year of Publication
2016
Journal
Hum Mol Genet
Volume
25
Issue
10
Pages
2082-2092
Date Published
2016 May 15
ISSN
1460-2083
URL
DOI
10.1093/hmg/ddw055
PubMed ID
26908616
PubMed Central ID
PMC5062577
Links
Grant list
UL1 TR001070 / TR / NCATS NIH HHS / United States
G9521010 / Medical Research Council / United Kingdom
R01 DK075787 / DK / NIDDK NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
R01 HL116747 / HL / NHLBI NIH HHS / United States
P30 DK020595 / DK / NIDDK NIH HHS / United States