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Genetic architecture of human thinness compared to severe obesity

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Locke, Adam E, Riveros-McKay, Fernando, Mistry, Vanisha, Bounds, Rebecca, Hendricks, Audrey, Keogh, Julia M., Thomas, Hannah, Henning, Elana, Corbin, Laura J., O’Rahilly, Stephen, Zeggini, Eleftheria, Wheeler, Eleanor, Barroso, Inês and Farooqi, I. Sadaf (2019) Genetic architecture of human thinness compared to severe obesity. PLoS Genetics, 15 (1). e1007603. doi:10.1371/journal.pgen.1007603 ISSN 1553-7390.

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Official URL: http://dx.doi.org/10.1371/journal.pgen.1007603

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Abstract

The variation in weight within a shared environment is largely attributable to genetic factors. Whilst many genes/loci confer susceptibility to obesity, little is known about the genetic architecture of healthy thinness. Here, we characterise the heritability of thinness which we found was comparable to that of severe obesity (h2 = 28.07 vs 32.33% respectively), although with incomplete genetic overlap (r = -0.49, 95% CI [-0.17, -0.82], p = 0.003). In a genome-wide association analysis of thinness (n = 1,471) vs severe obesity (n = 1,456), we identified 10 loci previously associated with obesity, and demonstrate enrichment for established BMI-associated loci (pbinomial = 3.05x10-5). Simulation analyses showed that different association results between the extremes were likely in agreement with additive effects across the BMI distribution, suggesting different effects on thinness and obesity could be due to their different degrees of extremeness. In further analyses, we detected a novel obesity and BMI-associated locus at PKHD1 (rs2784243, obese vs. thin p = 5.99x10-6, obese vs. controls p = 2.13x10-6 pBMI = 2.3x10-13), associations at loci recently discovered with much larger sample sizes (e.g. FAM150B and PRDM6-CEP120), and novel variants driving associations at previously established signals (e.g. rs205262 at the SNRPC/C6orf106 locus and rs112446794 at the PRDM6-CEP120 locus). Our ability to replicate loci found with much larger sample sizes demonstrates the value of clinical extremes and suggest that characterisation of the genetics of thinness may provide a more nuanced understanding of the genetic architecture of body weight regulation and may inform the identification of potential anti-obesity targets.

Item Type: Journal Article
Subjects: R Medicine > RC Internal medicine
Divisions: Faculty of Science, Engineering and Medicine > Science > Psychology
Library of Congress Subject Headings (LCSH): Leanness -- Genetics, Body weight -- Health aspects, Obesity -- Genetics, Human body, Body image
Journal or Publication Title: PLoS Genetics
Publisher: Public Library of Science
ISSN: 1553-7390
Official Date: 24 January 2019
Dates:
DateEvent
24 January 2019Published
Volume: 15
Number: 1
Article Number: e1007603
DOI: 10.1371/journal.pgen.1007603
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 6 March 2020
Date of first compliant Open Access: 12 March 2020
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
UNSPECIFIEDEuropean Research Councilhttp://dx.doi.org/10.13039/501100000781
098497/Z/12/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
WT098051Wellcome Trusthttp://dx.doi.org/10.13039/100010269
WT206194Wellcome Trusthttp://dx.doi.org/10.13039/100010269
MRC_MC_UU_12012/5Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
UNSPECIFIEDNational Institute for Health Research Cambridge Biomedical Research Centre UNSPECIFIED
UNSPECIFIEDBernard Wolfe Health Neuroscience EndowmentUNSPECIFIED
FP7/2007-2013Seventh Framework Programmehttp://dx.doi.org/10.13039/100011102
Beta-JUDO n˚279153 Seventh Framework Programmehttp://dx.doi.org/10.13039/100011102
UNSPECIFIED[ESRC] Economic and Social Research Councilhttp://dx.doi.org/10.13039/501100000269
076467/Z/05/ ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
Contributors:
ContributionNameContributor ID
ResearcherWolke, Dieter18428

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