Genetic architecture of human thinness compared to severe obesity

Fernando Riveros-Mckay, Vanisha Mistry, Rebecca Bounds, Audrey Hendricks, Julia M Keogh, Hannah Thomas, Elana Henning, Laura Corbin, Understanding Society Scientific Group, Stephen O'Rahilly, Eleftheria Zeggini, Eleanor Wheeler, Inês Barroso, I Sadaf Farooqi

Research output: Contribution to journalArticle (Academic Journal)peer-review

23 Citations (Scopus)
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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=28.07vs 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 forestablished 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 withmuch 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.
Original languageEnglish
Article numbere1007603
Number of pages25
JournalPLoS Genetics
Issue number1
Publication statusPublished - 24 Jan 2019

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