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Weighted burden analysis in 200,000 exome-sequenced subjects characterises rare variant effects on BMI

Curtis, David; (2022) Weighted burden analysis in 200,000 exome-sequenced subjects characterises rare variant effects on BMI. International Journal of Obesity , 46 (4) pp. 782-792. 10.1038/s41366-021-01053-4. Green open access

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Abstract

Introduction: A number of genes have been identified in which rare variants can cause obesity. Here we analyse a sample of exome sequenced subjects from UK Biobank using BMI as a phenotype with the aims of identifying genes in which rare, functional variants influence BMI and characterising the effects of different categories of variant. Methods: There were 199,807 exome sequenced subjects for whom BMI was recorded. Weighted burden analysis of rare, functional variants was carried out, incorporating population principal components and sex as covariates. For selected genes, additional analyses were carried out to clarify the contribution of different categories of variant. Statistical significance was summarised as the signed log 10 of the p value (SLP), given a positive sign if the weighted burden score was positively correlated with BMI. Results: Two genes were exome-wide significant, MC4R (SLP = 15.79) and PCSK1 (SLP = 6.61). In MC4R, disruptive variants were associated with an increase in BMI of 2.72 units and probably damaging nonsynonymous variants with an increase of 2.02 units. In PCSK1, disruptive variants were associated with a BMI increase of 2.29 and protein-altering variants with an increase of 0.34. Results for other genes were not formally significant after correction for multiple testing, although SIRT1, ZBED6 and NPC2 were noted to be of potential interest. Conclusion: Because the UK Biobank consists of a self-selected sample of relatively healthy volunteers, the effect sizes noted may be underestimates. The results demonstrate the effects of very rare variants on BMI and suggest that other genes and variants will be definitively implicated when the sequence data for additional subjects becomes available.

Type: Article
Title: Weighted burden analysis in 200,000 exome-sequenced subjects characterises rare variant effects on BMI
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41366-021-01053-4
Publisher version: https://doi.org/10.1038/s41366-021-01053-4
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, Nutrition & Dietetics, PROTEIN
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10146475
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