Abstract
Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). Protein-truncating variants in GPR75 were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of Gpr75 in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.
Highlights
Introduction and Background1.1 This policy aims to ensure that UK Biobank’s decision-making processes for access to the UK Biobank Resource are conducted in accordance with the highest standards of integrity
1.2 UK Biobank confirms that for the purposes of this Material Transfer Agreement (MTA): 1.2.1 It is entitled to supply the Materials to the Applicant; 1.2.2 Consent in relation to the Data Protection Act 1998 and the Human Tissue Act 2004 has been obtained from the relevant UK Biobank participants; and
4.1 The Applicant hereby confirms to UK Biobank that all work using the Materials will be carried out in compliance with all applicable laws, regulations, guidelines and approvals, including without limitation the Human Tissue Act 2004, the Data Protection Act 1998 and any approvals required from a Research Ethics Committee
Summary
1.2.1 It is entitled to supply the Materials to the Applicant; 1.2.2 Consent in relation to the Data Protection Act 1998 and (where applicable) the Human Tissue Act 2004 has been obtained from the relevant UK Biobank participants; and. For the avoidance of doubt, nothing in this MTA will prevent UK Biobank from supplying the same Materials (or other data and/or samples in the UK Biobank Resource) to another third party. 3.2 UK Biobank hereby grants the Applicant a limited, revocable, worldwide, royalty-free, non-exclusive licence (but not any ownership rights) to use the Samples for the Permitted Purpose only. 3.3 UK Biobank is the owner of the Intellectual Property Rights in the Data currently in the Resource. 3.4 UK Biobank hereby grants the Applicant a limited, revocable, worldwide, royalty-free, non-exclusive licence (but not any ownership rights) to use the Data for the Permitted Purpose only
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