Contribution of common and rare genetic variation to adiposity and metabolic phenotype

Abstract

Obesity is a major health concern with cardiometabolic co-morbidities, affecting more than 650 million people worldwide. Here, I have assessed the contribution of common and rare genetic variation to adiposity and metabolic phenotypes, including identifying genetic factors influencing location of abdominal fat storage. A GWAS of MRI-measured abdominal fat distribution in the UK Biobank (UKBB) identified two novel SNPs at genome-wide significant level: i) in both men and women, rs182052 in ADIPOQ associated with higher visceral adiposity (β=0.114 SD; P=3.04×10-8) and ii) in women only, rs181635166 in NALCN associated with having more subcutaneous abdominal fat (βfemales=0.338 SD, Pfemales=1.51×10-8). A genetic risk score (GRS) composed of “favourable adiposity” SNPs, was associated with 0.040 (0.008) SD (P=1.08×10-6) lower liver fat and preferential lower body, rather than central, adiposity, in women only. In men, it was associated with a higher adiposity overall. Attention was then turned to examination of the phenotypic implications of rarer genetic variants, revealing that a predicted-deleterious, low frequency variant, rs11568563 (c.A516C, p.E172D, MAF=0.045) in SLCO1A2, conferred diminished and delayed post-prandial increase of conjugated bile acids in plasma, compared to non-carriers, after nutritional challenge tests (OGTT and MMTT): this may have important implications for cardiovascular risk and diabetes. Finally, I examined the phenotypic implications of mutations in the MC4R gene – the commonest form of monogenic obesity. The combined prevalence of 72 rare reportedly-deleterious MC4R mutations in the White British participants of the UKBB (N~330,000) was 0.39%, but only 8/72 mutations showed full penetrance for obesity (S19fs, P48S, N62S, L106P, S136P, F261S, P299H or A303T). There was slight enrichment of LoF mutations in overweight/obese compared to underweight/lean individuals (132 carriers (0.1%) vs 49 carriers (0.04%), P=0.04). This work highlights the need to consider penetrance and expressivity in genetic counselling of families with MC4R mutations.