Contribution of common and rare genetic variation to adiposity and metabolic phenotype
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Author(s)
Yiorkas, Andrianos Marios
Type
Thesis
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.
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.
Version
Open Access
Date Issued
2018-07
Date Awarded
2019-03
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Blakemore, Alexandra I
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)