The current obesity 'epidemic': segregation of familial genetic risk in NHANES cohort supports a major role for large genetic effects [article]

Arthur B Jenkins, Marijka Batterham, Lesley V Campbell
2019 bioRxiv   pre-print
Background/Objectives: The continuing increase in many countries in adult body mass index (BMI kg/m2) and its dispersion is contributed to by interactions between genetic susceptibilities and an increasingly obesogenic environment. Whether population susceptibility to obesogenic environments is mainly determined by a subgroup with high genetic susceptibility or susceptibility is more evenly distributed throughout the population is unresolved, due to uncertainties around relevant genetic and
more » ... ant genetic and environmental architecture. We aimed to test the predictions of a Mendelian genetic architecture based on collectively common but individually rare large-effect variants and its ability to account for current trends in a large population-based sample. Subjects/Methods: We studied publicly available adult BMI data (n = 9102) from 3 cycles of NHANES (1999, 2005, 2013) adjusted for age, gender and race/ethnicity. A first degree family history of diabetes (FH) served as a binary marker (FH0/FH1) of genetic obesity susceptibility. We tested for multi-modality in BMI non-parametrically using a runs tests in conditional quantile regression (CQR) models of FH effects, obtained parametric fits to a Mendelian model in FH1, and estimated FH-environment interactions in CQR models and in ANCOVA models incorporating secular time. Results: A unimodal FH effect on BMI was excluded (p≤0.0001) in CQR models and parametric fits to a Mendelian model in FH1 identified 3 modes at 25.8±1.0 (SEM), 32.1±1.8 and 40.6±2.5 kg/m2. Mode separation accounted for ~40% of BMI variance in FH1 providing a lower bound for the contribution of large effects. CQR analysis identified strong interactions between FH and environmental factors (p≤0.01) and FH1 accounted for ~60% of the secular trends in BMI and its SD in ANCOVA models. Conclusions: Multimodality in the FH effect is inconsistent with a predominantly polygenic small effect architecture. We conclude that large genetic effects interacting with obesogenic environment provide a better, quantitative explanation for current trends in BMI.
doi:10.1101/749606 fatcat:hsbrtzmdpzbhbkttwftxhuoziq