%0 Journal Article
%T Segregation of a Latent High Adiposity Phenotype in Families with a History of Type 2 Diabetes Mellitus Implicates Rare Obesity-Susceptibility Genetic Variants with Large Effects in Diabetes-Related Obesity
%A Arthur B. Jenkins
%A Marijka Batterham
%A Dorit Samocha-Bonet
%A Katherine Tonks
%A Jerry R. Greenfield
%A Lesley V. Campbell
%J PLOS ONE
%D 2013
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0070435
%X Background We recently reported significantly greater weight gain in non-diabetic healthy subjects with a 1st degree family history (FH+) of type 2 diabetes mellitus (T2DM) than in a matched control group without such history (FH£¿) during voluntary overfeeding, implying co-inheritance of susceptibilities to T2DM and obesity. We have estimated the extent and mode of inheritance of susceptibility to increased adiposity in FH+. Methods Normoglycaemic participants were categorised either FH+ (¡Ý1 1st degree relative with T2DM, 50F/30M, age 45¡À14 (SD) yr) or FH£¿ (71F/51M, age 43¡À14 yr). Log-transformed anthropometric measurements (height, hip and waist circumferences) and lean, bone and fat mass (Dual Energy X-ray Absorptiometry) data were analysed by rotated Factor Analysis. The age- and gender-adjusted distributions of indices of adiposity in FH+ were assessed by fits to a bimodal model and by relative risk ratios (RR, FH+/FH£¿) and interpreted in a purely genetic model of FH effects. Results The two orthogonal factors extracted, interpretable as Frame and Adiposity accounted for 80% of the variance in the input data. FH+ was associated with significantly higher Adiposity scores (p<0.01) without affecting Frame scores. Adiposity scores in FH+ conformed to a bimodal normal distribution, consistent with dominant expression of major susceptibility genes with 59% (95% CI 40%, 74%) of individuals under the higher mode. Calculated risk allele frequencies were 0.09 (0.02, 0.23) in FH£¿, 0.36 (0.22, 0.48) in FH+ and 0.62 (0.36, 0.88) in unobserved T2DM-affected family members. Conclusions The segregation of Adiposity in T2DM-affected families is consistent with dominant expression of rare risk variants with major effects, which are expressed in over half of FH+ and which can account for most T2DM-associated obesity in our population. The calculated risk allele frequency in FH£¿ suggests that rare genetic variants could also account for a substantial fraction of the prevalent obesity in this society.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0070435