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.

Abstract

We recently reported significantly greater weight gain in non-diabetic healthy subjects with a 1(st) 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+. Normoglycaemic participants were categorised either FH+ (≥1 1(st) degree relative with T2DM, 50 F/30 M, age 45 ± 14 (SD) yr) or FH- (71F/51M, age 43 ± 14 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. 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. 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.