Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases

Abstract

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m\(^2\)) compared to obese cases (BMI\(\geq\)30 Kg/m\(^2\)). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m\(^2\)) or 4,123 obese cases (BMI\(\geq\)30 kg/m\(^2\)), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4×10\(^{-9}\), OR = 1.13 [95% CI 1.09–1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00–1.06]). A variant in HMG20A—previously identified in South Asians but not Europeans—was associated with type 2 diabetes in obese cases (P = 1.3×10\(^{-8}\), OR = 1.11 [95% CI 1.07–1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02–1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10–1.17], P = 3.2×10\(^{-14}\) This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05–1.08], P = 2.2×10\(^{-16}\). This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.