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/m²) compared to obese cases (BMI≥30 Kg/m²). 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/m²) or 4,123 obese cases (BMI≥30 kg/m²), 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.

Figure 1. Test statistics for LAMA1 association in lean and obese cases versus all controls.

Figure 2. Regional association plot for the LAMA1 gene in lean type 2 diabetes samples.

Figure 3. Test statistics for HMG20A association in lean and obese cases versus all controls.

Figure 4. Regional association plot for the HMG20A gene in obese type 2 diabetes samples.

Figure 5. Risk allele distribution for known type 2 diabetes SNPs in GoDARTs.

Plot shows number of type 2 diabetes risk alleles carried by the 263 lean type 2 diabetes cases, 1,735 obese type 2 diabetes cases and 3,691 controls from the GoDARTs study.

Figure 6. Relative risk for type 2 diabetes depending on risk allele quintile, split by lean and obese BMI.

Individuals binned into quintiles based on risk-allele count of known SNPs, weighted by effect size of SNP. Risk estimates relative to median quintile. Total sample size across all quintiles is 263 lean type 2 diabetes cases, 1735 obese type 2 diabetes cases and 3691 controls from the GoDARTs study.