Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases.
Perry JR., Voight BF., Yengo L., Amin N., Dupuis J., Ganser M., Grallert H., Navarro P., Li M., Qi L., Steinthorsdottir V., Scott RA., Almgren P., Arking DE., Aulchenko Y., Balkau B., Benediktsson R., Bergman RN., Boerwinkle E., Bonnycastle L., Burtt NP., Campbell H., Charpentier G., Collins FS., Gieger C., Green T., Hadjadj S., Hattersley AT., Herder C., Hofman A., Johnson AD., Kottgen A., Kraft P., Labrune Y., Langenberg C., Manning AK., Mohlke KL., Morris AP., Oostra B., Pankow J., Petersen AK., Pramstaller PP., Prokopenko I., Rathmann W., Rayner W., Roden M., Rudan I., Rybin D., Scott LJ., Sigurdsson G., Sladek R., Thorleifsson G., Thorsteinsdottir U., Tuomilehto J., Uitterlinden AG., Vivequin S., Weedon MN., Wright AF., MAGIC None., DIAGRAM Consortium None., GIANT Consortium None., Hu FB., Illig T., Kao L., Meigs JB., Wilson JF., Stefansson K., van Duijn C., Altschuler D., Morris AD., Boehnke M., McCarthy MI., Froguel P., Palmer CN., Wareham NJ., Groop L., Frayling TM., Cauchi S.
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.