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, John R.B.; Voight, BF; Yengo, L; et al.Amin, N; Dupuis, J; Ganser, M; Grallert, H; Navarro, P; Li, M; Qi, L; Steinthorsdottir, V; Scott, RA; Almgren, P; Arking, DE; Aulchenko, Yurii; Balkau, B; Benediktsson, R; Bergman, RN; Boerwinkle, E; Bonnycastle, Lori; Burtt, NP; Campbell, H; Charpentier, G; Collins, FS; Gieger, C; Green, Todd; Hadjadj, S; Hattersley, Andrew T.; 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, Michael N.; Wright, AF; MAGIC; DIAGRAM Consortium; GIANT Consortium; 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, Leif; Frayling, Timothy M.; Cauchi, S
Date: 1 May 2012
Public Library of Science
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 ...
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.
Institute of Biomedical & Clinical Science
College of Medicine and Health
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