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

JRB Perry, BF Voight, L Yengo, Najaf Amin, J Dupuis, M Ganser, H Grallert, P Navarro, M Li, L Qi, V Steinthorsdottir, RA Scott, P Almgren, DE Arking, Yuriy Aulchenko, B Balkau, R Benediktsson, RN Bergman, E Boerwinkle, L BonnycastleNP Burtt, H Campbell, G Charpentier, FS Collins, C Gieger, T Green, S Hadjadj, AT Hattersley, Cindy Herder, Bert Hofman, AD Johnson, A Kottgen, P Kraft, Y Labrune, C Langenberg, AK Manning, KL Mohlke, AP Morris, Ben Oostra, J Pankow, AK Petersen, PP Pramstaller, I Prokopenko, W Rathmann, W Rayner, M Roden, I Rudan, D Rybin, LJ Scott, G Sigurdsson, R Sladek, G Thorleifsson, U Thorsteinsdottir, J Tuomilehto, André Uitterlinden, S Vivequin, MN Weedon, AF Wright, FB Hu, T Illig, L Kao, JB Meigs, JF Wilson, K Stefansson, Cornelia Duijn, D Altschuler, AD Morris, M Boehnke, MI McCarthy, P Froguel, CNA Palmer, NJ Wareham, L Groop, TM Frayling, S Cauchi

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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 >= 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 >= 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 = 8.4610 29, 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 x 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 x 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 x 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.
Original languageUndefined/Unknown
JournalPLoS Genetics (print)
Issue number5
Publication statusPublished - 2012

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