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

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

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Title: Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases
Author: Perry, John R. B.; Voight, Benjamin F.; Yengo, Loïc; Amin, Najaf; Dupuis, Josée; Ganser, Martha; Grallert, Harald; Navarro, Pau; Li, Man; Steinthorsdottir, Valgerdur; Almgren, Peter; Arking, Dan E.; Aulchenko, Yurii; Balkau, Beverley; Benediktsson, Rafn; Bergman, Richard N.; Boerwinkle, Eric; Bonnycastle, Lori; Burtt, Noël P.; Campbell, Harry; Charpentier, Guillaume; Collins, Francis S.; Gieger, Christian; Green, Todd; Hadjadj, Samy; Hattersley, Andrew T.; Herder, Christian; Kottgen, Anna; Labrune, Yann; Langenberg, Claudia; Mohlke, Karen L.; Morris, Andrew P.; Oostra, Ben; Pankow, James; Petersen, Ann-Kristin; Pramstaller, Peter P.; Prokopenko, Inga; Rathmann, Wolfgang; Rayner, William; Roden, Michael; Rudan, Igor; Rybin, Denis; Sigurdsson, Gunnar; Sladek, Rob; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tuomilehto, Jaakko; Uitterlinden, Andre G.; Vivequin, Sidonie; Weedon, Michael N.; Wright, Alan F.; Illig, Thomas; Kao, Linda; Wilson, James F.; Stefansson, Kari; van Duijn, Cornelia; Altschuler, David; Morris, Andrew D.; Boehnke, Michael; McCarthy, Mark I.; Froguel, Philippe; Palmer, Colin N. A.; Wareham, Nicholas J.; Groop, Leif; Frayling, Timothy M.; Cauchi, Stéphane; Qi, Lu; Scott, Robert A.; Hofman, Albert; Johnson, Andrew D.; Kraft, Peter; Manning, Alisa K.; Scott, Laura J.; Hu, Frank B.; Meigs, James Benjamin

Note: Order does not necessarily reflect citation order of authors.

Citation: Perry, John R. B., Benjamin F. Voight, Loïc Yengo, Najaf Amin, Josée Dupuis, Martha Ganser, Harald Grallert, et al. 2012. Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases. PLoS Genetics 8(5): e1002741.
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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.
Published Version: doi:10.1371/journal.pgen.1002741
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364960/pdf/
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10406339
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