Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases

John R. B. Perry, Benjamin F. Voight, Loic Yengo, Najaf Amin, Josee Dupuis, Martha Ganser, Harald Grallert, Pau Navarro, Man Li, Lu Qi, Valgerdur Steinthorsdottir, Robert A. Scott, Peter Almgren, Dan E. Arking, Yurii Aulchenko, Beverley Balkau, Rafn Benediktsson, Richard N. Bergman, Eric Boerwinkle, Lori BonnycastleNoel P. Burtt, Harry Campbell, Guillaume Charpentier, Francis S. Collins, Christian Gieger, Todd Green, Samy Hadjadj, Andrew T. Hattersley, Christian Herder, Albert Hofman, Andrew D. Johnson, Anna Kottgen, Peter Kraft, Yann Labrune, Claudia Langenberg, Alisa K. Manning, Karen L. Mohlke, Andrew P. Morris, Ben Oostra, James Pankow, Ann-Kristin Petersen, Peter P. Pramstaller, Inga Prokopenko, Wolfgang Rathmann, William Rayner, Michael Roden, Igor Rudan, Denis Rybin, Andrew D. Morris, Colin N. A. Palmer, GIANT Consortium, DIAGRAM Consortium, MAGIC

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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 >= 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 languageEnglish
    Article numbere1002741
    Pages (from-to)-
    Number of pages14
    JournalPLoS Genetics
    Volume8
    Issue number5
    DOIs
    Publication statusPublished - 2012

    Cite this

    Perry, J. R. B., Voight, B. F., Yengo, L., Amin, N., Dupuis, J., Ganser, M., Grallert, H., Navarro, P., Li, M., Qi, L., Steinthorsdottir, V., Scott, R. A., Almgren, P., Arking, D. E., Aulchenko, Y., Balkau, B., Benediktsson, R., Bergman, R. N., Boerwinkle, E., ... GIANT Consortium, DIAGRAM Consortium, MAGIC (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]. https://doi.org/10.1371/journal.pgen.1002741