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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

Perry, John R. B.; Voight, Benjamin F.; Yengo, Loic; Amin, Najaf; Dupuis, Josee; Ganser, Martha; Grallert, Harald; Navarro, Pau; Li, Man and Qi, Lu, et al. (2012) In PLoS Genetics 8(5).
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... (More)
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. (Less)
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PLoS Genetics
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5
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Public Library of Science
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  • scopus:84863670156
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1553-7404
DOI
10.1371/journal.pgen.1002741
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English
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065336c1-4e0b-4762-9502-a33a047533a0 (old id 2895661)
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@article{065336c1-4e0b-4762-9502-a33a047533a0,
  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&lt;25 Kg/m(2)) compared to obese cases (BMI &gt;= 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&lt;25 kg/m(2)) or 4,123 obese cases (BMI &gt;= 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.},
  author       = {Perry, John R. B. and Voight, Benjamin F. and Yengo, Loic and Amin, Najaf and Dupuis, Josee and Ganser, Martha and Grallert, Harald and Navarro, Pau and Li, Man and Qi, Lu and Steinthorsdottir, Valgerdur and Scott, Robert A. and Almgren, Peter and Arking, Dan E. and Aulchenko, Yurii and Balkau, Beverley and Benediktsson, Rafn and Bergman, Richard N. and Boerwinkle, Eric and Bonnycastle, Lori and Burtt, Noel P. and Campbell, Harry and Charpentier, Guillaume and Collins, Francis S. and Gieger, Christian and Green, Todd and Hadjadj, Samy and Hattersley, Andrew T. and Herder, Christian and Hofman, Albert and Johnson, Andrew D. and Kottgen, Anna and Kraft, Peter and Labrune, Yann and Langenberg, Claudia and Manning, Alisa K. and Mohlke, Karen L. and Morris, Andrew P. and Oostra, Ben and Pankow, James and Petersen, Ann-Kristin and Pramstaller, Peter P. and Prokopenko, Inga and Rathmann, Wolfgang and Rayner, William and Roden, Michael and Rudan, Igor and Rybin, Denis and Scott, Laura J. and Sigurdsson, Gunnar and Sladek, Rob and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tuomilehto, Jaakko and Uitterlinden, Andre G. and Vivequin, Sidonie and Weedon, Michael N. and Wright, Alan F. and Hu, Frank B. and Illig, Thomas and Kao, Linda and Meigs, James B. and Wilson, James F. and Stefansson, Kari and van Duijn, Cornelia and Altschuler, David and Morris, Andrew D. and Boehnke, Michael and McCarthy, Mark I. and Froguel, Philippe and Palmer, Colin N. A. and Wareham, Nicholas J. and Groop, Leif and Frayling, Timothy M. and Cauchi, Stephane},
  issn         = {1553-7404},
  language     = {eng},
  number       = {5},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  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},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1002741},
  volume       = {8},
  year         = {2012},
}