PLoS Genetics (May 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.

  • John R B Perry,
  • Benjamin F Voight,
  • Loïc Yengo,
  • Najaf Amin,
  • Josée 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 Bonnycastle,
  • Noël 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,
  • Laura J Scott,
  • Gunnar Sigurdsson,
  • Rob Sladek,
  • Gudmar Thorleifsson,
  • Unnur Thorsteinsdottir,
  • Jaakko Tuomilehto,
  • Andre G Uitterlinden,
  • Sidonie Vivequin,
  • Michael N Weedon,
  • Alan F Wright,
  • MAGIC,
  • DIAGRAM Consortium,
  • GIANT Consortium,
  • Frank B Hu,
  • Thomas Illig,
  • Linda Kao,
  • James B Meigs,
  • James F Wilson,
  • Kari Stefansson,
  • Cornelia van Duijn,
  • David Altschuler,
  • Andrew D Morris,
  • Michael Boehnke,
  • Mark I McCarthy,
  • Philippe Froguel,
  • Colin N A Palmer,
  • Nicholas J Wareham,
  • Leif Groop,
  • Timothy M Frayling,
  • Stéphane Cauchi

DOI
https://doi.org/10.1371/journal.pgen.1002741
Journal volume & issue
Vol. 8, no. 5
p. e1002741

Abstract

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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/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.