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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

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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Authors

  • 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 Bonnycastle
  • And 56 others
  • Noel 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
  • 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
  • Stephane Cauchi
  • GIANT Consortium, DIAGRAM Consortium, MAGIC

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Info

Original languageEnglish
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Pages-
Number of pages14
JournalPLoS Genetics
Journal publication date2012
Journal number5
Volume8
DOIs
StatePublished

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.

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