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, Qi, Lu, Steinthorsdottir, Valgerdur, Scott, Robert A., Almgren, Peter, Arking, Dan E., Aulchenko, Yurii, Balkau, Beverley, Benediktsson, Rafn, Bergman, Richard N., Boerwinkle, Eric, Bonnycastle, Lori, Burtt, Noel P., Campbell, Harry, Charpentier, Guillaume, Collins, Francis S., Gieger, Christian, Green, Todd, Hadjadj, Samy, Hattersley, Andrew T., Herder, Christian, Hofman, Albert, Johnson, Andrew D., Kottgen, Anna, Kraft, Peter, Labrune, Yann, Langenberg, Claudia, Manning, Alisa K., 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, Scott, Laura J., Sigurdsson, Gunnar, Sladek, Rob, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Uitterlinden, Andre G., Vivequin, Sidonie, Weedon, Michael N., Wright, Alan F., Hu, Frank B., Illig, Thomas, Kao, Linda, Meigs, James B., 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. and Cauchi, Stephane (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: . doi:10.1371/journal.pgen.1002741

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Author Perry, John R. B.
Voight, Benjamin F.
Yengo, Loic
Amin, Najaf
Dupuis, Josee
Ganser, Martha
Grallert, Harald
Navarro, Pau
Li, Man
Qi, Lu
Steinthorsdottir, Valgerdur
Scott, Robert A.
Almgren, Peter
Arking, Dan E.
Aulchenko, Yurii
Balkau, Beverley
Benediktsson, Rafn
Bergman, Richard N.
Boerwinkle, Eric
Bonnycastle, Lori
Burtt, Noel P.
Campbell, Harry
Charpentier, Guillaume
Collins, Francis S.
Gieger, Christian
Green, Todd
Hadjadj, Samy
Hattersley, Andrew T.
Herder, Christian
Hofman, Albert
Johnson, Andrew D.
Kottgen, Anna
Kraft, Peter
Labrune, Yann
Langenberg, Claudia
Manning, Alisa K.
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
Scott, Laura J.
Sigurdsson, Gunnar
Sladek, Rob
Thorleifsson, Gudmar
Thorsteinsdottir, Unnur
Tuomilehto, Jaakko
Uitterlinden, Andre G.
Vivequin, Sidonie
Weedon, Michael N.
Wright, Alan F.
Hu, Frank B.
Illig, Thomas
Kao, Linda
Meigs, James B.
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, Stephane
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
Formatted 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
Journal name Plos Genetics   Check publisher's open access policy
ISSN 1553-7390
Publication date 2012-05-31
Year available 2012
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1002741
Open Access Status DOI
Volume 8
Issue 5
Total pages 14
Place of publication San Francisco, United States
Publisher Public Library of Science
Language eng
Formatted 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/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.
Keyword Genetics & Heredity
Genetics & Heredity
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 092447/Z/10/Z
R01 DK078616
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 94 times in Thomson Reuters Web of Science Article | Citations
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