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Perry, J.R.* ; 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.* ; Bonnycastle, L.* ; Burtt, N.P.* ; Campbell, H.* ; Charpentier, G.* ; Collins, F.S.* ; Gieger, C. ; Green, T.* ; Hadjadj, S.* ; Hattersley, A.T.* ; Herder, C.* ; Hofman, A.* ; Johnson, A.D.* ; Köttgen, A.* ; Kraft, P.* ; Labrune, Y.* ; Langenberg, C.* ; Manning, A.K.* ; Mohlke, K.L.* ; Morris, A.P.* ; Oostra, B.* ; Pankow, J.* ; Petersen, A.-K. ; Pramstaller, P.P.* ; Prokopenko, I.* ; Rathmann, W.* ; Rayner, W.* ; Roden, M.* ; Rudan, I.* ; Rybin, D.* ; Scott, L.J.* ; Sigurdsson, G.* ; Sladek, R.* ; Thorleifsson, G.* ; Thorsteinsdottir, U.* ; Tuomilehto, J.* ; Uitterlinden, A.G.* ; Vivequin, S.* ; Weedon, M.N.* ; Wright, A.F.* ; Hu, F.B.* ; Illig, T. ; Kao, L.* ; Meigs, J.B.* ; Wilson, J.F.* ; Stefansson, K.* ; van Duijn, C.M.* ; Altschuler, D.* ; Morris, A.D.* ; Boehnke, M.* ; McCarthy, M.I.* ; Froguel, P.* ; Palmer, C.N.* ; Wareham, N.J.* ; Groop, L.* ; Frayling, T.M.* ; Cauchi, S.*

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 Genet. 8:e1002741 (2012)
Verlagsversion Volltext DOI PMC
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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/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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; EXPRESSION; CELLS; DIFFERENTIATION; INSULIN; DISEASE; GLUCOSE; MOUSE; PROTEIN
Sprache englisch
Veröffentlichungsjahr 2012
HGF-Berichtsjahr 2012
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Zeitschrift PLoS Genetics
Quellenangaben Band: 8, Heft: 5, Seiten: , Artikelnummer: e1002741 Supplement: ,
Verlag Public Library of Science (PLoS)
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Molecular Epidemiology (AME)
Institute of Genetic Epidemiology (IGE)
German Center for Diabetes Reseach (DZD)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
90000 - German Center for Diabetes Research
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504200-002
G-504100-001
G-504200-001
G-501900-421
PubMed ID 22693455
DOI 10.1371/journal.pgen.1002741
WOS ID WOS:000304864000058
Scopus ID 84863670156
Erfassungsdatum 2012-07-05
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