dc.contributor.author | Perry, John R.B. | |
dc.contributor.author | Voight, BF | |
dc.contributor.author | Yengo, L | |
dc.contributor.author | Amin, N | |
dc.contributor.author | Dupuis, J | |
dc.contributor.author | Ganser, M | |
dc.contributor.author | Grallert, H | |
dc.contributor.author | Navarro, P | |
dc.contributor.author | Li, M | |
dc.contributor.author | Qi, L | |
dc.contributor.author | Steinthorsdottir, V | |
dc.contributor.author | Scott, RA | |
dc.contributor.author | Almgren, P | |
dc.contributor.author | Arking, DE | |
dc.contributor.author | Aulchenko, Yurii | |
dc.contributor.author | Balkau, B | |
dc.contributor.author | Benediktsson, R | |
dc.contributor.author | Bergman, RN | |
dc.contributor.author | Boerwinkle, E | |
dc.contributor.author | Bonnycastle, Lori | |
dc.contributor.author | Burtt, NP | |
dc.contributor.author | Campbell, H | |
dc.contributor.author | Charpentier, G | |
dc.contributor.author | Collins, FS | |
dc.contributor.author | Gieger, C | |
dc.contributor.author | Green, Todd | |
dc.contributor.author | Hadjadj, S | |
dc.contributor.author | Hattersley, Andrew T. | |
dc.contributor.author | Herder, C | |
dc.contributor.author | Hofman, A | |
dc.contributor.author | Johnson, AD | |
dc.contributor.author | Kottgen, A | |
dc.contributor.author | Kraft, P | |
dc.contributor.author | Labrune, Y | |
dc.contributor.author | Langenberg, C | |
dc.contributor.author | Manning, AK | |
dc.contributor.author | Mohlke, KL | |
dc.contributor.author | Morris, AP | |
dc.contributor.author | Oostra, B | |
dc.contributor.author | Pankow, J | |
dc.contributor.author | Petersen, AK | |
dc.contributor.author | Pramstaller, PP | |
dc.contributor.author | Prokopenko, I | |
dc.contributor.author | Rathmann, W | |
dc.contributor.author | Rayner, W | |
dc.contributor.author | Roden, M | |
dc.contributor.author | Rudan, I | |
dc.contributor.author | Rybin, D | |
dc.contributor.author | Scott, LJ | |
dc.contributor.author | Sigurdsson, G | |
dc.contributor.author | Sladek, R | |
dc.contributor.author | Thorleifsson, G | |
dc.contributor.author | Thorsteinsdottir, U | |
dc.contributor.author | Tuomilehto, J | |
dc.contributor.author | Uitterlinden, AG | |
dc.contributor.author | Vivequin, S | |
dc.contributor.author | Weedon, Michael N. | |
dc.contributor.author | Wright, AF | |
dc.contributor.author | MAGIC | |
dc.contributor.author | DIAGRAM Consortium | |
dc.contributor.author | GIANT Consortium | |
dc.contributor.author | Hu, FB | |
dc.contributor.author | Illig, T | |
dc.contributor.author | Kao, L | |
dc.contributor.author | Meigs, JB | |
dc.contributor.author | Wilson, JF | |
dc.contributor.author | Stefansson, K | |
dc.contributor.author | van Duijn, C | |
dc.contributor.author | Altschuler, D | |
dc.contributor.author | Morris, AD | |
dc.contributor.author | Boehnke, M | |
dc.contributor.author | McCarthy, MI | |
dc.contributor.author | Froguel, P | |
dc.contributor.author | Palmer, CN | |
dc.contributor.author | Wareham, NJ | |
dc.contributor.author | Groop, Leif | |
dc.contributor.author | Frayling, Timothy M. | |
dc.contributor.author | Cauchi, S | |
dc.date.accessioned | 2013-12-09T14:22:43Z | |
dc.date.issued | 2012-05 | |
dc.description.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. | en_GB |
dc.identifier.citation | PLoS Genetics, 2012, Vol. 8, Issue 5 | en_GB |
dc.identifier.doi | 10.1371/journal.pgen.1002741 | |
dc.identifier.uri | http://hdl.handle.net/10871/14219 | |
dc.language.iso | en | en_GB |
dc.publisher | Public Library of Science | en_GB |
dc.relation.url | http://www.ncbi.nlm.nih.gov/pubmed/22693455 | en_GB |
dc.relation.url | http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1002741 | en_GB |
dc.subject | Aged | en_GB |
dc.subject | Alleles | en_GB |
dc.subject | Asian Continental Ancestry Group | en_GB |
dc.subject | Body Mass Index | en_GB |
dc.subject | Case-Control Studies | en_GB |
dc.subject | Diabetes Mellitus, Type 2 | en_GB |
dc.subject | European Continental Ancestry Group | en_GB |
dc.subject | Female | en_GB |
dc.subject | Genetic Predisposition to Disease | en_GB |
dc.subject | Genome-Wide Association Study | en_GB |
dc.subject | High Mobility Group Proteins | en_GB |
dc.subject | Humans | en_GB |
dc.subject | Laminin | en_GB |
dc.subject | Male | en_GB |
dc.subject | Middle Aged | en_GB |
dc.subject | Obesity | en_GB |
dc.subject | Polymorphism, Single Nucleotide | en_GB |
dc.subject | Risk Factors | en_GB |
dc.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 | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2013-12-09T14:22:43Z | |
dc.identifier.issn | 1553-7390 | |
exeter.place-of-publication | United States | |
dc.description | addresses: Genetics of Complex Traits, Peninsula Medical School, University of Exeter, Exeter, United Kingdom. | en_GB |
dc.description | notes: PMCID: PMC3364960 | en_GB |
dc.description | This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | en_GB |
dc.identifier.journal | PLoS Genetics | en_GB |