DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Type 2 diabetes. The EFO term type II diabetes mellitus was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: type II diabetes mellitus

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

JR Perry, BF Voight, L Yengo, N Amin, J Dupuis, M Ganser, H Grallert, P Navarro, M Li, L Qi, V Steinthorsdottir, RA Scott, P Almgren, DE Arking, Y Aulchenko, B Balkau, R Benediktsson, RN Bergman, E Boerwinkle, L Bonnycastle, NP Burtt, H Campbell, G Charpentier, FS Collins, C Gieger, T Green, S Hadjadj, AT Hattersley, C Herder, A Hofman, AD Johnson, A Kottgen, P Kraft, Y Labrune, C Langenberg, AK Manning, KL Mohlke, AP Morris, B Oostra, J Pankow, AK Petersen, PP Pramstaller, I Prokopenko, W Rathmann, W Rayner, M Roden, I Rudan, D Rybin, LJ Scott, G Sigurdsson, R Sladek, G Thorleifsson, U Thorsteinsdottir, J Tuomilehto, AG Uitterlinden, S Vivequin, MN Weedon, AF Wright, FB Hu, T Illig, L Kao, JB Meigs, JF Wilson, K Stefansson, C van Duijn, D Altschuler, AD Morris, M Boehnke, MI McCarthy, P Froguel, CN Palmer, NJ Wareham, L Groop, TM Frayling, S Cauchi

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:

PLoS genetics May 2012, Vol 8, pp. e1002741

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. PUBMED: 22693455
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