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 article

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=8.4x10(-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=1.3x10(-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=3.2x10(-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=2.2x10(-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.

Authors: Perry, JR; Voight, B; Yengo, L; Amin, N; Dupuis, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Public Library of Science
• Journal: PLoS genetics
• Volume: 8
• Issue: 5
• Article number: e1002741
• Publication date: 2012-05-31
• DOI: 10.1371/journal.pgen.1002741
• EISSN: 1553-7404
• ISSN: 1553-7390
• Language: English
• Keywords: Risk Factors; Asian Continental Ancestry Group; Case-Control Studies; High Mobility Group Proteins; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Body Mass Index; GIANT Consortium; Aged; Humans; DIAGRAM Consortium; European Continental Ancestry Group; Genome-Wide Association Study; Male; Laminin; Alleles; MAGIC; Obesity; Diabetes Mellitus, Type 2; Female; Middle Aged