Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases
Author(s)
Type
Journal Article
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 = 8.461029
, 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 = 1.361028
, 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 = 3.2610214. This was larger than the same model fitted in the obese analysis where the
OR = 1.06 [95% CI 1.05–1.08], P = 2.2610216. 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.
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 = 8.461029
, 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 = 1.361028
, 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 = 3.2610214. This was larger than the same model fitted in the obese analysis where the
OR = 1.06 [95% CI 1.05–1.08], P = 2.2610216. 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.
Date Issued
2012-05-01
Date Acceptance
2012-04-14
Citation
PLOS Genetics, 2012, 8 (5)
ISSN
1553-7390
Publisher
Public Library of Science
Journal / Book Title
PLOS Genetics
Volume
8
Issue
5
Copyright Statement
© 2012 Perry et al. 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.
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENETICS & HEREDITY
GENOME-WIDE ASSOCIATION
SUSCEPTIBILITY LOCI
EXPRESSION
CELLS
DIFFERENTIATION
INSULIN
DISEASE
GLUCOSE
MOUSE
PROTEIN
Publication Status
Published
Article Number
e1002741