Journal
AMERICAN JOURNAL OF EPIDEMIOLOGY
Volume 176, Issue 5, Pages 423-430Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/aje/kws123
Keywords
expression single nucleotide polymorphism; gene set enrichment analysis; genome-wide association study; integrative genomic analysis; single nucleotide polymorphism; type 2 diabetes
Categories
Funding
- Gene Environment-Association Studies (GENEVA) under the National Institutes of Health (NIH) Genes, Environment, and Health Initiative (GEI) [U01HG004738, U01HG004422, U01HG004402, U01H G004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG 006033]
- NIH Institutes (National Institute of Dental and Craniofacial Research) [U01DE018993, U01DE018903]
- National Institute on Alcohol Abuse and Alcoholism [U10AA008401]
- National Institute on Drug Abuse [P01CA089392, R01DA013423]
- National Cancer Institute [CA63464, CA54281, CA136792, Z01CP010200]
- NIH GEI [U01HG04424, U01HG004438]
- Johns Hopkins University Center for Inherited Disease Research
- NIH [HHSN 268200782096C]
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Large-scale genome-wide association studies (GWAS) have identified over 40 genomic regions significantly associated with type 2 diabetes mellitus. However, GWAS results are not always straightforward to interpret, and linking these loci to meaningful disease etiology is often difficult without extensive follow-up studies. The authors expanded on previously reported type 2 diabetes mellitus GWAS from the nested case-control studies of 2 prospective US cohorts by incorporating expression single nucleotide polymorphism (SNP) information and applying SNP set enrichment analysis to identify sets of SNPs associated with genes that could provide further biologic insight to traditional genome-wide analysis. Using data collected between 1989 and 1994 in these previous studies to form a nested case-control study, the authors found that 3 of the most significantly associated SNPs to type 2 diabetes mellitus in their study are expression SNPs to the lymphocyte antigen 75 gene (LY75), the ubiquitin-specific peptidase 36 gene (USP36), and the phosphatidylinositol transfer protein, cytoplasmic 1 gene (PITPNC1). SNP set enrichment analysis of the GWAS results identified enrichment for expression SNPs to the macrophage-enriched module and the Gene Ontology (GO) biologic process fat cell differentiation human, which includes the transcription factor 7-like 2 gene (TCF7L2), as well as other type 2 diabetes mellitus-associated genes. Integrating genome-wide association, gene expression, and gene set analysis may provide valuable biologic support for potential type 2 diabetes mellitus susceptibility loci and may be useful in identifying new targets or pathways of interest for the treatment and prevention of type 2 diabetes mellitus.
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