title: Integrating genetic association, genetics of gene expression, and single nucleotide polymorphism set analysis to identify susceptibility Loci for type 2 diabetes mellitus.
abstract: 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.
authors.affiliation: Department of Genetics, Merck Research Laboratories, Pasteur, Boston, MA 02115, USA. danielle_greenawalt@merck.com
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Greenawalt
authors.forename: Solveig K
authors.initials: SK
authors.lastname: Sieberts
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Cornelis
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Girman
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Justin
authors.initials: J
authors.lastname: Guinney
authors.forename: Lu
authors.initials: L
authors.lastname: Qi
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071119:ADAMTS9 Protein; D015703:Antigens, CD / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C093569:DEC-205 receptor; D005819:Genetic Markers; D037181:Lectins, C-Type; D026901:Membrane Transport Proteins; D015778:Minor Histocompatibility Antigens; C107847:PITPNC1 protein, human; D011956:Receptors, Cell Surface; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C501066:USP36 protein, human; D043222:Ubiquitin Thiolesterase; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human