Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from Starr County, Texas

Abstract

Aims/hypothesis We report a genome-wide association study of type 2 diabetes in an admixed sample from Mexico City and describe the results of a meta-analysis of this study and another genome-wide scan in a Mexican-American sample from Starr County, TX, USA. The top signals observed in this meta-analysis were followed up in the Diabetes Genetics Replication and Meta-analysis Consortium (DIAGRAM) and DIAGRAM+ datasets. Methods We analysed 967 cases and 343 normoglycaemic controls. The samples were genotyped with the Affymetrix Genome-wide Human SNP array 5.0. Associations of genotyped and imputed markers with type 2 diabetes were tested using a missing data likelihood score test. A fixed-effects meta-analysis including 1,804 cases and 780 normoglycaemic controls was carried out by weighting the effect estimates by their inverse variances. Results In the meta-analysis of the two Hispanic studies, markers showing suggestive associations (p<10−5) were identified in two known diabetes genes, HNF1A and KCNQ1, as well as in several additional regions. Meta-analysis of the two Hispanic studies and the recent DIAGRAM+ dataset identified genome-wide significant signals (p<5×10−8) within or near the genes HNF1A and CDKN2A/CDKN2B, as well as suggestive associations in three additional regions, IGF2BP2, KCNQ1 and the previously unreported C14orf70. Conclusions/interpretation We observed numerous regions with suggestive associations with type 2 diabetes. Some of these signals correspond to regions described in previous studies. However, many of these regions could not be replicated in the DIAGRAM datasets. It is critical to carry out additional studies in Hispanic and American Indian populations, which have a high prevalence of type 2 diabetes.

Quantitative candidate gene association studies of metabolic traits in Han Chinese type 2 diabetes patients

“…Several loci near or in the CNKN2A/2B gene are involved in T2DM susceptibility. CDKN2A/B polymorphisms are associated with impaired insulin release and impaired glucose tolerance, and the TT genotype is associated with higher 2-h post-load glucose levels (Hribal et al, 2011;Parra et al, 2011). The MYH9 (non-muscle myosin heavy chain 9) gene encodes non-muscle myosin IIA and is expressed in glomerular podocytes and mesangial cells.…”

Understanding Genetic Heterogeneity in Type 2 Diabetes by Delineating Physiological Phenotypes:SIRT1and its Gene Network in Impaired Insulin Secretion

“…These studies have provided strong evidence of an association of the genes involved in β-cell development, proliferation, function, and apoptosis [5][6][7][8][9][10][11][12][13]. Other associated genes are involved in glucose homeostasis [5,7,14], insulin secretion, resistance, and function [5,7,[12][13][14][15][16][17][18][19][20][21][22][23], membrane transporters [5,24], transcription factors (TFs) [25][26][27], and energy sensing and fat metabolism [7,8,10,12,24,[28][29][30].…”

Fine Mapping Type 2 Diabetes Susceptibility Loci

“…These loci have primarily been discovered through GWAS efforts in populations of European descent [1-4, 8•], but lately in other ancestry groups, including East Asians [7•], South Asians [6•], Hispanics [5], African Americans [9] and, most recently, through trans-ethnic meta-analysis [10••]. For the vast majority of these loci, the causal variants and the transcripts through which their effects on T2D susceptibility are mediated, remain obscure.…”

“…Large-scale genome-wide association studies (GWAS) have proved to be an extremely successful approach to identifying loci contributing genetic effects to type 2 diabetes (T2D) susceptibility across ethnicities [1][2][3][4][5]6•, 7•, 8•, 9, 10••]. These loci are typically represented by a common lead SNP, defined here to have minor allele frequency (MAF) of more than 5 %.…”