Computational protocol: Cross-Sectional and Longitudinal Replication Analyses of Genome-Wide Association Loci of Type 2 Diabetes in Han Chinese

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Protocol publication

[…] A total of 29 single nucleotide polymorphisms (SNPs) from 28 established T2D loci in populations of European ancestry were genotyped among the DMS case-control sample using the Illumina GoldenGate Indexing assay (Illumina Inc., San Diego, CA). Twenty-five SNPs from 25 loci were successfully genotyped with an average call rate of 98.4% (Table S1 in ). Two of these SNPs, rs1801282 and rs7578597, are non-synonymous SNPs and are predicted to have potential impacts on exonic splicing. There are no predicted functions for the other SNPs based on the SNPinfo database (http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm), a web tool for SNP function prediction . The concordance rate was 100% for 229 duplicate samples. The genotypes of the selected SNPs were extracted from the genotyped (Affymetrix Genomewide Human SNP array 6.0 (Affymetrix, Inc., Santa Clara, CA)) and imputed data of the GenSalt sample . [...] Each SNP was tested for deviation from the Hardy-Weinberg equilibrium (HWE) within the DMS control group and the GenSalt sample using an exact test implemented in Haploview software . In the DMS case-control sample, an additive genetic model with age and sex as covariates was used to test for the association of each SNP with T2D using logistic regression models. Body mass index (BMI) was further adjusted for in these models to examine whether a SNP's effect on T2D was independent of BMI. Associations between SNPs and quantitative glycemic traits under an additive genetic model were analyzed among DMS controls using general linear models that included age and sex. BMI was further adjusted in these models. Log-transformed values for fasting insulin, HOMA-B, HOMA-IR, and insulinogenic index were used as dependent variables.During the conduction of this study, the association results of 22 genotyped SNPs in this study became available in the Asian Genetic Epidemiology Network (AGEN) consortium, which included 6,952 T2D cases and 11,865 controls of East Asian descent in its GWAS meta-analysis discovery stage. To provide more precise estimates of effect sizes for risk alleles of the tested SNPs in East Asians, we conducted a meta-analysis to combine our results with those from the Asian Genetic Epidemiology Network (AGEN) consortium using a fixed effects model weighted by inverse variance .To test the effect of the replicated SNPs on long-term change in FPG and the development of T2D, a genetic risk score was calculated for each individual in the GenSalt sample. The sum of the number of risk alleles at each SNP was weighted according to the SNP's relative effect size which was derived from the meta-analysis of AGEN and this study. We rescaled the weighted score to reflect the number of risk alleles each individual carried, and each point of the genetic-predisposition score corresponded to one risk allele . Generalized estimating equations were used to test the associations of genetic risk score with FPG change and T2D incidence over follow-up accounting for non-independence of GenSalt family members. Age, sex, and baseline BMI were adjusted in these models. SAS statistical software (version 9.2; SAS Institute Inc., Cary, NC) was used to conduct association analyses. […]

Pipeline specifications

Software tools SNPinfo, Haploview
Application GWAS
Diseases Diabetes Mellitus, Type 2
Chemicals Glucose