Genome-wide Association Study-identified Loci Research Articles

Abstract P112: Genes in Genome-wide Association Study-identified Loci and Risk of Atherosclerosis in Adolescents and Young Adults

Background: Genome-wide association studies (GWASs) have identified multiple genomic loci associated with atherosclerotic diseases. However, specific genes underlying the observed associations are largely unknown. Objectives: We aimed to examine the associations between genes that harbor variants in high LD with index variants in GWAS-identified loci and pathologically determined atherosclerosis in major arteries from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. Methods and Results: Data for 1,938 single nucleotide polymorphisms (SNPs) from 28 genes were retrieved from whole exome sequence data. Atherosclerosis was confirmed by postmortem examination of major arteries from 1,005 young persons (aged 15-34 years) who died from non-cardiovascular causes. Logistic regression was used to evaluate associations between common SNPs and atherosclerosis controlling for age and sex. Gene-based analysis was conducted using Sequence Kernel Association Test (SKAT) method to test the combined effect of rare and common variants on atherosclerosis controlling for age and gender. All analyses were performed separately in blacks and whites. Statistical significance was determined by false positive discovery rate (FDR) method. In gene-based analyses, BUD13 ( P =1.11х10 -2 ) and COL4A1 ( P =3.58х10 -2 ) were associated with atherosclerosis among young blacks; none of the 28 genes was associated with atherosclerosis in whites. In single marker analysis of common SNPs, LRP1 missense variant rs7397167 ( P =8.50х10 -3 ), COL4A1 variant rs16975492 ( P =4.60х10 -3 ), STK32B variant rs168985 ( P =4.00х10 -3 ), and SMARCA4 variant rs8104480 ( P =1.20х10 -3 ) were associated with atherosclerosis in blacks; MIA3 variant rs17465637 ( P =8.00х10 -3 ), DUS4L missense variant rs6957510 ( P =6.4х10 -3 ), BOLL variant rs771018 ( P =6.2х10 -3 ), BUD3 missense variant rs11820589 ( P =2.1х10 -3 ), and COL4A1 variant rs1133219 ( P =1.8х10 -3 ) were associated with atherosclerosis in whites. Conclusion: Genes in GWAS-identified loci may play a role in the development of atherosclerosis at a young age.

Confirmation of novel type 1 diabetes risk loci in families

Aims/hypothesisOver 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study.MethodsWe genotyped the most disease-predicting single-nucleotide polymorphisms at the 18 susceptibility loci in 3,108 families and used existing genotype data for 2,319 families from the original study, providing 7,013 parent–child trios for analysis. We tested for association using the transmission disequilibrium test.ResultsSeventeen of the 18 susceptibility loci reached nominal levels of significance (p < 0.05) in the expanded family collection, with 14q24.1 just falling short (p = 0.055). When we allowed for multiple testing, ten of the 17 nominally significant loci reached the required level of significance (p < 2.8 × 10−3). All susceptibility loci had consistent direction of effects with the original study.Conclusions/interpretationThe results for the novel GWA study-identified loci are genuine and not due to population stratification. The next step, namely correlation of the most disease-associated genotypes with phenotypes, such as RNA and protein expression analyses for the candidate genes within or near each of the susceptibility regions, can now proceed.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-012-2450-3) contains peer-reviewed but unedited supplementary material, including a full list of members of the Type 1 Diabetes Genetics Consortium, which is available to authorised users.