Association between Expression Quantitative Trait Loci and Metabolic Traits in Two Korean Populations

<div><p>Most genome-wide association studies consider genes that are located closest to single nucleotide polymorphisms (SNPs) that are highly significant for those studies. However, the significance of the associations between SNPs and candidate genes has not been fully determined. An alternative approach that used SNPs in expression quantitative trait loci (eQTL) was reported previously for Crohn’s disease; it was shown that eQTL-based preselection for follow-up studies was a useful approach for identifying risk loci from the results of moderately sized GWAS. In this study, we propose an approach that uses eQTL SNPs to support the functional relationships between an SNP and a candidate gene in a genome-wide association study. The genome-wide SNP genotypes and 10 biochemical measures (fasting glucose levels, BUN, serum albumin levels, AST, ALT, gamma GTP, total cholesterol, HDL cholesterol, triglycerides, and LDL cholesterol) were obtained from the Korean Association Resource (KARE) consortium. The eQTL SNPs were isolated from the SNP dataset based on the RegulomeDB eQTL-SNP data from the ENCODE projects and two recent eQTL reports. A total of 25,658 eQTL SNPs were tested for their association with the 10 metabolic traits in 2 Korean populations (Ansung and Ansan). The proportion of phenotypic variance explained by eQTL and non-eQTL SNPs showed that eQTL SNPs were more likely to be associated with the metabolic traits genetically compared with non-eQTL SNPs. Finally, via a meta-analysis of the two Korean populations, we identified 14 eQTL SNPs that were significantly associated with metabolic traits. These results suggest that our approach can be expanded to other genome-wide association studies.</p></div

In silico annotation of eQTLs.

<p>Note. CHR: chromosome, BP: base position based on the human genome (NCBI36/hg18), SNP: single-nucleotide polymorphism, eQTL: expression quantitative trait loci, TF: Transcription factor binding in liver or pancreas cells, DHS: DNase1 Hypersensitive site in liver or pancreas cells.</p><p>In silico annotation of eQTLs.</p

Estimated genetic variance explained by eQTL SNPs and non-eQTL SNPs.

<p>Note. H2: previously reported heritability of the trait, Vg: estimated genetic variance, Vp: estimated phenotypic variance, Vg/Vp: percent of estimated genetic variance explained by SNPs for each trait.</p><p>Estimated genetic variance explained by eQTL SNPs and non-eQTL SNPs.</p

Significantly associated SNPs in the Ansung and Ansan cohorts and meta-analysis results.

<p>Note. CHR: chromosome, SNP: single-nucleotide polymorphism, BP: base position based on the human genome (NCBI36/hg18), A1: minor allele, MAF: minor allele frequency, Beta: effect size, SE: standard error, FDR: adjusted p-value by false discovery rate, BONF: adjusted p-value by bonferroni correction.</p><p>Significantly associated SNPs in the Ansung and Ansan cohorts and meta-analysis results.</p

Clinical characteristics of the Ansung and Ansan cohorts and the exclusion criteria for each biochemical trait.

<p>Clinical characteristics of the Ansung and Ansan cohorts and the exclusion criteria for each biochemical trait.</p

Mean personality domain scores by genotype for chimpanzees living in Chimpanzee Sanctuary Uto, the sanctuary in Guinea, and the combined sample.

†<p>The combined samples includes 26 subjects from Chimpanzee Sanctuary Uto, 21 subjects from Guinea, and a total of 10 subjects from the Kyoto University Primate Research Institute (<i>n</i> = 5), Higashiyama Zoo (<i>n</i> = 2), Itouzu-no-mori Zoo (<i>n</i> = 1), Kouchi Zoo (<i>n</i> = 1), and Tama Zoo (<i>n</i> = 1).</p

Summary table of the subjects' sex, age, genotype, and personality <i>T</i>-score^†.

<p>Note.</p>†<p><i>Mean</i> = 50 and <i>SD</i> = 10. Dom = Dominance, Ext = Extraversion, Con = Conscientiousness, Agr = Agreeableness, Neu = Neuroticism, Opn = Openness.</p><p>*Other Japanese chimpanzees include 5 subjects from the Kyoto University Primate Research Institute, 2 subjects from the Higashiyama Zoo, 1 chimpanzee from the Itouzu-no-mori Zoo, 1 chimpanzee from the Kouchi Zoo, and 1 chimpanzee from the Tama Zoo.</p

Effect of Tryptophan hydroxylase 2 polymorphism on chimpanzee personality trait: Linear regression analysis with sex and age as the covariates.

<p>Note.</p>†<p>MAF: minor allele frequency.</p><p>*The combined samples includes 26 subjects from Chimpanzee Sanctuary Uto, 21 subjects from Guinea, and a total of 10 subjects from the Kyoto University Primate Research Institute (<i>n</i> = 5), Higashiyama Zoo (<i>n</i> = 2), Itouzu-no-mori Zoo (<i>n</i> = 1), Kouchi Zoo (<i>n</i> = 1), and Tama Zoo (<i>n</i> = 1). Boldfaced values indicate statistically significant effects (<i>p</i><.05). Underlined values indicate trends (<i>p</i><0.1).</p