Most existing expression quantitative trait locus (eQTL) mapping studies have been focused on individuals of European ancestry and are underrepresented in other populations including populations with ...African ancestry. Lack of large-scale well-powered eQTL mapping studies in populations with African ancestry can both impede the dissemination of eQTL mapping results that would otherwise benefit individuals with African ancestry and hinder the comparable analysis for understanding how gene regulation is shaped through evolution. We fill this critical knowledge gap by performing a large-scale in-depth eQTL mapping study on 1,032 African Americans (AA) and 801 European Americans (EA) in the GENOA cohort. We identified a total of 354,931 eSNPs in AA and 371,309 eSNPs in EA, with 112,316 eSNPs overlapped between the two. We found that eQTL harboring genes (eGenes) are enriched in metabolic pathways and tend to have higher SNP heritability compared to non-eGenes. We found that eGenes that are common in the two populations tend to be less conserved than eGenes that are unique to one population, which are less conserved than non-eGenes. Through conditional analysis, we found that eGenes in AA tend to harbor more independent eQTLs than eGenes in EA, suggesting potentially diverse genetic architecture underlying expression variation in the two populations. Finally, the large sample sizes in GENOA allow us to construct accurate expression prediction models in both AA and EA, facilitating powerful transcriptome-wide association studies. Overall, our results represent an important step toward revealing the genetic architecture underlying expression variation in African Americans.
Identifying genetic variants that are associated with variation in DNA methylation, an analysis commonly referred to as methylation quantitative trait locus (meQTL) mapping, is an important first ...step towards understanding the genetic architecture underlying epigenetic variation. Most existing meQTL mapping studies have focused on individuals of European ancestry and are underrepresented in other populations, with a particular absence of large studies in populations with African ancestry. We fill this critical knowledge gap by performing a large-scale cis-meQTL mapping study in 961 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We identify a total of 4,565,687 cis-acting meQTLs in 320,965 meCpGs. We find that 45% of meCpGs harbor multiple independent meQTLs, suggesting potential polygenic genetic architecture underlying methylation variation. A large percentage of the cis-meQTLs also colocalize with cis-expression QTLs (eQTLs) in the same population. Importantly, the identified cis-meQTLs explain a substantial proportion (median = 24.6%) of methylation variation. In addition, the cis-meQTL associated CpG sites mediate a substantial proportion (median = 24.9%) of SNP effects underlying gene expression. Overall, our results represent an important step toward revealing the co-regulation of methylation and gene expression, facilitating the functional interpretation of epigenetic and gene regulation underlying common diseases in African Americans.
Genetic studies of plasma TG levels have identified associations with multiple candidate loci on chromosome11q23.3, which harbors a number of genes, including BUD13, ZNF259, and APOA5-A4-C3-A1. This ...study aimed to examine whether these multiple candidate genes on the 11q23.3 regions exert independent effects on TG levels or whether their effects are confounded by linkage disequilibrium (LD). We performed a genome-wide association study and consequent fine-mapping analyses on TG levels in two Korean population-based cohorts: the Korea Association Resource study (n = 8,223) and the Healthy Twin study (n = 1,735). A total of 301 loci reached genome-wide significance level in pooled analysis, including 10 SNPs with weak LD (r2 < 0.06) clustered on 11q23.3: ApoA5 (rs651821, rs2075291); ZNF259 (rs964184, rs603446); BUD13 (rs11216126); Apoa4 (rs7396851); SIK3 (rs12292858); PCSK7 (rs199890178); PAFAH1B2 (rs12420127), and SIDT2 (rs2269399). When the inter-dependence between alleles was examined using conditional models, five loci on BUD13, ZNF259, and ApoA5 showed possible independent associations. A haplotype analysis using five SNPs revealed both hyper- and hypotriglyceridemic haplotypes, which are relatively common in Koreans (haplotype frequency 0.08–0.22). Our findings suggest the presence of multiple functional loci on 11q23.3, which might exert their effects on plasma TG level independently or through complex interactions between functional loci.
Target organ damage (TOD) manifests as vascular injuries in the body organ systems associated with long-standing hypertension. DNA methylation in peripheral blood leukocytes can capture inflammatory ...processes and gene expression changes underlying TOD. We investigated the association between epigenome-wide DNA methylation and five measures of TOD (estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI), relative wall thickness (RWT), and white matter hyperintensity (WMH)) in 961 African Americans from hypertensive sibships. A multivariate (multi-trait) model of eGFR, UACR, LVMI, and RWT identified seven CpGs associated with at least one of the traits (cg21134922, cg04816311 near C7orf50, cg09155024, cg10254690 near OAT, cg07660512, cg12661888 near IFT43, and cg02264946 near CATSPERD) at FDR q < 0.1. Adjusting for blood pressure, body mass index, and type 2 diabetes attenuated the association for four CpGs. DNA methylation was associated with cis-gene expression for some CpGs, but no significant mediation by gene expression was detected. Mendelian randomization analyses suggested causality between three CpGs and eGFR (cg04816311, cg10254690, and cg07660512). We also assessed whether the identified CpGs were associated with TOD in 614 African Americans in the Hypertension Genetic Epidemiology Network (HyperGEN) study. Out of three CpGs available for replication, cg04816311 was significantly associated with eGFR (p = 0.0003), LVMI (p = 0.0003), and RWT (p = 0.002). This study found evidence of an association between DNA methylation and TOD in African Americans and highlights the utility of using a multivariate-based model that leverages information across related traits in epigenome-wide association studies.
Hypertension is a major modifiable risk factor for arteriosclerosis that can lead to target organ damage (TOD) of heart, kidneys, and peripheral arteries. A recent epigenome-wide association study ...for blood pressure (BP) identified 13 CpG sites, but it is not known whether DNA methylation at these sites is also associated with TOD.
In 1218 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study, a cohort of hypertensive sibships, we evaluated the associations between methylation at these 13 CpG sites measured in peripheral blood leukocytes and five TOD traits assessed approximately 5 years later.
Ten significant associations were found after adjustment for age, sex, blood cell counts, time difference between CpG and TOD measurement, and 10 genetic principal components (FDR q < 0.1): two with estimated glomerular filtration rate (eGFR, cg06690548, cg10601624), six with urinary albumin-to-creatinine ratio (UACR, cg16246545, cg14476101, cg19693031, cg06690548, cg00574958, cg22304262), and two with left ventricular mass indexed to height (LVMI, cg19693031, cg00574958). All associations with eGFR and four associations with UACR remained significant after further adjustment for body mass index (BMI), smoking status, and diabetes. We also found significant interactions between cg06690548 and BMI on UACR, and between 3 CpG sites (cg19693031, cg14476101, and cg06690548) and diabetes on UACR (FDR q < 0.1). Mediation analysis showed that 4.7% to 38.1% of the relationship between two CpG sites (cg19693031 and cg00574958) and two TOD measures (UACR and LVMI) was mediated by blood pressure (Bonferroni-corrected P < 0.05). Mendelian randomization analysis suggests that methylation at two sites (cg16246545 and cg14476101) in PHGDH may causally influence UACR.
In conclusion, we found compelling evidence for associations between arteriosclerotic traits of kidney and heart and previously identified blood pressure-associated DNA methylation sites. This study may lend insight into the role of DNA methylation in pathological mechanisms underlying target organ damage from hypertension.
Background: Salt is essential in our diet, but excess intake is a well-established risk factor for hypertension. The presence and importance of genetic contributions to salt intake, however, are not ...well understood.Objective: The aim of this study was to examine whether a genetic predisposition and an environmental influence exist for sodium intake and salt habit.Design: In a twin-family cohort, half-day urine samples from 1204 individuals (133 pairs of monozygotic twins, 29 pairs of dizygotic twins, and 880 singletons) were collected to assess 24-h sodium intakes. Daily total sodium intake, sodium density per calorie (Na-D), and salt habit questions were analyzed with adjustment for other epidemiologic characteristics. We calculated heritability (h2) and intraclass correlations to examine the genetic and shared environmental contributions to total sodium intake traits.Results: The average sodium intake was 208.4 ± 107.0 mmol/d. Men had a higher absolute sodium intake (242.6 ± 117.4 mmol/d), but Na-D did not differ by sex. Moderate genetic influences existed (h2 = 0.31–0.34) for sodium intake and Na-D. We also found that sharing current residence rather than being a family member explained 22% of the variance in Na-D.Conclusion: Our findings suggest that both genetic predisposition and shared environment contribute to sodium intakes and salt habits alike.
The Healthy Twin Study, Korea (HT) is an ongoing multi-center cohort study that was initiated in 2005, based on a nation-wide twin and family database. Since its inception, the HT has recruited 815 ...pairs of adult twins and a total of 3,690 individual twins and their families as of July 2012. Here we summarize updates since the previous report in 2006. Besides the increase in size, the HT has been enriched in several aspects: a biobank was constructed for ongoing and future omics studies; and genome-wide single nucleotide polymorphism markers (Affymetrix GeneChip version 6.0, 1 M probes) have been analyzed for 2,200 individuals, which enabled gene identification studies for measured phenotypes. In addition, longitudinal study protocols were established through the HT and a second wave survey was finished in 2010 with >70% follow-up rate. The parallel genome research projects were recently launched, which would expedite multi-omics studies maximizing the twin potentials such as metagenomics and epigenetics studies, and endow us with resources for recruiting more participants. We submit this report to share updates and research opportunities from the HT.
Both social and genetic factors contribute to cognitive impairment and decline, yet genetic factors identified through genome-wide association studies (GWAS) explain only a small portion of trait ...variability. This “missing heritability” may be due to rare, potentially functional, genetic variants not assessed by GWAS, as well as gene-by-social factor interactions not explicitly modeled. Gene-by-social factor interactions may also operate differently across race/ethnic groups. We selected 39 genes that had significant, replicated associations with cognition, dementia, and related traits in published GWAS. Using gene-based analysis (SKAT/iSKAT), we tested whether common and/or rare variants were associated with episodic memory performance and decline either alone or through interaction with education in >10,000 European ancestry (EA) and >2200 African ancestry (AA) respondents from the Health and Retirement Study (HRS). Nine genes in EA and five genes in AA were associated with memory performance or decline (p < 0.05), and these effects did not attenuate after adjusting for education. Interaction between education and CLPTM1 on memory performance was significant in AA (p = 0.003; FDR-adjusted p = 0.038) and nominally significant in EA (p = 0.026). In both ethnicities, low memory performance was associated with CLPTM1 genotype (rs10416261) only for those with less than high school education, and effects persisted after adjusting for APOE ε4. For over 70% of gene-by-education interactions across the genome that were at least nominally significant in either ethnic group (p < 0.05), genetic effects were only observed for those with less than high school education. These results suggest that genetic effects on memory identified in this study are not mediated by education, but there may be important gene-by-education interactions across the genome, including in the broader APOE genomic region, which operate independently of APOE ε4. This work illustrates the importance of developing theoretical frameworks and methodological approaches for integrating social and genomic data to study cognition across ethnic groups.
•Investigates genetic effects on longitudinal trajectories of memory performance.•Evaluates whether education modifies genetic effects on memory trajectories.•Genetic effects on memory were not mediated by educational attainment.•Education may offset genetic influences on memory performance and decline.
Later life cognitive function is influenced by genetics as well as early- and later-life socioeconomic context. However, few studies have examined the interaction between genetics and early childhood ...factors. Using gene-based tests (iSKAT/iSKAT-O), we examined whether common and/or rare exonic variants in 39 gene regions previously associated with cognitive performance, dementia, and related traits had an interaction with childhood socioeconomic context (parental education and financial strain) on memory performance or decline in European ancestry (EA, N=10,468) and African ancestry (AA, N=2,252) participants from the Health and Retirement Study. Of the 39 genes, 22 in EA and 19 in AA had nominally significant interactions with at least one childhood socioeconomic measure on memory performance and/or decline; however, all but one (father's education by SLC24A4 in AA) were not significant after multiple testing correction (FDR <0.05). In trans-ethnic meta-analysis, two genes interacted with childhood socioeconomic context (FDR <0.05): mother's education by MS4A4A on memory performance, and father's education by SLC24A4 on memory decline. Both interactions remained significant (p<0.05) after adjusting for respondent's own educational attainment, APOE ε4 status, lifestyle factors, BMI, and comorbidities. For both interactions in EA and AA, the genetic effect was stronger in participants with low parental education. Examination of common and rare variants in genes discovered through GWAS shows that childhood context may interact with key gene regions to jointly impact later life memory function and decline. Genetic effects may be more salient for those with lower childhood socioeconomic status.
Background
Later life cognitive function is influenced both by genetics as well as early‐ and later‐life socioeconomic context, and these factors may also interact with each other. Previous research ...has demonstrated interactions between adult socioeconomic status and several gene regions that influence memory performance and decline in older adulthood, but few studies have examined whether genetics also interacts with childhood socioeconomic factors.
Methods
We used growth curve modeling to estimate episodic memory performance at age 65 (trajectory intercept) and decline thereafter (trajectory slope) in European ancestry (EA, N = 10,468) and African ancestry (AA, N = 2,252) participants from the Health and Retirement Study. Early‐life socioeconomic context included measures of parental education and financial strain. We selected 39 gene regions previously associated with cognitive performance, dementia, and related traits from GWAS. We tested whether all variants (1000 Genomes imputed data) and/or rare exomic variants (exome chip data) in these gene regions interacted with childhood socioeconomic context to influence memory using gene‐based tests (Interaction Sequence Kernel Association Test (iSKAT) or iSKAT Optimal Unified Test (iSKAT‐O)). For iSKAT analyses, we conducted a trans‐ethnic meta‐analysis.
Results
Of the 39 genes, 22 in EA and 19 in AA had nominally significant interactions (p < 0.05) with at least one childhood socioeconomic measure on memory performance and/or decline; however, all but one (father’s education by SLC24A4 gene region in AA) were not significant after multiple testing correction (FDR <0.1). In trans‐ethnic meta‐analysis, two gene regions interacted with childhood socioeconomic context (FDR <0.05). Both interactions were robust to adjustment for respondent’s own educational attainment and APOE ε4. For both interactions (mother’s education by MS4A4A on memory performance (meta‐analysis p = 0.0005), and father’s education by SLC24A4 on memory decline (meta‐analysis p = 0.0009)) in both EA and AA, the genetic effect was stronger in participants with low parental education.
Conclusions
Examination of common and rare variants in genes discovered through GWAS shows that childhood socioeconomic context may interact with a few key gene regions to jointly impact memory function and decline in later life. Genetic effects may be more salient for those with lower childhood socioeconomic status.
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