Dataset Information

Whole exome sequence-based association analyses of plasma amyloid-? in African and European Americans; the Atherosclerosis Risk in Communities-Neurocognitive Study.

ABSTRACT: Objective: We performed single-variant and gene-based association analyses of plasma amyloid-? (a?) concentrations using whole exome sequence from 1,414 African and European Americans. Our goal was to identify genes that influence plasma a?42 concentrations and a?42:a?40 ratios in late middle age (mean = 59 years), old age (mean = 77 years), or change over time (mean = 18 years).

Methods: Plasma a? measures were linearly regressed onto age, gender, APOE ?4 carrier status, and time elapsed between visits (fold-changes only) separately by race. Following inverse normal transformation of the residuals, seqMeta was used to conduct race-specific single-variant and gene-based association tests while adjusting for population structure. Linear regression models were fit on autosomal variants with minor allele frequencies (MAF)?1%. T5 burden and Sequence Kernel Association (SKAT) gene-based tests assessed functional variants with MAF?5%. Cross-race fixed effects meta-analyses were Bonferroni-corrected for the number of variants or genes tested.

Results: Seven genes were associated with a? in late middle age or change over time; no associations were identified in old age. Single variants in KLKB1 (rs3733402; p = 4.33x10-10) and F12 (rs1801020; p = 3.89x10-8) were significantly associated with midlife a?42 levels through cross-race meta-analysis; the KLKB1 variant replicated internally using 1,014 additional participants with exome chip. ITPRIP, PLIN2, and TSPAN18 were associated with the midlife a?42:a?40 ratio via the T5 test; TSPAN18 was significant via the cross-race meta-analysis, whereas ITPRIP and PLIN2 were European American-specific. NCOA1 and NT5C3B were associated with the midlife a?42:a?40 ratio and the fold-change in a?42, respectively, via SKAT in African Americans. No associations replicated externally (N = 725).

Conclusion: We discovered age-dependent genetic effects, established associations between vascular-related genes (KLKB1, F12, PLIN2) and midlife plasma a? levels, and identified a plausible Alzheimer's Disease candidate gene (ITPRIP) influencing cell death. Plasma a? concentrations may have dynamic biological determinants across the lifespan; plasma a? study designs or analyses must consider age.

SUBMITTER: Simino J

PROVIDER: S-EPMC5509141 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Whole exome sequence-based association analyses of plasma amyloid-β in African and European Americans; the Atherosclerosis Risk in Communities-Neurocognitive Study.

Simino Jeannette J Wang Zhiying Z Bressler Jan J Chouraki Vincent V Yang Qiong Q Younkin Steven G SG Seshadri Sudha S Fornage Myriam M Boerwinkle Eric E Mosley Thomas H TH

PloS one 20170713 7

<h4>Objective</h4>We performed single-variant and gene-based association analyses of plasma amyloid-β (aβ) concentrations using whole exome sequence from 1,414 African and European Americans. Our goal was to identify genes that influence plasma aβ42 concentrations and aβ42:aβ40 ratios in late middle age (mean = 59 years), old age (mean = 77 years), or change over time (mean = 18 years).<h4>Methods</h4>Plasma aβ measures were linearly regressed onto age, gender, APOE ε4 carrier status, and time e ...[more]

PMID: 28704393

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Project description:BackgroundLow serum magnesium levels have been associated with multiple chronic diseases. The regulation of serum magnesium homeostasis is not well understood. A previous genome-wide association study (GWAS) of European ancestry (EA) populations identified nine loci for serum magnesium. No such study has been conducted in African-Americans, nor has there been an evaluation of the interaction of magnesium-associated SNPs with environmental factors. The goals of this study were to identify genetic loci associated with serum magnesium in an African-American (AA) population using both genome-wide and candidate region interrogation approaches and to evaluate gene-environment interaction for the magnesium-associated variants in both EA and AA populations. We conducted a GWAS of serum magnesium in 2737 AA participants of the Atherosclerosis Risk in Communities (ARIC) Study and interrogated the regions of the nine published candidate loci in these results. Literature search identified the influence of progesterone on MUC1 expression and insulin on TRPM6 expression.ResultsThe GWAS approach in African-American participants identified a locus near MUC1 as genome-wide significant (rs2974937, beta=-0.013, p=6.1x10(-9)). The candidate region interrogation approach identified two of the nine loci previously discovered in EA populations as containing SNPs that were significantly associated in African-American participants (SHROOM3 and TRPM6). The index variants at these three loci together explained 2.8 % of the variance in serum magnesium concentration in ARIC African-American participants. On the test of gene-environment interaction in ARIC EA participants, the index variant at MUC1 had 2.5 times stronger association in postmenopausal women with progestin use (beta=-0.028, p=7.3x10(-5)) than in those without any hormone use (beta=-0.011, p=7.0x10(-8), p for interaction 0.03). At TRPM6, the index variant had 1.6 times stronger association in those with lower fasting insulin levels (<80 pmol/L: beta=-0.013, p=1.6x10(-7); ≥80 pmol/L: beta=-0.008, p=1.8x10(-2), p for interaction 0.03).ConclusionsWe identified three loci that explained 2.8% of the variance in serum magnesium concentration in ARIC African-American participants. Following-up on functional studies of gene expression identified gene-environment interactions between progestin use and MUC1 and between insulin and TRPM6 on serum magnesium concentration in ARIC European-American participants. These results extend our understanding of the metabolism of serum magnesium.

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Dataset Information

Whole exome sequence-based association analyses of plasma amyloid-? in African and European Americans; the Atherosclerosis Risk in Communities-Neurocognitive Study.

Publications

Whole exome sequence-based association analyses of plasma amyloid-β in African and European Americans; the Atherosclerosis Risk in Communities-Neurocognitive Study.

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