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

Objective We performed single-variant and gene-based association analyses of plasma amyloid-beta (a beta) concentrations using whole exome sequence from 1,414 African and European Americans. Our goal was to identify genes that influence plasma a beta(42) concentrations and a beta(42): a beta(40) ratios in late middle age (mean = 59 years), old age (mean = 77 years), or change over time (mean = 18 years). Methods Plasma a beta measures were linearly regressed onto age, gender, APOE epsilon 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 beta 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 beta(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 beta(42): a beta(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 beta(42): a beta(40) ratio and the fold-change in a beta(42), respectively, via SKAT in African Americans. No associations replicated externally (N = 725). Conclusion We discovered age-dependent genetic effects, established associations between vascularrelated genes (KLKB1, F12, PLIN2) and midlife plasma a beta levels, and identified a plausible Alzheimer's Disease candidate gene (ITPRIP) influencing cell death. Plasma a beta concentrations may have dynamic biological determinants across the lifespan; plasma a beta study designs or analyses must consider age.