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Objective  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 aβ 42  concentrations and aβ 42 :aβ 40  ratios in late middle age (mean = 59 years), old age (mean = 77 years), or change over time (mean = 18 years).    Methods  Plasma aβ measures were linearly regressed onto age, gender,  APOE  ε4 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 aβ 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 aβ 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 aβ 42 :aβ 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 aβ 42 :aβ 40  ratio and the fold-change in aβ 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 aβ levels, and identified a plausible Alzheimer’s Disease candidate gene ( ITPRIP ) influencing cell death. Plasma aβ concentrations may have dynamic biological determinants across the lifespan; plasma aβ study designs or analyses must consider age.

plos one

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