ABCA7 frameshift deletion associated with Alzheimer disease in African Americans

Abstract

Objective:To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.Methods:Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.Results:A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance (p = 1.414 × 10−5, OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function.Conclusions:This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

ABCA7 risk variant in healthy older African Americans is associated with a functionally isolated entorhinal cortex mediating deficient generalization of prior discrimination training

“…Consistent with this, rs115550680 was found to be in LD with a 44‐base pair deletion (rs142076058) in ABCA7 that is associated with AD in individuals of African ancestry (Cukier et al, ). This deletion is rare in Caucasians but relatively common in African Americans and confers AD risk by interfering with the transportation of lipids and increased Aβ brain levels (Cukier et al, ). Therefore, ABCA7 rs115550680 may be an ethnicity‐specific risk variant that contributes to AD in African Americans through APP processing and suppression of Aβ clearance.…”

“…This further supports the notion that while there may be a common underlying mechanism, distinct alleles confer AD risk in different ethnicities with variable impact on protein structure or function. Consistent with this, rs115550680 was found to be in LD with a 44-base pair deletion (rs142076058) in ABCA7 that is associated with AD in individuals of African ancestry (Cukier et al, 2016). This deletion is rare in Caucasians but relatively common in African Americans and confers AD risk by interfering with the transportation of lipids and increased Aβ brain levels (Cukier et al, 2016).…”

ABCA7 loss-of-function variants, expression, and neurologic disease risk

“…Additional putative LOF mutations were identified in North American Caucasian AD cases of which p.E1679X 3 was statistically significant. These initial studies were followed by replications and/or identification of additional rare ABCA7 putative LOF mutations in other AD cohorts, 4–6 in addition to one study in Parkinson disease. 7 …”

ABCA7 and risk of dementia and vascular disease in the Danish population

“…A potential limitation of our study may be that we only studied white individuals from an ethnically homogeneous population. For instance, a GWAS risk allele (rs115550680) in African Americans was prevalent in this ethnic group in contrast to non‐hispanic whites,45 and was in high LD with a 44‐base pair exonic deletion (rs142076058). This common ABCA7 deletion could represent an ethnic‐specific pathogenic alteration in Alzheimer's disease.…”