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.

Figure 1. Location of the deletion in the ABCA7 gene and protein

(A) ABCA7 gene (chr19:1,040,103-1,065,571, hg38), 44-base pair deletion (blue), African American risk allele (blue and underlined), and 3 non-Hispanic white (NHW) risk alleles (rs3764650, rs3752246, and rs4147929). (B) Wild-type ABCA7 protein (2,146 amino acids) and the location of frameshift deletion (blue) identified in this study. Below, the protein predicted to be generated from deletion would contain only 2 of the 11 transmembrane domains (yellow) and neither of the 2 AAA domains (green), but incorporate 168 aberrant amino acids (black). The remaining frameshift, nonsense, and splicing variants designated are rare alterations (<1% minor allele frequency) previously reported in NHW populations to be associated with Alzheimer disease.

Figure 2. Pedigree of an AD family from the Dominican Republic with the ABCA7 deletion

Family 360 has 6 individuals diagnosed with Alzheimer disease (AD) and 2 individuals presenting with mild dementia. The numbers beneath each individual in the pedigree represent the individual's sample number, the age at onset of AD (for AD cases) or the age at examination, and the APOE genotype. All 7 siblings carry the ABCA7 deletion and the African Americans (AA) risk allele, whereas individual 3 had neither the deletion nor the AA risk allele.

Figure 3. Deletion allele produces an RNA transcript

(A) Real-time PCR from cDNA of 3 samples without the ABCA7 deletion (+/+) and 3 samples heterozygous for the ABCA7 deletion (deletion/+). All samples produce an amplicon of 316 base pairs, but only the samples with deletion generate a lower, 272-base pair amplicon (arrow). (B) Sanger sequencing from the 5′ end of the deletion in an African American control lacking the deletion and Alzheimer disease (AD)-specific line heterozygous for the deletion. The arrow denotes where the deleted allele begins to be out of frame with the wild-type allele C. Sanger sequencing from the 3′ end of the deletion from the same control and AD individuals.