RT Journal Article SR Electronic T1 ABCA7 frameshift deletion associated with Alzheimer disease in African Americans JF Neurology Genetics JO Neurol Genet FD Lippincott Williams & Wilkins SP e79 DO 10.1212/NXG.0000000000000079 VO 2 IS 3 A1 Holly N. Cukier A1 Brian W. Kunkle A1 Badri N. Vardarajan A1 Sophie Rolati A1 Kara L. Hamilton-Nelson A1 Martin A. Kohli A1 Patrice L. Whitehead A1 Beth A. Dombroski A1 Derek Van Booven A1 Rosalyn Lang A1 Derek M. Dykxhoorn A1 Lindsay A. Farrer A1 Michael L. Cuccaro A1 Jeffery M. Vance A1 John R. Gilbert A1 Gary W. Beecham A1 Eden R. Martin A1 Regina M. Carney A1 Richard Mayeux A1 Gerard D. Schellenberg A1 Goldie S. Byrd A1 Jonathan L. Haines A1 Margaret A. Pericak-Vance A1 For the Alzheimer's Disease Genetics Consortium YR 2016 UL http://ng.neurology.org/content/2/3/e79.abstract AB 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.AA=African Americans; ABC=ATP-binding cassette; AD=Alzheimer disease; CH=Caribbean Hispanic; CI=confidence interval; GATK=Genome Analysis Toolkit; GWAS=genome-wide association study; OR=odds ratio; SNV=single-nucleotide variant