Alzheimer Disease Risk Variants at ABCA7 Tag Tandem Repeat Length

Background and Objectives ATP-binding cassette subfamily A member 7 ( ABCA7 ) variants are a well-established genetic risk factor for Alzheimer disease (AD). This risk includes increased length of a variable number tandem repeat (VNTR) with a ∼25bp repeat motif in intron 18 of ABCA7 . We sought to examine VNTR length, exact internal sequence composition, and correlation with genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) in AD. Methods Three hundred and seven ABCA7 alleles based on long-read sequencing were evaluated from the 1000 Genomes Project. Short read sequences from 7,968 cases and 6,792 controls were evaluated from the AD Sequencing Project (ADSP). RNA sequencing data from 130 cases and 253 controls from the Religious Orders Study/Memory and Aging Project were used to identify alternative splicing at ABCA7 . Results We found that the top AD GWAS SNPs at ABCA7 tag tandem repeat length in an allele-specific manner. Homozygous carriers of the rs3764650 risk allele average 87 copies of the ABCA7 VNTR compared with 65 repeat copies in heterozygous individuals and 53 copies in individuals homozygous for the reference allele. This effect was specific to samples of European descent because rs3764650 had no correlation with repeat length in samples of African ancestry in 1000 Genomes Project samples. Nevertheless, an African-specific sentinel GWAS variant (rs115550680) is adjacent to the 25bp VNTR. In ADSP samples, we found that tandem repeat length was significantly associated with rs3764650, rs78117248, and rs4147929 regardless of affection status. ABCA7 repeat length was associated with aberrant splicing leading to mRNAs with premature termination codons. Discussion Converging lines of genetic and functional evidence implicate ABCA7 VNTR length as a potential risk factor for AD.