Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

Abstract

We sought to identify new susceptibility loci for Alzheimer’s disease (AD) through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer’s Disease Genetic Consortium (ADGC). First, we undertook a combined analysis of four genome-wide association datasets (Stage 1) and identified 10 novel variants with P≤1×10−5. These were tested for association in an independent sample (Stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (Stage 3). Meta-analyses of all data provide compelling evidence that ABCA7 (meta-P 4.5×10−17; including ADGC meta-P=5.0×10−21) and the MS4A gene cluster (rs610932, meta-P=1.8×10−14; including ADGC meta-P=1.2×10−16; rs670139, meta-P=1.4×10−9; including ADGC meta-P=1.1×10−10) are novel susceptibility loci for AD. Second, we observed independent evidence for association for three suggestive loci reported by the ADGC GWAS, which when combined shows genome-wide significance: CD2AP (GERAD+ P=8.0×10−4; including ADGC meta-P=8.6×10−9), CD33 (GERAD+ P=2.2×10−4; including ADGC meta-P=1.6×10−9) and EPHA1 (GERAD+ P=3.4×10−4; including ADGC meta-P=6.0×10−10). These findings support five novel susceptibility genes for AD.

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

“…Of the genes identified within the 2 Mb region surrounding the previously identified GWAS loci from the IGAP study,1, 2, 3, 4, 5, 6 several were nominally significant. CYP3A43 is a member of the cytochrome P450 superfamily of enzymes.…”

“…We also included known early‐onset AD genes and genes implicated in earlier sequencing efforts in LOAD 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16. Candidate genes evaluated included: APP, PSEN1, PSEN2, GRN, MAPT, TREM2, PLD3, APOE, ABCA7, SORL1, CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, CD33, HLA‐DRB5, HLA‐DRB1, PTK2B, SLC24A4, RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, TREML2, and AKAP9 .…”

“…Several genes within LOAD susceptibility loci cluster in specific pathways,1, 2, 3, 4, 5, 6 including amyloid processing, oxidative stress and immune or inflammatory pathways. Collectively, GWAS demonstrates that apart from the strongest risk factor, APOE‐ε4 a large number of loci with modest effect size also contribute to LOAD risk.…”

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

“…Expression of human ABCA7 (hABCA7) carrying the rs3752246 risk allele led to increases in secreted amyloid‐ β 40 and amyloid‐ β 42 and β ‐secretase activity in CHO‐ and HEK‐A β PPSwe cells, and molecular weight determination showed loss of post‐translational modification in the risk‐allele peptide spanning position 1527 41. Another common variant, rs3764650, was the first top significant hit reported in ABCA7 6. This variant is located in intron 13, and is not in strong LD with the present rs4147929 (http://snipa.helmholtz-muenchen.de/snipa3/, r 2 = 0.21), and therefore most likely does not contribute to the present findings.…”

“…Recent demographic studies have shown a decrease in incidences in developed countries most likely due to improved treatment and prevention of vascular risk factors 2, 3, 4. Genome‐wide association studies (GWAS) have revealed novel molecular pathways, among these the ATP‐binding‐cassette transporter A7 ( ABCA7 ),5, 6 which may be involved in both transmembrane lipid transport and phagocytosis of amyloid‐ β in the brain 7, 8, 9, 10, 11, 12, 13, 14. Following these GWAS findings, rare loss‐of‐function variants in ABCA7 were reported to confer risk of Alzheimer's disease in case–control studies in Icelandic and Belgian populations 15, 16.…”