Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

Abstract

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study (GWAS) of late-onset Alzheimer disease (LOAD) using a 3 stage design consisting of a discovery stage (Stage 1) and two replication stages (Stages 2 and 3). Both joint and meta-analysis analysis approaches were used. We obtained genome-wide significant results at MS4A4A [rs4938933; Stages 1+2, meta-analysis (PM) = 1.7 × 10−9, joint analysis (PJ) = 1.7 × 10−9; Stages 1–3, PM = 8.2 × 10−12], CD2AP (rs9349407; Stages 1–3, PM = 8.6 × 10−9), EPHA1 (rs11767557; Stages 1–3 PM = 6.0 × 10−10), and CD33 (rs3865444; Stages 1–3, PM = 1.6 × 10−9). We confirmed that CR1 (rs6701713; PM = 4.6×10−10, PJ = 5.2×10−11), CLU (rs1532278; PM = 8.3 × 10−8, PJ = 1.9×10−8), BIN1 (rs7561528; PM = 4.0×10−14; PJ = 5.2×10−14), and PICALM (rs561655; PM = 7.0 × 10−11, PJ = 1.0×10−10) but not EXOC3L2 are LOAD risk loci1–3.

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 evaluated the segregation with LOAD of the 147 observed rare functional variants in 30 candidate genes implicated in LOAD by GWAS,4, 5 next‐generation sequencing or associated with early‐onset Alzheimer's disease. Sixteen of these variants were segregating in at least one family (Table S3).…”

“…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.…”

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…In 2009, the first replicable GWAS confirmed APOE as the first genetic risk factor for late-onset AD (LOAD). Since then, as a result of European and international genome-wide association collaborations, at least nine novel risk loci have been reported, including CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, ABCA7 and CD33 (Harold et al 2009;Hollingworth et al 2011;Lambert et al 2009;Naj et al 2011;Seshadri et al 2010). Recently, a meta-analysis by the International Genomics of Alzheimer's Project found 11 new AD risk genes, including CASS4, CELF1, FERMT2, HLA-DRB5/ DRB1, INPP5D, MEF2C, NME8, PTK2B, SLC24A4/RIN3, SORL1 and ZCWPW1.…”