Genome-wide Analysis of Genetic Loci Associated With Alzheimer Disease

Abstract

Context Genome wide association studies (GWAS) have recently identified CLU, PICALM and CR1 as novel genes for late-onset Alzheimer’s disease (AD). Objective In a three-stage analysis of new and previously published GWAS on over 35000 persons (8371 AD cases), we sought to identify and strengthen additional loci associated with AD and confirm these in an independent sample. We also examined the contribution of recently identified genes to AD risk prediction. Design, Setting, and Participants We identified strong genetic associations (p<10−3) in a Stage 1 sample of 3006 AD cases and 14642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (1367 AD cases (973 incident)) with previously reported results from the Translational Genomics Research Institute (TGEN) and Mayo AD GWAS. We identified 2708 single nucleotide polymorphisms (SNPs) with p-values<10−3, and in Stage 2 pooled results for these SNPs with the European AD Initiative (2032 cases, 5328 controls) to identify ten loci with p-values<10−5. In Stage 3, we combined data for these ten loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases, 6995 controls) to identify four SNPs with a p-value<1.7×10−8. These four SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Main outcome measure Alzheimer’s Disease. Results We showed genome-wide significance for two new loci: rs744373 near BIN1 (OR:1.13; 95%CI:1.06–1.21 per copy of the minor allele; p=1.6×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR:1.18; 95%CI1.07–1.29; p=6.5×10−9). Associations of CLU, PICALM, BIN1 and EXOC3L2 with AD were confirmed in the Spanish sample (p<0.05). However, CLU and PICALM did not improve incident AD prediction beyond age, sex, and APOE (improvement in area under receiver-operating-characteristic curve <0.003). Conclusions Two novel genetic loci for AD are reported that for the first time reach genome-wide statistical significance; these findings were replicated in an independent population. Two recently reported associations were also confirmed, but these loci did not improve AD risk prediction, although they implicate biological pathways that may be useful targets for potential interventions.

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.…”

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.…”

Rare coding mutations identified by sequencing of Alzheimer disease genome‐wide association studies loci

“…The first large‐scale genome‐wide association studies (GWAS) using common single nucleotide polymorphisms (SNPs) identified CLU , PICALM , CR1, and BIN1 as late onset Alzheimer disease (LOAD) susceptibility loci,1, 2, 3 which were widely confirmed by others 4, 5. The effect sizes of these genetic associations were much smaller than for APOE ,2, 6 with odds ratios ranging from 1.16 to 1.20.…”