Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

Abstract

Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease.

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

“…We obtained GWAS summary statistics for three neurodegenerative diseases: AD,1 ALS,2 and PD 3. We used MS33 as a positive control, as it is a disease affecting the brain with known immune etiology.…”

“…Recently there has been much progress in identifying genetic variants associated with neurodegenerative diseases. In the latest AD meta‐analysis, 19 loci in addition to the well‐established APOE locus were pinpointed 1. The latest ALS meta‐analysis identified three ALS‐associated loci2 and the latest PD meta‐analysis brought the total number of established PD loci to 26 3.…”

“…There is extensive functional and clinical evidence that immune dysfunction plays a key role in the pathogenesis of the relapse‐remitting phase of MS 20, 21. For AD, Yokoyama et al22 showed that eight variants were associated with both AD and immune‐mediated diseases, and there is further evidence from pathway analysis1, 23, 24 and from animal models 25. For PD, the role of the immune system has been suggested through pathway analyses,26, 27 animal models,28 and variants in the Human Leukocyte Antigen (HLA) region reaching statistical significance in GWASs 3, 29.…”

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

“…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.…”

“…For this purpose, we genotyped the rs4147929 genetic variant in ABCA7 , previously identified as a GWAS top hit for Alzheimer's disease,5 as well as APOE genotypes (rs7412 and rs429358) in a prospective study of the general population totaling 104,258 individuals. Finally, in meta‐analyses we included consortia data from the International Genomics of Alzheimer's Projects (IGAP) including 74,046 individuals and the CARDIoGRAMplusC4D including 184,305 individuals.…”