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

By J. Lambert, C. Ibrahim-Verbaas, D. Harold, A. Naj, R. Sims, C. Bellenguez, G. Jun, A. Destefano, J. Bis, G. Beecham and 172 more. Nature Genetics, 2013

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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.

Subfields: Genetics, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/7df8343e00e3d09d3b2944643294ddb4b8af1554

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Citations in the corpus

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, neutral): “Meta-analysis of late onset AD (LOAD) datasets identified other risk genes: CASS4, CELF1, DSG2, HLA, DRB5, DBR1, FERMT2, NPP5D, MEF2C, NME8, SLC24H4 RIN3, SORL1, ZCWPW1 [378].”
Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease (2014, methodology): “Stage 2 data 11,632 SNPs with p-values ,10(23) in the IGAP meta-analysis were successfully genotyped in a Stage 2 sample comprising 8,572 cases and 11,312 controls (see primary IGAP manuscript[9,19] for more details).”
An environment-dependent transcriptional network specifies human microglia identity (2017, background): “rs6733839 is a noncoding risk allele for AD (59) that lieswithinanenhancer-like region~25kbupstream of the BIN1 transcriptional start site, suggesting regulatory function.”
Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. (2015, background): “These genes include CD33 (11-13), TREM2 (14,15) and the HLA-DRB4-DRB1 region (16), etc.”
Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future (2023, background): “RIN3, CLU and PTK2B) are linked to Aβ degradation.(33,34) Extensive genetic studies have supported the causative role of Aβ accumulation in AD pathogenesis.”
Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines (2018, background): “In AD and PD, the application of genome-wide association studies (GWAS) has demonstrated a number of key genes, relating to immunity, including the human leukocyte antigen (HLA) complex on chromosome six that regulates the immune and inflammatory response (372, 373).”