Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10^-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Fig. 1 |. Manhattan plot of meta-analysis of stage 1, 2, and 3 results for genome-wide association with Alzheimer’s disease.

The threshold for genomewide significance (P < 5 × 10⁻⁸) is indicated by the red line, while the blue line represents the suggestive threshold (P < 1 × 10⁻⁵). Loci previously identified by the Lambert et al. IGAP GWAS are shown in blue and newly associated loci are shown in red. Loci are named for the closest gene to the sentinel variant for each locus. Diamonds represent variants with the smallest P values for each genome-wide locus.

Fig. 2 |. Top prioritized genes of 400 genes located in genome-wide-significant loci.

The criteria include: (1) deleterious coding, LOF or splicing variant in the gene; (2) significant gene-based tests; (3) expression in a tissue relevant to Alzheimer’s disease (astrocytes, neurons, microglia/macrophages, oligodendrocytes); (4) a HuMi microglial-enriched gene; (5) having an eQTL effect on the gene in any tissue, in Alzheimer’s disease–relevant tissue, and/ or a co-localized eQTL; (6) being involved in a biological pathway enriched in Alzheimer’s disease (from the current study); (7) expression correlated with the BRAAK stage; and (8) differential expression in a 1 + Alzheimer’s disease (AD) study. Novel genome-wide loci from the current study are listed first, followed by known genome-wide loci. Each category is assigned an equal weight of 1, with the priority score equaling the sum of all categories. Colored fields indicate that the gene meets the criteria. Genes with a priority score ≥ 4 are listed for each locus. If no gene reached a score of ≥ 5 in a locus, then the top ranked gene(s) is listed.