Genomic mechanisms in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease and, owing to its increasing prevalence, represents one of the leading public health problems in aging populations. The molecular causes underlying the onset and progression of AD are manifold and hitherto still incompletely understood. Research over nearly four decades has clearly delineated genetics to play a crucial role in AD susceptibility, likely in concert with non-genetic factors. The field has gained considerable momentum and novel insights over the past 10 years owing to the advent and application of high-throughput genomics technologies in datasets of increasing size. In this contribution to the Mini-Symposium on the Molecular Etiology of Alzheimer's Disease, we review the current status of genomics research in AD. To this end, we scrutinize and discuss the main findings from the two largest and most current genome-wide association studies (GWAS) in the field, that is, the papers published by Jansen et al (Nat Genet 51:404-413) and Kunkle et al (Nat Genet 51:414-430). Particular focus is laid on genomics findings overlapping across both studies and on the novel insights they provide in terms of improving our understanding of the "genomic mechanisms" underlying this devastating disease.

Keywords: Alzheimer's disease; GWAS; genomics; risk genes.

Figure 1

Manhattan plots of “discovery phase” GWAS findings from the two GWAS discussed in this review. A. Jansen et al (14); B. Kunkle et al (16). Results are based on data distributed by the two respective studies (see “Data Availability Statement” section for more details). P‐values are truncated at 1E‐25 for didactic reasons. For Manhattan plots of non‐truncated results see Figure S1.

Figure 2

Functional consequences of SNPs on genes for the GWAS by Jansen et al (14). The histogram displays the proportion of SNPs (all SNPs in LD with independent significant SNPs) which have corresponding functional annotation assigned by ANNOVAR. Bars are colored by log2 (enrichment) relative to all SNPs in the selected reference panel. Plots are made with FUMA (25) using data described in “Data Availability Statement” section. For equivalent results of the GWAS by Kunkle et al (16) see Figure S3.

Figure 3

Results of tissue expression analysis for the GWAS by Jansen et al (14). Results are based on MAGMA gene‐property analyses as implemented in FUMA (25) using GTEx (1) v6 data on 53 tissue types. Input GWAS data as described in “Data Availability Statement” section. Red bars represent study‐wide significant results correcting for the 53 tissue types.