GWAS on family history of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a public health priority for the 21st century. Risk reduction currently revolves around lifestyle changes with much research trying to elucidate the biological underpinnings. We show that self-report of parental history of Alzheimer’s dementia for case ascertainment in a genome-wide association study of 314,278 participants from UK Biobank (27,696 maternal cases, 14,338 paternal cases) is a valid proxy for an AD genetic study. After meta-analysing with published consortium data (n = 74,046 with 25,580 cases across the discovery and replication analyses), three new AD-associated loci (P < 5 × 10−8) are identified. These contain genes relevant for AD and neurodegeneration: ADAM10, BCKDK/KAT8 and ACE. Novel gene-based loci include drug targets such as VKORC1 (warfarin dose). We report evidence that the association of SNPs in the TOMM40 gene with AD is potentially mediated by both gene expression and DNA methylation in the prefrontal cortex. However, it is likely that multiple variants are affecting the trait and gene methylation/expression. Our discovered loci may help to elucidate the biological mechanisms underlying AD and, as they contain genes that are drug targets for other diseases and disorders, warrant further exploration for potential precision medicine applications.

Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

“…We obtained in total 63 modules (). GSEA with the GWAS gene set generated from Marioni et al (), at different cut‐offs for statistical significance as explained above (Fig A and ), demonstrated that the largest set of risk genes (e.g., n = 1,799 genes at P mar < 0.05) enrich among 4 APPtg‐ and TAUtg‐based modules (Turquoise, Blue, Fig A and ). However, when taking gene sets defined by increasing statistical significance ( P mar < 0.001 or smaller), the only module that persistently demonstrates significant enrichment with GWAS genes is the APPtg‐Blue module (see Fig A).…”

“…In the genotype comparison, mRNA expression in all transgenic (TG) mice is compared to all wild‐type (WT) mice. In the age*genotype comparison, we assess which transcripts are differentially expressed in the 10M TG mice compared to all other groups. DBased on Marioni et al (), various sets of AD GWAS risk genes were created using different cut‐off P ‐values indicated on the x ‐axis (number of genes within each set is written in gray). Enrichment for AD risk genes was assessed among the different statistical comparisons for APPtg and TAUtg mice (A*G: age*genotype, Gen: genotype), using gene set enrichment analysis (GSEA, Subramanian et al , ).…”

“…We included established AD risk variants, i.e., loci with P < 5 × 10e‐8 in various GWAS studies, as well as subthreshold AD risk variants as these contribute significantly to AD risk predictions through polygenic inheritance (Escott‐Price et al , , ). We examined multiple sets of such genes taken from Marioni et al (), which combines UK Biobank AD‐by‐proxy data with the IGAP database and which confers risk loci onto genes based on proximity (thus from here on, AD risk variants are referred to as AD risk genes, noticing that this is based on these assumptions). Using arbitrary Bonferroni‐adjusted P ‐value ( P mar ) cut‐offs with decreasing significance for AD association, gene sets of increasing size were created (see Fig D and ).…”

“… AGene set enrichment analysis using Fisher's exact test of GWAS genes from Marioni et al () at different P ‐value cut‐offs among the WGCNA‐derived modules in APPtg or TAUtg mice (see also ). Colors represent −log10 (Benjamini–Yekutieli‐adjusted P ‐value) for the enrichment.…”

A functional variant in the miR‐142 promoter modulating its expression and conferring risk of Alzheimer disease

“…The lower association signal for the 17q22 locus in the UK biobank cohort could be explained by differences in case ascertainment of AD. In the UK biobank, Alzheimer dementia is ascertained via self‐report information from family history (parent or a first‐degree relative with AD or dementia) as a proxy‐phenotype for the participants (Marioni et al, ). This method relies on people to provide accurate information about whether their parents developed AD, for which misclassification of case status is of greater concern than consortia relying upon clinician‐reported diagnoses.…”