Characterization of regulatory roles of genetic signals curated from more than 200 GWA studies in the Alzheimer's Disease Variant Portal (ADVP). (1st February 2022)

• Record Type: Journal Article
• Authors: Leung, Yuk Yee; Kuksa, Pavel P.; Chou, Yi‐Fan; Liu, Chia‐Lun; Fu, Wei; Qu, Liming; Zhao, Yi; Katanic, Zivadin; Kuzma, Amanda B; Ho, Pei‐chuan; Tzeng, Kai‐Teh; Valladares, Otto; Chou, Shin‐Yi; Naj, Adam C; Schellenberg, Gerard D.; Wang, Li‐San
• Is Part Of: Alzheimer's & dementia. Volume 17:(2021)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-02-01
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.054255
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: The Alzheimer's Disease Variant Portal (ADVP, https://advp.niagads.org) is a curated and harmonized interactive platform providing the research community with a unified way to access and visualize the largest up‐to‐date collection of Alzheimer's disease (AD) genetic findings from >200 genome‐wide association studies (GWASs). In this study, we aim to characterize the regulatory roles and mechanisms underlying these genetic signals in AD. Methods: We analyzed all Caucasian genome‐wide significant signals in ADVP (348 genetic variants and 186 loci) using FILER (Kuksa et al ., 2021) and SparkINFERNO (Kuksa et al ., 2020). The SparkINFERNO high throughput system analyses framework is coupled with the FILER (https://lisanwanglab.org/FILER), a rich resource of >50, 000 harmonized functional genomic datasets across many different sources including ENCODE, FANTOM5, GTEx, Roadmap, DASHR2 and others. With this systematic, hypothesis‐free analysis approach, we analyzed and ranked relevant tissue categories by quantifying the significance and enrichment of tissue‐specific enhancer overlaps with ADVP variants compared to the empirical overlap distribution for matching background (non‐AD) variants. Further integration with the AMP‐AD expression quantitative trait loci (eQTL) datasets from three brain regions (dorsolateral prefrontal cortex, cerebellum and temporal cortex), enable us to discover the potentially causal genes affected by these variants. Results: The ADVP variants were enriched in regulatory elements profiled by FANTOM5 and Roadmap Epigenomics (ChromHMM). Top tissues enriched in Roadmap enhancers include blood (OR=3.7), digestive (OR=3.5), brain (OR=2.8), and skeletal muscles (OR=2.6). 31% of the analyzed ADVP variants were identified as significant eQTLs in at least one of the three AMP‐AD eQTL datasets (FDR<0.01), and 32% among these were eQTLs in all three brain regions. Altogether, these variants targeted 130 genes (including HLA regions), of which 31 were also the nearest genes reported in ADVP. These target genes (e.g. ACE, PVR, KANSL1, NARS2 ) were enriched in cell junction organization, DNA repair (nucleotide‐excision repair) and acetyltransferase activity (cholinergic system), which recapitulated some of the molecular and cellular mechanisms underlying the pathogenesis of AD. Conclusions: Conducted analysis of genetic associations across >200 GWASs in ADVP and identified known AD culprit genes, relevant tissue/cell type categories, and regulatory mechanisms.