P3–021: Variant‐domain mapping in confirmed late‐onset Alzheimer disease (LOAD) loci identifies multiple genomic regions with potentially functional variants
Year: 2013
Type: article
Study design: Observational Study
Abstract: Recent genome-wide association studies (GWAS) have identified common variants in ten or more genes (CLU, BIN1, etc.) that confer LOAD risk. To identify other potential risk variants in these genes/regions, we performed targeted resequencing on these risk loci in a discovery set of 291 LOAD cases and 103 controls, and identified candidate variants for follow-up protein-domain mapping and validation in independent case-control sets. Targeted resequencing used NimbleGen capture and Illumina HiSeq 2000 sequencing, capturing an average 368.3 kilobase region per locus which including all overlapping linkage disequilibrium blocks (r 2<0.80). We filtered variants on three criteria: (a) functionality (missense, nonsense, or splice-site variant), (b) potentially damaging effect as defined by Polyphen-2, and (c) polymorphic only in cases. Remaining variants were binned by protein functional domain to identify domains with excess burden of rare variants among cases. Selected variants were genotyped and examined in multiple independent datasets including Caucasian, African-American, and Amish isolates. We identified 28,894 variants across the nine regions, of which 73.4% were variants of minor allele frequency (MAF)<5% and 51.4% were novel. Polyphen-2 rated 247 variants (180 novel) as “probably“/”possibly” damaging. Most of the 247 damaging variants were rare (222 with MAF <5%; 209 with <2%), and a subset (n=145; 129 novel) were present in one or more cases while absent in controls (average MAF = 0.002). Missense variants were found in PICALM (n=1), CLU (n=1), CD33 (n=1), CR1 (n=3), BIN1 (n=4), CD2AP (n=3), EPHA1 (n=6), MS4A region (n=6), and ABCA7 (n=14). Binning variants by protein domain identified 3 domains for follow-up, one each in BIN1, ABCA7, and EPHA1. Subsequent genotyping identified several regions upstream of ABCA7 in the genes GRIN3B and C19orf6 as overrepresented in cases vs. controls in all three validation groups. Deep resequencing identified multiple novel rare and potentially functional variants clustering in distinct protein domains and genotyping of candidate variants identified several missense variants overrepresented in cases, suggesting that functional prioritization of variants may highlight important rare variants affecting LOAD risk.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2050677753