Family-Based Association between Alzheimer's Disease and Variants in<i>UBQLN1</i>

TLDR

Recent analyses indicate that known AD genes explain less than half of the disease’s genetic variance, and the UBQLN1 gene near a chromosome 9q22 linkage peak has emerged as a candidate for further study. The authors genotyped 19 SNPs in three genes within the 9q22 region in 437 multiplex AD families, then tested significant SNPs in an independent cohort of 217 sibships and examined the functional impact of a key SNP on UBQLN1 splicing in brain tissue from AD patients and controls. They found significant associations of UBQLN1 SNPs with AD in both cohorts, identified a risk haplotype defined by an intronic SNP downstream of exon 8, and showed that the risk allele drives a dose‑dependent increase in an exon‑8‑skipping UBQLN1 transcript, suggesting that alternative splicing contributes to disease risk.

Abstract

Recent analyses suggest that the known Alzheimer's disease genes account for less than half the genetic variance in this disease. The gene encoding ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer's disease located near a well-established linkage peak on chromosome 9q22.We evaluated 19 single-nucleotide polymorphisms in three genes within the chromosome 9q linkage region in 437 multiplex families with Alzheimer's disease from the National Institute of Mental Health (NIMH) sample (1439 subjects). We then tested the single-nucleotide polymorphisms showing a positive result in an independently identified set of 217 sibships discordant for Alzheimer's disease (Consortium on Alzheimer's Genetics [CAG] sample; 489 subjects) and assessed the functional effect of an implicated single-nucleotide polymorphism in brain tissue from 25 patients with Alzheimer's disease and 17 controls.In the NIMH sample, we observed a significant association between Alzheimer's disease and various single-nucleotide polymorphisms in UBQLN1. We confirmed these associations in the CAG sample. The risk-conferring haplotype in both samples was defined by a single intronic single-nucleotide polymorphism located downstream of exon 8. The risk allele was associated with a dose-dependent increase in an alternatively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain samples of patients with Alzheimer's disease.Our findings suggest that genetic variants in UBQLN1 on chromosome 9q22 substantially increase the risk of Alzheimer's disease, possibly by influencing alternative splicing of this gene in the brain.