BACKGROUND: Recent analyses suggest that the known Alzheimer’s disease genes account for less than half the genetic variance in this disease. The gene encodi ng ubiquilin 1 (UBQLN1) is one of several candidate genes ...BACKGROUND: Recent analyses suggest that the known Alzheimer’s disease genes account for less than half the genetic variance in this disease. The gene encodi ng ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer’s disea se located near a well-established linkage peak on chromosome 9q22. METHODS:We evaluated 19 single-nucleotide polymorphisms in three genes within the chromoso me 9q linkage region in 437 multiplex families with Alzheimer’s disease from th e National Institute of Mental Health (NIMH) sample (1439 subjects). We then tes ted the single-nucleotide polymorphisms showing a positive result in an indepen dently identified set of 217 sibships discordant for Alzheimer’s disease (Conso rtium on Alzheimer’s Genetics [CAG] sample; 489 subjects) and assessed the func tional effect of an implicated single-nucleotide polymorphism in brain tissue f rom 25 patients with Alzheimer’s disease and 17 controls. RESULTS: In the NIMH sample, we observed a significant association between Alzheimer’s disease and v arious single-nucleotide polymorphisms in UBQLN1. We confirmed these associatio ns 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 alterna tively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain sa mples of patients with Alzheimer’s disease. CONCLUSIONS: Our findings suggest t hat genetic variants in UBQLN1 on chromosome 9q22 substantially increase the ris k of Alzheimer’s disease, possibly by influencing alternative splicing of this gene in the brain.展开更多
文摘BACKGROUND: Recent analyses suggest that the known Alzheimer’s disease genes account for less than half the genetic variance in this disease. The gene encodi ng ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer’s disea se located near a well-established linkage peak on chromosome 9q22. METHODS:We evaluated 19 single-nucleotide polymorphisms in three genes within the chromoso me 9q linkage region in 437 multiplex families with Alzheimer’s disease from th e National Institute of Mental Health (NIMH) sample (1439 subjects). We then tes ted the single-nucleotide polymorphisms showing a positive result in an indepen dently identified set of 217 sibships discordant for Alzheimer’s disease (Conso rtium on Alzheimer’s Genetics [CAG] sample; 489 subjects) and assessed the func tional effect of an implicated single-nucleotide polymorphism in brain tissue f rom 25 patients with Alzheimer’s disease and 17 controls. RESULTS: In the NIMH sample, we observed a significant association between Alzheimer’s disease and v arious single-nucleotide polymorphisms in UBQLN1. We confirmed these associatio ns 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 alterna tively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain sa mples of patients with Alzheimer’s disease. CONCLUSIONS: Our findings suggest t hat genetic variants in UBQLN1 on chromosome 9q22 substantially increase the ris k of Alzheimer’s disease, possibly by influencing alternative splicing of this gene in the brain.
