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O1‐03‐02: Exome sequencing of late‐onset extended Alzheimer families
Author(s) -
Zuchner Stephan,
Beecham Gary,
Haines Jonathan,
Pericak-Vance Margaret
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.218
Subject(s) - genetics , international hapmap project , biology , exome sequencing , pedigree chart , dbsnp , genotyping , exome , haplotype , allele , gene , mutation , single nucleotide polymorphism , genotype
collapsed across variants. Results: We confirmed association at numerous SNPs across the gene, all located within one block of LD spanning intron 3 to the 3’ downstream region of CLU. Interestingly, association was also observed using circulating CLU as an endophenotype, both with common and rare variants. Sequencing further uncovered 40 mutations that were detected in AD patients only. Among these patient-specific mutations were 8 missense and 11 mutations in predicted regulatory regions of CLU. Interestingly, Polyphen analysis supported a pathogenic nature for several missense mutations in patients. Conclusions: The CLU locus appears to harbor both common and rare variants that affect risk of AD, possibly through an effect on circulating CLU levels. Functional characterization of predicted pathogenic variants is ongoing.