Association studies with ubiquilin and Alzheimer's Disease.

Katherine Eriksen, Alison M. Goate, D.Phil (P.I.), Petra Nowotny Ph.D. Department of Psychiatry, Washington University Medical School

The genetic causes of Early-Onset Alzheimer's Diseases are related to mutations in genes on chromosomes 1, 14, and 21. These mutations are in the β-amyloid precursor protein, presenilin-1, and presenilin-2 and they affect Aβ production. Susceptibility to Late-Onset Alzheimer's is likely influenced by several genes. Evidence of genetic linkage has been found on chromosomes 12, 10, 9, and 6. The ubiquilin gene (on chromosome 9) is located in close proximity to a linkage peak at 9q21. Ubiquilin also possesses biological significance in the Alzheimer's Disease pathway. The ubiquilin protein is associated with neurofibrillary tangles, a hallmark of AD pathology. Ubiquilin is thought to be involved in tagging proteins for degradation and may also modulate presenilin protein accumulation.

To assess the role of Ubiiquillin in susceptibility to AD we perform an association study with two single nucleotide polymorphisms (rs3814507 and rs4877797) located in the ubiquilin gene: no significant association was found in 270 AD cases and 270 matched controls. An intronic SNP, which is believed to change splicing, will also be genotyped. Haplotype analysis will also be performed once SNPs have been genotyped throughout the gene. It is not yet possible to draw any firm conclusions about the role of ubiquilin in Late-Onset AD.