In collaboration with translational genomics a genome wide association analysis in Alzheimers disease was completed, this work involved generation and analysis of more than 1/2 billion genotypes; and these analyses have now been released into the public domain. This work showed elegantly that the APO E locus is the single over-riding common genetic risk factor for Alzheimers disease. Subsequent analysis revealed a potential role for genetic variability in GAB2-A as a novel risk factor in Alzheimers disease. In addition to this work we have begun collecting related phenotypes (for eg dementia) from subjects genotyped by genome wide SNP association and from neurologically normal controls also genotyped within the laboratory in order to increase the power of the initial study. ? A subset of the samples involved in the genome wide association study were collected by the laboratory of neurogenetics from brain banks; generation of expression data in these Alzheimer's disease samples was performed last year and these data are currently being analyzed and compared to similar data in control samples in an attempt to produce an expression quantitative trait locus map of the Alzheimer's disease brain and to potentially identify a genetic basis of expression differences observed between brains from neurologically normal subjects and those with Alzheimer's disease.? Resequencing analysis of APP and presenilin genes in novel disease populations has lead to new insights into the potential pathogenicity previously reported presenilin-1 and presenilin-2 mutations. In addition we are analyzing young-onset samples without known mutations and families where parental consanguinity is suspected using dense SNP genotyping in an attempt to identify novel recessive loci for Alzheimer's disease, the first portion of this work was published this year and a second phase, involving a larger young-onset but outbred population, is ongoing.
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