To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, we performed a genomic screen for AAO in families with Alzheimer disease (AD;) and Parkinson disease (PD. (Li et al, AJHG, April, 2002). Heritabilities between 40 percent-60 percent were found in both the AD and PD datasets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD =3.41). In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S 1239 and D10S 1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases. We propose to further map and identify the genes contributing to this age-of-onset effect. We will continue to collect new AD and PD families to further map the peaks, and test candidate genes within the region for association to age of onset in these two disorders. Candidates will be prioritized using initially obvious biological candidates, then candidates that lie within the linkage peaks that are identified through Serial Analysis of Gene Expression and Microarray studies in both AD and PD (being performed in our lab in concurrent studies) and finally through fine mapping of the linkage peak for high areas of association using a DNA pooling approach and a new Single base pair- denaturing high performance liquid chromatography methodology. Candidates lying within these high association areas will be investigated further. Once identified, the genes will be investigated in collaboration with known mouse models, at present the Parkin model of Dr. Jian Feng and the APOE models of Dr. Don Schmechel of the DUMC Alzheimer Disease Research Center. Identifying age-of-onset genes may lead to treatment and delay of these late-onset disorders and a better understanding of the pathological processes they share.
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