Genes influencing Parkinson disease onset: replication of PARK3 and identification of novel loci.

A genome screen to identify genes influencing the age at Parkinson disease (PD) onset was completed using 276 families without parkin mutations. Significant evidence of linkage to chromosome 2p near the PARK3 locus (logarithm of odds (lod) 4.8) was observed. Evidence of linkage was also detected to chromosomes 1q (lod 3.0) and 8q (lod 2.6). These data suggest that the genes influencing age at PD onset likely differ from those that contribute to PD susceptibility. NEUROLOGY 2004;62:1616-1618 Parkinson disease (PD) age at onset has wide vari- ability, ranging anywhere from juvenile to very late (80s to 90s), with an average age at onset of 60 years. Although few families include both juvenile- and late-onset PD, wide disparity in age at onset, even within the same family, has been found. An impor- tant question is whether the genes that contribute to PD susceptibility also contribute to age at disease onset or whether different genes are involved. As large multiplex PD datasets are ascertained to iden- tify PD susceptibility genes, it has become possible to directly answer this question. Evidence of linkage for age at onset of PD to chromosomes 1, 6, and 10 1 and chromosomes 2, 9, 20, and 21 2 has been reported. Materials and methods. Subjects. Three hundred sixty-six families (n 788 individuals), consisting of at least one pair of living siblings diagnosed with PD, were recruited through 59 Par- kinson Study Group sites located throughout North America. The average age at onset of the PD subjects was 60.9 years, with a range of 18 to 87 years. DNA samples were obtained from all individuals after appropriate written informed consent approved by each individual institution's institutional review board was completed. As previously described,3 all study participants completed a rigorous clinical evaluation (including Unified Parkinson's Dis- ease Rating Scale Parts II and III), and the Diagnostic Checklist developed for this project was used to classify participants as either verified PD or nonverified PD. Families with at least two individuals meeting criteria for verified PD were included in the more restrictive primary analyses (Model I), whereas all families were employed in the more inclusive Model II analyses. Parkin screening. Thirty-one different parkin mutations were previously identified in 39 of the 173 families analyzed,3 after both