Segregation analysis of Parkinson disease.

Parkinson disease (PD) is a prevalent movement disorder of unknown cause whose incidence rises with increasing age. Nearly 20% of PD is familial, a small subset of which exhibits autosomal dominant transmission. However, in most families, the inheritance is not clear. To determine the most likely mode of inheritance of PD, we performed complex segregation analyses using kindreds of 136 PD patients randomly ascertained from a clinic population. The hypotheses of a nontransmissible environmental factor, no major gene or type (sporadic), and all Mendelian inheritance (dominant, recessive, additive, decreasing) were rejected (P <0.001). Familial clustering of PD in this data set is best explained by a rare familial factor which a) is transmitted in a nonMendelian fashion, and b) influences the age at onset of PD. If confirmed, our results have immediate implications in gene-mapping studies which often search for genes that behave in a Mendelian fashion that affect susceptibility rather than age at onset and long term implications in understanding the pathogenesis of PD.