Linkage analysis of a Japanese family with autosomal dominant Parkinsonism

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We performed genome-wide linkage analysis of a Japanese family with autosomal-dominant parkinsonism, which exhibits clinical features compatible with those of common Parkinson's disease. Parametric two-point linkage analysis yielded a highest LOD score of 4.32 at D12S345 (12p11.21). Parametric multipoint linkage analysis of the 13.6 cM interval around this marker yielded LOD scores almost uniformly higher than 4.0 with a Zmax of 4.71 at D12S85 (12q12). Haplotype analysis detected two obligate recombination events at D12S 1631 and D12S339 and defined the disease-associated haplotype in the 13.6 cM interval in 12p11.2-q13.1. This haplotype was shared by all the patients and some unaffected carriers, suggesting that the disease penetration in this family is incomplete. This low penetrance suggests that environmental or other genetic factors modify expression of the disease. Nonparametric two-point and multipoint linkage analyses, which are penetrance-independent, yielded Zmax LOD scores of 14.2 and 24.9 at D12S345, respectively, strongly supporting the mapping of the parkinsonism locus in this family to 12p11.23-q13.11. This chromosome region is different from any known locus for hereditary parkinsonism, in keeping with the unique genetic features of the parkinsonism in this family. The nomenclature of PARK8 was assigned to the new locus.