To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 x 10(-12)) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 x 10(-9)). We also detected strong associations at SNCA on 4q22 (P = 7.35 x 10(-17)) and LRRK2 on 12q12 (P = 2.72 x 10(-8)), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.

We performed genomewide 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 log odds (LOD) score of 4.32 at D12S345 (12p11.21). Parametric multipoint linkage analysis of the 13.6cM interval around this marker yielded LOD scores almost uniformly of >4.0 with a Z(max) of 4.71 at D12S85 (12q12). Haplotype analysis detected two obligate recombination events at D12S1631 and D12S339 and defined the disease-associated haplotype in the 13.6cM interval in 12p11.2-q13.1. This haplotype was shared by all the patients and by some unaffected carriers, suggesting that 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 Z(max) 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.

We detected a missense mutation in the kinase domain of the LRRK2 gene in members with autosomal dominant Parkinson's disease of the Japanese family (the Sagamihara family) who served as the basis for the original defining of the PARK8 Parkinson's disease locus. The results of the Sagamihara family, in combination with the unique pathological features characterized by pure nigral degeneration without Lewy bodies, provided us with valuable information for elucidating the protein structure-pathogenesis relationship for the gene product of LRRK2. We did not detect this mutation or other known mutations of the LRRK2 gene in Japanese patients with sporadic Parkinson's disease.

CD14 is a myelomonocytic differentiation antigen expressed by monocytes, macrophages, and activated granulocytes and is detectable with the monoclonal antibodies MO2, MY4, and LeuM3. Analyses of complementary DNA and genomic clones of CD14 show that it has a novel structure and that it maps to chromosome 5 within a region containing other genes encoding growth factors and receptors; it may therefore represent a new receptor important for myeloid differentiation. In addition, the CD14 gene is included in the "critical" region that is frequently deleted in certain myeloid leukemias.

Leucine-rich repeat kinase 2 (LRRK2), a large protein kinase containing multi-functional domains, has been identified as the causal molecule for autosomal-dominant Parkinson's disease (PD). In the present study, we demonstrated for the first time that (i) LRRK2 interacts with tau in a tubulin-dependent manner; (ii) LRRK2 directly phosphorylates tubulin-associated tau, but not free tau; (iii) LRRK2 phosphorylates tau at Thr181 as one of the target sites; and (iv) The PD-associated LRRK2 mutations, G2019S and I2020T, elevated the degree of tau-phosphorylation. These results provide direct proof that tau is a physiological substrate for LRRK2. Furthermore, we revealed that LRRK2-mediated phosphorylation of tau reduces its tubulin-binding ability. Our results suggest that LRRK2 plays an important role as a physiological regulator for phosphorylation-mediated dissociation of tau from microtubules, which is an integral aspect of microtubule dynamics essential for neurite outgrowth and axonal transport.