Abstract

The cytoplasmic dynein-dynactin complex has been implicated in the aetiology of motor neuron degeneration in both mouse models and human forms of motor neuron disease. We have previously shown that mutations in the cytoplasmic dynein 1 heavy chain 1 gene (Dync1h1) are causal in a mouse model of late-onset motor neuron degeneration but have found no association of the homologous sites in human DYNC1H1 with human motor neuron disease. Here we extend these analyses to investigate the DYNC1H1 genomic locus to determine if it is associated with sporadic amyotrophic lateral sclerosis (ALS) in a northern European-derived population. Among the 16 single nucleotide polymorphisms (SNPs) we examined, just two SNPs (rs2251644 and rs941793) were sufficient to tag the majority of haplotypic variation (r2 > or = 0.85) and these were tested in a case-control association study with 266 North American sporadic ALS patients and 225 matched controls. We found no association between genetic variation at DYNC1H1 and sporadic ALS (rs2251644; p = 0.538, rs941793; p = 0.204, haplotype; p = 0.956). In addition we investigated patterns of diversity at DYNC1H1 in Japanese and Cameroonian populations to establish the evolutionary history for this gene and observed reduced genetic diversity in the northern Europeans suggestive of selection at this locus.