[Overview -- exploring molecular basis of sporadic neurologic disorders]

During the past three decades, we have witnessed remarkable advances in our understanding of the molecular bases of hereditary neurodegenerative diseases, which have been accomplished by "positional cloning" strategies. The molecular bases of sporadic neurologic disorders, however, largely remain to be elucidated. Genome-wide association studies (GWAS) based on the "common disease-common variants hypothesis" are currently undertaken to elucidate the disease-relevant alleles. Although GWAS have successfully revealed numerous susceptibility genes for neurodegenerative diseases, odds ratios associated with risk alleles are generally low and account for only a small proportion of estimated heritability. In contrast to these observations, involvement of genetic factors with strong effect sizes has been suggested even in sporadic neurodegenerative diseases. Recent studies have revealed that the effect sizes of the disease-relevant alleles that are identified based on comprehensive genome sequencing are substantially larger than those identified by GWAS. These findings strongly argue for the role of the "common disease-multiple rare variants hypothesis" in sporadic neurodegenerative diseases. Given the rapidly improving technologies of next generation sequencing (NGS), we expect that NGS will eventually enable us to identify all the variants relevant to the molecular bases of neurologic disorders.