Genetics of neurodegenerative diseases: insights from high-throughput resequencing.
During the past three decades, we have witnessed remarkable advances in our understanding of the molecular etiologies of hereditary neurodegenerative diseases, which have been accomplished by 'positional cloning' strategies. The discoveries of the causative genes for hereditary neurodegenerative diseases accelerated not only the studies on the pathophysiologic mechanisms of diseases, but also the studies for the development of disease-modifying therapies. Genome-wide association studies (GWAS) based on the 'common disease-common variants hypothesis' are currently undertaken to elucidate 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. Recent studies have revealed that the effect sizes of the disease-relevant alleles that are identified based on comprehensive resequencing of large data sets of Parkinson disease 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 next-generation sequencing (NGS), we expect that NGS will eventually enable us to identify all the variants in an individual's personal genome, in particular, clinically relevant alleles. Beyond this, whole genome resequencing is expected to bring a paradigm shift in clinical practice, where clinical practice including diagnosis and decision-making for appropriate therapeutic procedures is based on the 'personal genome'. The personal genome era is expected to be realized in the near future, and society needs to prepare for this new era.
Tsuji
Shoji
S
Department of Neurology, University of Tokyo, Tokyo 113-8655, Japan. tsuji@m.u-tokyo.ac.up
D055106:Genome-Wide Association Study; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics*; D017422:Sequence Analysis, DNA