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Neurological Review |

The Neurogenomics View of Neurological Diseases

Shoji Tsuji, MD, PhD
JAMA Neurol. 2013;70(6):689-694. doi:10.1001/jamaneurol.2013.734.
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The availability of high-throughput genome sequencing technologies is expected to revolutionize our understanding of not only hereditary neurological diseases but also sporadic neurological diseases. The molecular bases of sporadic diseases, particularly those of sporadic neurodegenerative diseases, largely remain unknown. As potential molecular bases, various mechanisms can be considered, which include those underlying apparently sporadic neurological diseases with low-penetrant mutations in the gene for hereditary diseases, sporadic diseases with de novo mutations, and sporadic diseases with variations in disease-susceptible genes. With unprecedentedly robust power, high-throughput genome sequencing technologies will enable us to explore all of these possibilities. These new technologies will soon be applied in clinical practice. It will be a new era of datacentric clinical practice.

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Figure 1. Diagram showing the road map to personal genome medicine. Since the completion of the human genome sequence in 2003, the research focus in human genetics has moved to how human genome variations affect human health. Human genome variations are considered to be associated not only with hereditary diseases but also with sporadic diseases. In addition, human genome variations are also associated with differences in drug responses and adverse effects. Optimization of treatment and prevention based on personal genome information will soon be a realistic paradigm in clinical practice.

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Figure 2. Diagram showing the paradigm shift (ie, the explosive growth in genome science and medical genomics). Over the past decade, genome-wide association studies (GWASs) using common single-nucleotide polymorphisms (SNPs) have been conducted to identify genomic variations in sporadic neurological diseases. The theoretical framework of GWASs is the common disease–common variants hypothesis. Although GWASs have successfully revealed numerous susceptibility genes for common diseases such as diabetes mellitus, as well as neurodegenerative diseases, the odds ratios associated with these risk alleles are generally low and account for only a small proportion of estimated heritability. The availability of high-throughput genome sequencing technologies will enable us to identify all the genomic variants, and eventually those of disease-relevant alleles based on the common disease–multiple rare variants hypothesis.

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Figure 3. Diagram showing the road map to the identification of disease-relevant variations. Shifting the paradigm from the common disease–common variants hypothesis to the common disease–multiple rare variants hypothesis will lead to the elucidation of the molecular bases of sporadic neurological diseases. Relatively rare sporadic neurological diseases will be good candidates for identifying disease-relevant alleles with large effect sizes because, depending on the effect sizes, the sample sizes can be small. GWAS indicates genome-wide association studies; SNPs, single-nucleotide polymorphisms.

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