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Genetics of neurodegenerative diseases: insights from high-throughput resequencing.

Tsuji S - Hum. Mol. Genet. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Tokyo, Tokyo 113-8655, Japan. tsuji@m.u-tokyo.ac.up

ABSTRACT
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.

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Increased throughput of next-generation sequencers.
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DDQ162F2: Increased throughput of next-generation sequencers.

Mentions: The automated Sanger method is considered a ‘first-generation’ technology, and newer methods are referred to as next-generation sequencing (NGS) (22). As shown in Figure 2, the throughput of NGS is dramatically increasing. As of 2010, the throughput is 100–200 Gb/run. Since the cost for whole genome resequencing for a read depth sufficient to identify variants with a high accuracy is still expensive, it is not easy to resequence the whole genome of a large number of individuals. Thus, we need to develop strategies to efficiently identify disease-relevant variants employing technologies with high accuracy and reasonable cost.


Genetics of neurodegenerative diseases: insights from high-throughput resequencing.

Tsuji S - Hum. Mol. Genet. (2010)

Increased throughput of next-generation sequencers.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2875051&req=5

DDQ162F2: Increased throughput of next-generation sequencers.
Mentions: The automated Sanger method is considered a ‘first-generation’ technology, and newer methods are referred to as next-generation sequencing (NGS) (22). As shown in Figure 2, the throughput of NGS is dramatically increasing. As of 2010, the throughput is 100–200 Gb/run. Since the cost for whole genome resequencing for a read depth sufficient to identify variants with a high accuracy is still expensive, it is not easy to resequence the whole genome of a large number of individuals. Thus, we need to develop strategies to efficiently identify disease-relevant variants employing technologies with high accuracy and reasonable cost.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Tokyo, Tokyo 113-8655, Japan. tsuji@m.u-tokyo.ac.up

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus