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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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Research paradigm to identify disease-related variations based on comparison of effect sizes of variants and allele frequencies of the variants in population. Adapted by permission from Macmillan Publishers Ltd: Nature, 461: 747–53 (2009) (16).
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DDQ162F1: Research paradigm to identify disease-related variations based on comparison of effect sizes of variants and allele frequencies of the variants in population. Adapted by permission from Macmillan Publishers Ltd: Nature, 461: 747–53 (2009) (16).

Mentions: The prominent role of rare variants in neurodegenerative disease is best highlighted by the recent discovery of the glucocerebrosidase gene (GBA) as a robust genetic risk factor for PD (17–18). PD, which is characterized by tremor, rigidity, bradykinesia, and postural instability, is the second most common neurodegenerative disease after Alzheimer disease, with onset typically in late adulthood. The prevalence of PD has been estimated to be 0.3% in the general population and 1% in people over 60 years of age. Although α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), UCHL-1, Parkin (PARK2), PTEN-induced putative kinase 1 (PINK1) and DJ-1 have been identified as causative genes for familial PD, PD patients with pathogenic mutations in these genes are rare, and most of the PD cases are sporadic, the etiologies of which are poorly understood. A population-based study coupled with genealogy information demonstrated that the estimated risk ratio for PD for siblings of patients with PD was significantly elevated (λs = 6.3), indicating that genetic factors substantially contribute to the development of sporadic PD (18). Recent clinical observations (19) suggested the association of sporadic PD with heterozygous mutations in the glucocerebrosidase gene (GBA) encoding the enzyme that is deficient in patients with Gaucher disease, an autosomal recessive lysosomal storage disease. Furthermore co-morbidity of PD and Gaucher disease had previously been described (20). We conducted an extensive resequencing analysis of GBA in PD patients and controls, and found that GBA variants that are pathogenic for Gaucher disease confer a robust susceptibility to sporadic PD, and, even account for familial clustering of PD (18) (Fig. 1). The combined carrier frequency of the ‘pathogenic variants’ was as high as 9.4% in PD patients and significantly more frequent than in controls (0.37%) with a markedly high odds ratio of 28.0 (95% CI, 7.3 to 238.3) for PD patients compared with controls.


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

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

Research paradigm to identify disease-related variations based on comparison of effect sizes of variants and allele frequencies of the variants in population. Adapted by permission from Macmillan Publishers Ltd: Nature, 461: 747–53 (2009) (16).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDQ162F1: Research paradigm to identify disease-related variations based on comparison of effect sizes of variants and allele frequencies of the variants in population. Adapted by permission from Macmillan Publishers Ltd: Nature, 461: 747–53 (2009) (16).
Mentions: The prominent role of rare variants in neurodegenerative disease is best highlighted by the recent discovery of the glucocerebrosidase gene (GBA) as a robust genetic risk factor for PD (17–18). PD, which is characterized by tremor, rigidity, bradykinesia, and postural instability, is the second most common neurodegenerative disease after Alzheimer disease, with onset typically in late adulthood. The prevalence of PD has been estimated to be 0.3% in the general population and 1% in people over 60 years of age. Although α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), UCHL-1, Parkin (PARK2), PTEN-induced putative kinase 1 (PINK1) and DJ-1 have been identified as causative genes for familial PD, PD patients with pathogenic mutations in these genes are rare, and most of the PD cases are sporadic, the etiologies of which are poorly understood. A population-based study coupled with genealogy information demonstrated that the estimated risk ratio for PD for siblings of patients with PD was significantly elevated (λs = 6.3), indicating that genetic factors substantially contribute to the development of sporadic PD (18). Recent clinical observations (19) suggested the association of sporadic PD with heterozygous mutations in the glucocerebrosidase gene (GBA) encoding the enzyme that is deficient in patients with Gaucher disease, an autosomal recessive lysosomal storage disease. Furthermore co-morbidity of PD and Gaucher disease had previously been described (20). We conducted an extensive resequencing analysis of GBA in PD patients and controls, and found that GBA variants that are pathogenic for Gaucher disease confer a robust susceptibility to sporadic PD, and, even account for familial clustering of PD (18) (Fig. 1). The combined carrier frequency of the ‘pathogenic variants’ was as high as 9.4% in PD patients and significantly more frequent than in controls (0.37%) with a markedly high odds ratio of 28.0 (95% CI, 7.3 to 238.3) for PD patients compared with controls.

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