Limits...
Association studies of sporadic Parkinson's disease in the genomic era.

Labbé C, Ross OA - Curr. Genomics (2014)

Bottom Line: These large scale studies allow the identification of genomic regions harboring common variants associated to disease risk.Cumulative risk estimates of associated variants suggest that more loci are still to be discovered.This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosis and as targets for the development of better, personalized treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

ABSTRACT
Parkinson's disease is a common age-related progressive neurodegenerative disorder. Over the last 10 years, advances have been made in our understanding of the etiology of the disease with the greatest insights perhaps coming from genetic studies, including genome-wide association approaches. These large scale studies allow the identification of genomic regions harboring common variants associated to disease risk. Since the first genome-wide association study on sporadic Parkinson's disease performed in 2005, improvements in study design, including the advent of meta-analyses, have allowed the identification of ~21 susceptibility loci. The first loci to be nominated were previously associated to familial PD (SNCA, MAPT, LRRK2) and these have been extensively replicated. For other more recently identified loci (SREBF1, SCARB2, RIT2) independent replication is still warranted. Cumulative risk estimates of associated variants suggest that more loci are still to be discovered. Additional association studies combined with deep re-sequencing of known genome-wide association study loci are necessary to identify the functional variants that drive disease risk. As each of these associated genes and variants are identified they will give insight into the biological pathways involved the etiology of Parkinson's disease. This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosis and as targets for the development of better, personalized treatment.

No MeSH data available.


Related in: MedlinePlus

Overlap in discovery samples of published PD GWAS and meta-analyses.Each rounded rectangle represents a GWAS in PD or a meta-analysis of GWAS. The reference, the number of samples in the discoveryphase, and the country of origin of the samples used are included in the rectangles. The color of the rectangle reflects the findings of thestudy: no new identified loci, identified loci with genome-wide significance, and replication of previously identified loci (see legend for colorchart). Differences between sample size of a meta-analysis and individual GWAS are due to quality control differences. The discovery sampleof IPDGC2 includes both the discovery and the replication samples of IPDGC. * The Fung et al. sample set is part of the replicationphase of IPDGC 2011.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3958956&req=5

Figure 1: Overlap in discovery samples of published PD GWAS and meta-analyses.Each rounded rectangle represents a GWAS in PD or a meta-analysis of GWAS. The reference, the number of samples in the discoveryphase, and the country of origin of the samples used are included in the rectangles. The color of the rectangle reflects the findings of thestudy: no new identified loci, identified loci with genome-wide significance, and replication of previously identified loci (see legend for colorchart). Differences between sample size of a meta-analysis and individual GWAS are due to quality control differences. The discovery sampleof IPDGC2 includes both the discovery and the replication samples of IPDGC. * The Fung et al. sample set is part of the replicationphase of IPDGC 2011.

Mentions: Following the first round of success at identifying risk genes in GWAS performed in larger cohorts, research groups began to pool their data together in order to achieve a greater power to identify genes with modest impact on disease risk. Three meta-analyses were published in a matter of months by collaborating groups, while these studies are not independent - a lot of genotyping data overlap from the earlier independent GWAS studies (see Fig. 1) – each identified at least one novel association signal. The first of these meta-analyses published in 2011 [31] by the International Parkinson Disease Genomics Consortium (IPDGC) pooled data from five PD GWAS from the USA and Europe [10, 11, 13, 18, 19, 32]. The discovery phase consisted of 5333 patient samples and 12019 control samples and the follow-up consisted of 7053 case and 9007 control samples (the samples were pooled from the replication phase of the five GWAS and from the discovery phase of [32]). Eleven loci reached genome-wide significance, six were previously nominated (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were novel (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The cumulated population attributable risk for these loci was calculated to be ~60% [31]. In an attempt to capture the missing loci, the IPDGC followed up on loci that had not quite reach genome-wide significance in the first meta-analysis (10-8>p>10-3) [33]. To reach power to detect these association signals with genome-wide significance, they combined data from their discovery and follow-up stages, and attempted to replicate their findings in the independent study sample of 23andMe [17]. In this combined analysis, four new loci reached genome-wide significance the strongest candidate at these loci are STX1B, FGF20 (which was previously reported in a candidate-gene study performed in a large family [34]), STBD1, and GPNMB. They also were the first to report a genome-wide significant association to the PARK16 locus in Europeans.


Association studies of sporadic Parkinson's disease in the genomic era.

Labbé C, Ross OA - Curr. Genomics (2014)

Overlap in discovery samples of published PD GWAS and meta-analyses.Each rounded rectangle represents a GWAS in PD or a meta-analysis of GWAS. The reference, the number of samples in the discoveryphase, and the country of origin of the samples used are included in the rectangles. The color of the rectangle reflects the findings of thestudy: no new identified loci, identified loci with genome-wide significance, and replication of previously identified loci (see legend for colorchart). Differences between sample size of a meta-analysis and individual GWAS are due to quality control differences. The discovery sampleof IPDGC2 includes both the discovery and the replication samples of IPDGC. * The Fung et al. sample set is part of the replicationphase of IPDGC 2011.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3958956&req=5

Figure 1: Overlap in discovery samples of published PD GWAS and meta-analyses.Each rounded rectangle represents a GWAS in PD or a meta-analysis of GWAS. The reference, the number of samples in the discoveryphase, and the country of origin of the samples used are included in the rectangles. The color of the rectangle reflects the findings of thestudy: no new identified loci, identified loci with genome-wide significance, and replication of previously identified loci (see legend for colorchart). Differences between sample size of a meta-analysis and individual GWAS are due to quality control differences. The discovery sampleof IPDGC2 includes both the discovery and the replication samples of IPDGC. * The Fung et al. sample set is part of the replicationphase of IPDGC 2011.
Mentions: Following the first round of success at identifying risk genes in GWAS performed in larger cohorts, research groups began to pool their data together in order to achieve a greater power to identify genes with modest impact on disease risk. Three meta-analyses were published in a matter of months by collaborating groups, while these studies are not independent - a lot of genotyping data overlap from the earlier independent GWAS studies (see Fig. 1) – each identified at least one novel association signal. The first of these meta-analyses published in 2011 [31] by the International Parkinson Disease Genomics Consortium (IPDGC) pooled data from five PD GWAS from the USA and Europe [10, 11, 13, 18, 19, 32]. The discovery phase consisted of 5333 patient samples and 12019 control samples and the follow-up consisted of 7053 case and 9007 control samples (the samples were pooled from the replication phase of the five GWAS and from the discovery phase of [32]). Eleven loci reached genome-wide significance, six were previously nominated (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were novel (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The cumulated population attributable risk for these loci was calculated to be ~60% [31]. In an attempt to capture the missing loci, the IPDGC followed up on loci that had not quite reach genome-wide significance in the first meta-analysis (10-8>p>10-3) [33]. To reach power to detect these association signals with genome-wide significance, they combined data from their discovery and follow-up stages, and attempted to replicate their findings in the independent study sample of 23andMe [17]. In this combined analysis, four new loci reached genome-wide significance the strongest candidate at these loci are STX1B, FGF20 (which was previously reported in a candidate-gene study performed in a large family [34]), STBD1, and GPNMB. They also were the first to report a genome-wide significant association to the PARK16 locus in Europeans.

Bottom Line: These large scale studies allow the identification of genomic regions harboring common variants associated to disease risk.Cumulative risk estimates of associated variants suggest that more loci are still to be discovered.This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosis and as targets for the development of better, personalized treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

ABSTRACT
Parkinson's disease is a common age-related progressive neurodegenerative disorder. Over the last 10 years, advances have been made in our understanding of the etiology of the disease with the greatest insights perhaps coming from genetic studies, including genome-wide association approaches. These large scale studies allow the identification of genomic regions harboring common variants associated to disease risk. Since the first genome-wide association study on sporadic Parkinson's disease performed in 2005, improvements in study design, including the advent of meta-analyses, have allowed the identification of ~21 susceptibility loci. The first loci to be nominated were previously associated to familial PD (SNCA, MAPT, LRRK2) and these have been extensively replicated. For other more recently identified loci (SREBF1, SCARB2, RIT2) independent replication is still warranted. Cumulative risk estimates of associated variants suggest that more loci are still to be discovered. Additional association studies combined with deep re-sequencing of known genome-wide association study loci are necessary to identify the functional variants that drive disease risk. As each of these associated genes and variants are identified they will give insight into the biological pathways involved the etiology of Parkinson's disease. This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosis and as targets for the development of better, personalized treatment.

No MeSH data available.


Related in: MedlinePlus