Complex segregation analysis of Parkinson's disease: The Mayo Clinic Family Study

McDonnell, Shannon K.; Schaid, Daniel J.; Elbaz, Alexis; Strain, Kari J.; Bower, James H.; Ahlskog, J. Eric; Maraganore, Demetrius M.; Rocca, Walter A.

doi:10.1002/ana.20844

Cited by 35 publications

(30 citation statements)

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“…While the available datasets were exploratory and may have been underpowered to detect the main effects of single SNPs or probe sets, our findings are consistent with recent studies that report greater statistical power to detect the joint effects of multiple loci than the main effects of single loci [44,45]. By contrast to familial aggregation and twin studies, our findings demonstrate that a largely sporadic disease such as PD can in fact have a strong genetic component [4,46,47] and suggest that a similar genomic pathway approach might provide insights into several other complex diseases. Finally, these findings provide important insights regarding the molecular mechanisms that may control dopamine circuit formation and programmed cell death in healthy versus diseased individuals.…”

Section: Discussionsupporting

confidence: 86%

“…They are thought to arise from multiple predisposing factors, both genetic and nongenetic, and joint effects of those factors are thought to be of key importance [1,2]. Parkinson disease (PD) serves as an example of a complex disease [3,4]. Other examples include Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several types of cancer [5].…”

Section: Introductionmentioning

confidence: 99%

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A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

et al. 2007

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While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R 2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

et al. 2007

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“…The age-dependent findings for SNCA REP1 are consistent with previous studies of SNCA promoter variability and PD 10 and consistent with the greater heritability of PD in younger subjects. 24,25 Although our multivariate analyses of SNCA REP1 score, pesticide exposures, and risk of PD were significant in younger subjects, there were no pairwise interactions. The lack of association of SNCA REP1 score with familial PD was unexpected.…”

Section: Resultsmentioning

confidence: 63%

α-Synuclein, pesticides, and Parkinson disease

et al. 2008

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“…PD is characterized pathologically by Lewy bodies and Lewy neurites in which the α-synuclein protein accumulates. Although approximately 15% of PD patients report a family history of PD [2], large families with Mendelian inheritance are rare. To date, various genetic methods have been applied to multiplex familial forms of PD revealing a total of 18 genomic loci, which now includes seven known genes.…”

Section: Introductionmentioning

confidence: 99%

Update on novel familial forms of Parkinson's disease and multiple system atrophy

Fujioka

Ogaki

Tacik

et al. 2014

Parkinsonism & Related Disorders

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Parkinson’s disease (PD) and multiple system atrophy (MSA) are progressive neurodegenerative disorders classified as synucleinopathies, which are defined by the presence of α-synuclein protein pathology. Genetic studies have identified a total of 18 PARK loci that are associated with PD. The SNCA gene encodes the α-synuclein protein. The first pathogenic α-synuclein p.A53T substitution was discovered in 1997; this was followed by the identification of p.A30P and p.E46K pathogenic substitutions in 1998 and 2004, respectively. In the last year, two possible α-synuclein pathogenic substitutions, p.A18T and p.A29S, and two probable pathogenic substitutions, p.H50Q and p.G51D have been nominated. Next-generation sequencing approaches in familial PD have identified mutations in the VPS35 gene. A VPS35 p.D620N substitution remains the only confirmed pathogenic substitution. A second synucleinopathy, MSA, originally was considered a sporadic condition with little or no familial aggregation. However, recessive COQ2 mutations recently were nominated to be the genetic cause in a subset of familial and sporadic MSA cases. Further studies on the clinicogenetics and pathology of parkinsonian disorders will facilitate clarification of the molecular characteristics and pathomechanisms underlying these disorders.

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Complex segregation analysis of Parkinson's disease: The Mayo Clinic Family Study

Abstract: The familial aggregation of PD may be explained in part by a major gene with additive effect on the penetrance.

Cited by 35 publications

References 39 publications

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

α-Synuclein, pesticides, and Parkinson disease

Update on novel familial forms of Parkinson's disease and multiple system atrophy

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