Familial aggregation of Parkinson’s disease

Elbaz, Alexis; Grigoletto, Francesco; Baldereschi, Marzia; Breteler, Monique M.B.; Manubens-Bertran, J. M.; López-Pousa, Secundino; Dartigues, J.-F.; Alpérovitch, A; Tzourio, Christophe; Rocca, Walter A.

doi:10.1212/wnl.52.9.1876

Cited by 140 publications

(107 citation statements)

References 31 publications

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“…A recent large population-based case-control study found that PD significantly aggregated in families, the strength of the association being age-dependent. This is in keeping with the fact that familial factors, which can be genetic, environmental, or both, play a role in PD (Elbaz et al 1998). Overall, the relative risk in first degree relatives of probands with PD is in the range of 2-3, which is similar to that found in AD (Farrer et al 1989).…”

Section: Epidemiological Studiessupporting

confidence: 78%

Genetics of Parkinsonism: a review

VAUGHAN¹,

DAVIS²,

WOOD³

2001

Annals of Human Genetics

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Idiopathic Parkinson's disease (IPD), a progressive neurodegenerative disorder, is a common cause of disability. No current therapies modify disease progression. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. Two genes (SNCA and parkin) as well as two gene loci have now been implicated in the pathogenesis of familial PD. These represent significant progress in our understanding of the disease, considering the rarity of large families, low heritability in the general population and genetic heterogeneity. Mutations in a further gene, UCHL1, have been described in familial PD although the evidence for its role in PD is less clear. Knowledge of the genes described in PD to date should help to define molecular mechanisms of neurodegeneration in PD, as well as in other diseases where defects in protein handling may be a common feature. Nigral degeneration with Lewy body formation and the resulting clinical picture of PD may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. This review discusses the major advances in the field to date and illustrates how the existence of genetic factors has now become firmly established.

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Section: Epidemiological Studiessupporting

confidence: 78%

Genetics of Parkinsonism: a review

VAUGHAN¹,

DAVIS²,

WOOD³

2001

Annals of Human Genetics

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“…This study joins several others finding sporadic PD subjects more commonly report positive PD family histories than control subjects [23,[25][26][27][28][29][30][31][32]. Perhaps PD itself increases ones awareness of PD or parkinsonism in others, or control status reduces awareness, rendering in either case a secondary artifact [33].…”

Section: Discussionsupporting

confidence: 82%

Complex I polymorphisms, bigenomic heterogeneity, and family history in Virginians with Parkinson's disease

Swerdlow

Weaver

Grawey

et al. 2006

Journal of the Neurological Sciences

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The electron transport chain enzyme complex I may play a role in Parkinson's disease (PD) pathogenesis. Association studies considering whether or not complex I-relevant gene polymorphisms contribute to PD risk are discordant. We evaluated four complex I-relevant gene polymorphisms alternatively reported to associate and not associate with PD (tRNA Gln T4336C, ND1 T4216C, ND2 G5460A, and the NDUFV2 exon 2 C182T transition). Our study included 111 PD subjects and 106 controls in central Virginia. Individuals with at least one copy of the NDUFV2 182T allele were more likely to report a PD family history than non-carriers, but aside from this no positive associations were found. Indeed, the tRNA Gln 4336C variant occurred more frequently in controls. We also observed that individuals in both groups often carried more than one of the assayed polymorphisms, and for the first time show bigenomic polymorphic variation (between nuclear and mtDNA complex I subunit genes) commonly occurs within individuals. In an exploratory sub-analysis, more control than case women had an ND1 4216C, NDUFV2 homozygous 182C compound genotype. Complex I compound genotype variation commonly occurs and may explain why particular complex I gene polymorphisms associate with PD in some populations but not others.

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“…The genetic hypothesis is supported by community-based studies showing that a substantial number of PD patients have similarly affected relatives. 3,4 This was also revealed by a PD study conducted by us on Crete, 5 an island of about 0.6 million people sharing the same genetic and cultural background and a common environment. Moreover, this study suggested an oligogenic model for PD, according to which disease-predisposing alleles from two or more genes need to be present in the same individual for the disorder to be expressed.…”

Section: Introductionmentioning

confidence: 68%

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

et al. 2009

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Parkinson's disease (PD), a common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and their terminations in the basal ganglia, is thought to be related to genetic and environmental factors. Although the pathophysiology of PD neurodegeneration remains unclear, protein misfolding, mitochondrial abnormalities, glutamate dysfunction and/or oxidative stress have been implicated. In this study, we report that a rare T1492G variant in GLUD2, an X-linked gene encoding a glutamate dehydrogenase (a mitochondrial enzyme central to glutamate metabolism) that is expressed in brain (hGDH2), interacted significantly with age at PD onset in Caucasian populations. Individuals hemizygous for this GLUD2 coding change that results in substitution of Ala for Ser445 in the regulatory domain of hGDH2 developed PD 6-13 years earlier than did subjects with other genotypes in two independent Greek PD groups and one North American PD cohort. However, this effect was not present in female PD patients who were heterozygous for the DNA change. The variant enzyme, obtained by substitution of Ala for Ser445, showed an enhanced basal activity that was resistant to GTP inhibition but markedly sensitive to modification by estrogens. Thus, a gain-of-function rare polymorphism in hGDH2 hastens the onset of PD in hemizygous subjects, probably by damaging nigral cells through enhanced glutamate oxidative dehydrogenation. The lack of effect in female heterozygous PD patients could be related to a modification of the overactive variant enzyme by estrogens. INTRODUCTIONParkinson's disease (PD) affects about 1.8% of people over the age of 65 years. 1 It is clinically characterized by tremor, rigidity and bradykinesia, which often occur along with disturbances of posture and gait. 2 About 80% of PD cases are sporadic, with males being more frequently affected than females (ratio¼1.5:1).The etiology of PD remains largely unknown, although interplay of environmental toxins with genetic susceptibility may be operational. The genetic hypothesis is supported by community-based studies showing that a substantial number of PD patients have similarly affected relatives. 3,4 This was also revealed by a PD study conducted by us on Crete, 5 an island of about 0.6 million people sharing the same genetic and cultural background and a common environment. Moreover, this study suggested an oligogenic model for PD, according to which disease-predisposing alleles from two or more genes need to be present in the same individual for the disorder to be expressed.With regard to the pathophysiology of PD, several hypotheses have been proposed in an attempt to explain the degeneration of dopaminergic neurons in this disorder. One of these suggests that mitochondrial dysfunction is involved, 6 a contention supported by the recent discovery of monogenetic forms of PD resulting from mutations of

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Familial aggregation of Parkinson’s disease

Abstract: In this large sample of prevalent PD patients and population-matched controls, PD significantly aggregates in families, with the strength of the association being age-dependent. Therefore, familial factors, which can be genetic, environmental, or both, play a role in PD.

Cited by 140 publications

References 31 publications

Genetics of Parkinsonism: a review

Genetics of Parkinsonism: a review

Complex I polymorphisms, bigenomic heterogeneity, and family history in Virginians with Parkinson's disease

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

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