Association Studies

The Parkinson's-Reversing Breakthrough

Is There A Cure for Parkinson Disease

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Despite substantial progress in identification, there are only a few known large pedigrees with PD. Furthermore, genetic linkage studies that use "identity-by-descent" mapping have been hampered because of the limited amount of DNA available from affected pedigree members, generally because of death, lack of consent, or geographic dispersion. Association or "identity-by-state" mapping is an alternate approach using groups of unrelated persons. Association studies measure differences in genetic variability between a group with the disease in question and a group of matched healthy persons. This method is most powerful in implicating genes for multigenic traits in homogeneous population isolates. Many past studies have been confounded by misconceived a priori notions about the causes of disease, by the candidate genes

TABLE 1 Familial Parkinsonism with Reported Mutations or Loci

Age at

Pathologic

Response to

Locus

Chromosome

Gene

Inheritance

onset3

Phenotype

findings

levodopa

Reference

PARK1,

4q21

SNCAb

AD

Young to middle

PD and D

LBs

Good

(34)

PARK4

PARK2

6q25.2-27

Parkin

AR

Young

PD

LB or tau

Good

(36)

PARK3

2p13

Unknown

AD

Middle to senior

PD

LBs

Good

(33)

PARK5

4p14

UCHL1c

AD

Middle

PD

Unknown

Good

(70,71)

PARK6

1 p35-36

PINK1

AR

Middle

PD

Unknown

Good

(38)

PARK7

1 p36

DJ-1

AR

Young to middle

PD

Unknown

Good

(37)

PARK8

12p11.2-q13.1

LRRK2

AD

Middle to senior

PD

LBs, tau(+) NFT

Good

(39,40)

PARK9

1 p36

Unknown

AR

Young

Atypical PD, D, PSP

Unknown

Good

(35)

PARK10

1P

Unknown

Unknown

Middle

PD

Unknown

Good

(71)

PARK11

2q36-37

Unknown

AD

Middle to senior

PD

Unknown

Good

(72)

Note: Since the submission of this chapter two additional parkinsonian loci (PARK12 and PARK13) have been identified (Pankratz N, Nichols CW, Uniacke KS, et al. Genome-wide linkage analysis and evidence of gene-by gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Mol Genet 2003; 15:2599-2608; Strauss KM, Martins LM, Plun-Favreau H, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet 2005; 14:2099-2111). aYounger age at onset, <40 years; middle age at onset, between 41 and 60 years; senior age at onset, >60 years. Three missense mutations or multiplications. Two mutations.

Abbreviations-. AD, autosomal dominant; AR, autosomal recessive; D, dementia; LBs, Lewy bodies; NFT, neurofibrillary tangle; PD, Parkinson's disease; PSP, progressive supranuclear palsy; UCH-L1, ubiquitin carboxy-terminal hydrolase L1.

or variants chosen for analysis, and by clinical, locus, and allelic heterogeneity. Results must be reproducible, preferably in different ethnic populations, and the genetic variability associated with disease should have some functional consequence (either directly or in disequilibrium) that alters gene expression or the resultant protein.

The genes for SNCA, parkin, UCHL1, PINK1, DJ-1,and LRRK2 harbor mutations that segregate with parkinsonism in affected family members (35-48) (Fig. 1). Although the relevance of these findings for sporadic PD is still unclear, there is no doubt that these proteins mark a pathway that is perturbed in both familial and sporadic PD. Understanding the components of the pathway and its regulation is the first step toward elucidating the molecular causes of parkinsonism (49). In some studies, common genetic variability in genes for SNCA (58,59), UCHL1 (60-62), DJ-1 (63-65), PARK2 (66), PINK1 (67), and LRRK2 (47-52,68,69) has been implicated in sporadic PD by association. These genes clearly contribute to risk in at least a subset of patients with idiopathic PD.

Genome-wide methods of association have taken a less biased view than candidate gene association studies in PD (69). Although promising, given their power and multiple testing, such methods nonetheless require genetic and functional validation of their results.

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