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Genetic Complexity and Parkinson's Disease

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Science  18 Jul 1997:
Vol. 277, Issue 5324, pp. 387-390
DOI: 10.1126/science.277.5324.387

Mihael H. Polymeropoulos et al. describe the genetic linkage of a large Parkinson's disease (PD) pedigree to chromosome 4q21-q23 (1). In this study, which affirms a long hypothesized genetic component to the disease, linkage was detected in a single large family with the use of an autosomal dominant model with 99% penetrance of the disease trait. The clinical presentation in this family, however, may differ from typical idiopathic PD because of the apparent autosomal dominant transmisson, early onset, rapid course, and less frequent occurrence of tremor as a significant sign (2). Thus, it is unclear whether the putative PD locus identified by Polymeropoulos et al. (which they termed PD1) is responsible for the majority of familial idiopathic PD cases.

As part of an ongoing multicenter study of the genetics of idiopathic PD, we have ascertained 94 Caucasian families (a total of 213 affected relatives sampled: 108 affected sibpairs and 31 affected relative pairs) with at least two individuals in each family meeting clinical criteria for idiopathic PD (3). We have identified approximately 200 multiplex idiopathic PD families to ascertain for a genomic screen. The 94 families discussed here were those completely ascertained, with DNA sampled, at the time of the analysis. Linkage analysis of chromosome 4q21-q23 markers in these idiopathic PD families did not reveal evidence for linkage of an autosomal dominant, highly penetrant gene, as was described by Polymeropoulos et al.(1, 4). We determined two-point log odds (lod) scores, with the use of the model of Polymeropoulos et al. as well as a low penetrance “affecteds-only” autosomal dominant model. These lod scores were strongly negative for markers D4S2361, D4S2409, D4S2380, D4S1647, and D4S2623. Multipoint analysis of the genetic mapD4S2361-17cM-D4S1647-10.5cM-D4S2623supported these findings for both models, excluding the entire candidate region. We found no evidence for heterogeneity of either the two-point (P > 0.20) or multipoint (ln likelihood = 1) lod scores (5). Because the power of the parametric lod score method suffers when the genetic model is misspecified, we also used nonparametric analyses of affected relative pairs (6). As with the parametric lod score analysis, we found no significant evidence for linkage using either two-point or multipoint analysis; in this data set, the multipoint location scores (MLS) exclude the entire 27.5 cM region for recurrence risks to siblings as low as 2.5 (Fig. 1). Because the pedigree analyzed by Polymeropoulos et al.contained many younger onset cases (mean age at onset of the disease was 46), we repeated our analysis in the 22 families with at least one affected individual with an onset earlier than age 45; the analysis in the subset supported the results from the full sample (7).

Figure 1

Multipoint exclusion map for chromosome 4q21-q23 markers. The multipoint lod scores (MLS) within the region are all less than −2.0 at λs = 2.5, excluding the entire candidate region identified by Polymeropoulos et al. (1). Arrows indicate chromosome markers.

The absence of linkage to chromosome 4q21-q23 in our dataset indicates that there is genetic heterogeneity in PD. It is possible that the region identified by Polymeropoulos et al. harbors a disease locus responsible only for a rare autosomal dominant form of PD. Such a situation would be analogous to the genetics of Alzheimer's disease (AD), where mutations (in the amyloid precursor protein and the presenilin 1 and presenilin 2 genes) that cause autosomal dominant AD are responsible for less than 2% of all cases (8). Therefore, although the report by Polymeropoulos et al. is a first step in unraveling the genetic etiology of PD, other independent genetic effects likely remain to be discovered.


Polymeropoulos et al. present results of a genome-wide screen for genetic linkage in a large family with autosomal-dominantly inherited l-Dopa-responsive parkinsonism with Lewy-body pathology (1). They convincingly demonstrate linkage with polymorphic markers on chromosome 4q21-4q23, with a maximum two-point lod score of 6.00 for markerD4S2380. The locus was termed PD1. The role of the PD1 locus in other families with inherited parkinsonism and in sporadic PD remains to be investigated.

We have examined polymorphic markers closely linked to PD1 in 13 multigenerational families with inherited parkinsonism (Table 11). Affected members in all families exhibited at least two of the three cardinal clinical signs of PD (akinesia, rigidity, and resting tremor), as well as asymmetry at onset and a marked improvement onl-Dopa treatment. Rigorous exclusion criteria were applied (supranuclear ophthalmoplegia, cerebellar or pyramidal signs, and severe autonomic or postural disturbance within 2 years of onset). The wide range of age at onset and spectrum of clinical features, including the presence of dementia in addition to parkinsonism in some affected individuals, was similar to that observed in the family studied by Polymeropoulos et al. (1). No additional neurologic deficit was observed except for amyotrophy in one affected of family A. Multipoint analysis with eight polymorphic markers spanning the region from GATA 10G07 to D4S2623excluded the entire 17 cM region likely to contain PD1 in five of the families (families A, B, C, D, and IT-1). In one additional family (G), the major portion of the critical region was also excluded, with lod scores between −1.9 and −2 for the remainder of the interval (Fig.11). Data from one (previously unpublished) family of southern Bavarian origin showed positive lod scores with a maximum multipoint score of 1.5 (family K, Fig. 11). This lod score is close to the theoretical maximum in this relatively small family.

Table 11

Demographic and clinical characteristics in 13 families with inherited parkinsonism.

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Figure 1

 Multipoint linkage analysis of the PD1-region on chromosome 4q21-q23 in seven families with familial parkinsonism. Polymorphic DNA fragments were amplified by PCR with the use of published primer sequences and a standard protocol. Multipoint analysis was performed using GENEHUNTER (8), and two-point analysis was done using VITESSE (9). An autosomal dominant model with an age-dependent penetrance was assumed. As was done by Polymeropoulos et al. (1), unaffected individuals were set to be unaffected only when they were older than the mean age of onset in the respective families; all other unaffected individuals were treated as unknown. Frequency of the disease allele was set to 0.001. Marker allele frequencies were set to be equal for all alleles. Estimating marker allele frequencies from founders in the pedigrees did not alter multipoint lod scores significantly.

In six families (FR-041, FR-722, FR-727, FR-755, UK-A, and UK-B), only the two polymorphic markers most closely linked to PD1 (D4S1647 and D4S2380) have been analysed. Obligate recombinations (no allele shared by all affecteds) were observed in five of these families either for each of the markers individually (three families), or for the haplotype of both markers (two families), again strongly arguing against linkage with the PD1 locus. In one family (FR-041), a positive pairwise lod score was obtained for D4S2380 (0.29 at Theta = 0). Positive lod scores in families K and FR-041 may reflect true linkage, but they may also be a result of random fluctuations, because the relatively small size of these families precludes definite proof of linkage.

We conclude that mutations at the PD1 locus are probably a rare cause of autosomal-dominant parkinsonism. The role of the PD-1 gene in sporadic PD is still to be determined.


Response: Scott et al. and Gasseret al. are discussing genetic studies of families with PD that are designed to examine whether a locus that we previously reported (1) on chromosome 4q21-q23 is operating in their sample. The results of Scott et al. in 94 Caucasian families do not demonstrate linkage even when the 22 families with earlier onset are examined separately. Similarly, Gasser et al. exclude linkage in 13 multigenerational families with Parkinson's disease, with the exception of one family for which they achieved a maximum multipoint lod score of 1.5 for genetic markers in the 4q21-q23 region. Cumulatively, these comments suggest that the chromosome 4 locus will not account for the majority of familial Parkinson's disease and will be expected to operate only in a small percentage of families with the illness.

We have recently demonstrated that a mutation in the alpha synuclein gene is responsible for the phenotype in four families with early onset Parkinson's disease (2). Because the mutation was not detected in 50 individuals with sporadic PD, or in two other families with late onset of the illness, we concluded that mutations in the alpha synuclein gene will not account for the majority of the genetic factors of PD, but rather for a proportion of those families with an early onset autosomal dominant form of the illness. These results are in agreement with the observation of Scott et al. and Gasseret al., and suggest that the understanding of genetic complexity of Parkinson's disease is just beginning to take shape.


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