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Familial Aggregation of Parkinson Disease
A Comparative Study of Early-Onset and Late-Onset Disease
Haydeh Payami, PhD;
Sepideh Zareparsi, PhD;
Dora James, BS;
John Nutt, MD
Arch Neurol. 2002;59:848-850.
ABSTRACT
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Context It is unclear whether late-onset Parkinson disease (PD), which is the
most typical and most common form of the disease, has a familial component.
Evidence for familial aggregation is key to whether research should focus
on gene discovery or search for environmental factors.
Objective To investigate familial aggregation of early-onset and late-onset PD
separately.
Methods Using survival methods, age-specific risk of PD was calculated and compared
for 525 parents and siblings of 117 patients with early-onset PD, 1642 parents
and siblings of 343 patients with late-onset PD, and 522 parents and siblings
of 114 controls. The index patients were ascertained from a movement disorder
clinic. Spouses and friends served as controls.
Results Compared with the relatives of controls, age-specific risk of PD was
increased 7.76-fold in the relatives of patients with early-onset disease
(P<.001) and 2.95-fold in the relatives of those
with late-onset disease (P = .02).
Conclusions Late-onset PD has a significant familial component. The magnitude of
recurrence risk to relatives suggests a genetic etiology, without ruling out
the possibility of a coexisting environmental component.
INTRODUCTION
PARKINSON DISEASE (PD) is a common neurodegenerative movement disorder.1 Familial aggregation of PD was established by case-control
studies in the last decade.2-7
Taken as evidence for a genetic component, studies were launched to search
for the putative PD genes. Several loci have since been identified, 3 of which
( -synuclein, parkin, and ubiquitin carboxy-terminal hydroxylase L1)
have been characterized and shown to contain mutations that cause PD.8-11 All
3 PD genes identified to date are associated with early-onset PD (prior to
age 50 years). No genes have yet been identified for late-onset PD, which
is the more typical form of PD.
A recent study of twins found a high monozygotic concordance rate for
early-onset PD, but not for late-onset PD, concluding that genetic factors
do not play a major role in typical PD.12 If
confirmed, this finding will have serious implications for genetic studies
that are underway, as well as for setting the research direction in the future.
The low twin concordance rate seems to contradict the case-control studies
that showed higher age-specific risk of PD in relatives of patients. Case-control
studies did not separate early-onset PD from late-onset PD. Therefore, the
increased risk to relatives of patients may have been driven by the inclusion
of patients who had early-onset PD, which is now known to have a strong genetic
component. Alternatively, the low twin concordance rate may have been due
to inadequate follow-up rather than absence of a genetic component. In concordant
pairs, nearly 10 years elapsed before the second twin was diagnosed. Therefore,
as authors have pointed out, additional concordant pairs are likely to be
identified with continued follow-up. Here, we report the first case-control
family study of PD to examine early-onset and late-onset disease separately.
Since a key issue is proper control for age, we used the case-control study
design and survival analysis methods that allow for age-specific risk calculations.
The null hypothesis was that, compared with relatives of controls, the risk
of developing PD is elevated in the relatives of patients with early-onset
PD, but not in the relatives of patients with late-onset PD.
PATIENTS AND METHODS
Four hundred sixty white patients with PD were ascertained from the
movement disorder clinic at Oregon Health Sciences University, Portland. Inclusion
criterion was clinical diagnosis of idiopathic PD by standard criteria.13 Patients were selected randomly, regardless of family
history or age at onset. Patients who were referred for genetic studies were
excluded to avoid overrepresentation of familial cases. The first 114 patients
enrolled were asked to invite their spouses or a friend of similar age and
ethnicity (all white) to serve as controls. Subjects signed an informed consent
approved by the institutional review board.
Family histories were obtained using a standardized, self-administered
questionnaire. Relatives who had PD were considered affected. Age at onset
of first PD symptom was established for 80 of 82 affected relatives. For the
2 with unknown onset ages, we assigned age at diagnosis (this was conservative
since both were among the relatives of patients). Of the 460 index patients,
117 had onset of disease before age 50 years (early onset), and 343 had onset
at or after age 50 years (late onset) (Table 1).
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Table 1. Subject Characteristics*
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The analysis included parents and siblings of patients and controls
(Table 1), excluding the index
patients and controls. Time followed was specified as age at onset for the
affected individuals, and as age at last contact or age at death for the unaffected.
Age-specific cumulative risk of PD was estimated and plotted using Kaplan-Meier
survival analysis and compared using log-rank statistics. Age-specific hazard
ratios were calculated using the Cox proportional hazard model.
RESULTS
EARLY-ONSET VS LATE-ONSET VS CONTROL
The age-specific cumulative risk of PD, shown by Kaplan-Meier curves
(Figure 1), was significantly different
for the 3 groups of relatives. Parents and siblings of patients with early-onset
disease had the highest age-specific risk, while parents and siblings of patients
with late-onset disease were intermediate, and parents and siblings of control
subjects had the lowest risk (Figure 1). Compared with the relatives of controls, age-specific risk of PD was increased
7.76-fold (P<.001) in the relatives of patients
with early-onset PD, and 2.95-fold (P = .02) in the
relatives of patients with late-onset disease (Table 2). Clearly, the hypothesis that late-onset PD has no familial
component was rejected.
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Age-specific cumulative probability of escaping Parkinson disease
(PD). Kaplan-Meier curves for parents and siblings of patients with early-onset
PD (triangles, left curve), parents and siblings of late-onset PD (circles,
middle curve), and parents and siblings of controls (squares, right curve).
For early-onset patients vs controls, P<.001; for late-onset
patients vs controls, P = .02; and for early-onset patients vs
late-onset patients, P<.001.
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Table 2. Age-Specific HR of Developing PD*
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PARENTS VS SIBLINGS
The crude prevalence of PD was twice as high in parents than in siblings;
however, parents were older than siblings (Table 1). To determine whether the difference in prevalence rates
was real or an artifact of age, we compared age-specific risk of PD in parents
vs siblings. The age-specific rates were nearly identical (hazard ratio [HR]
= 0.80, P = .33), indicating no intergenerational
difference once age is taken into account. One can therefore expect the number
of siblings with PD to rise as they age.
MEN VS WOMEN
In relatives of patients with late-onset PD, age-specific risk was significantly
higher in men than in women (HR = 1.89, P = .03).
No significant gender difference was detected among the relatives of patients
with early-onset PD (HR = 0.7, P = .40), reflecting
a nonsignificant decreased risk in men.
COMMENT
This study revealed a significant familial aggregation for late-onset
PD. Although the magnitude of the risk to relatives of patients with late-onset
PD was considerably lower than that for relatives of patients with early-onset
PD, it was still significantly higher than that for the relatives of controls.
The postulate that the familial component is present only in early-onset disease,
and not in late-onset PD, was ruled out. Familial aggregation of late-onset
PD is further supported by a recent genealogical study from Iceland that showed
that patients with late-onset PD were significantly more related to each other
than were subjects in matched groups of controls.14
Overall (combining early- and late-onset cases), parents and siblings
of patients had a 4-fold-higher age-specific risk of developing PD than relatives
of controls. The risk was considerably higher for relatives of patients with
early-onset PD than for relatives of those with late-onset disease, indicating
a much stronger genetic etiology in the early-onset subtype. Parkinson disease
is more common in men.5, 15 We
found no gender difference in early-onset PD, but a significantly higher risk
to men among the relatives of patients with late-onset PD, suggesting that
the gender difference in PD is a characteristic of late-onset disease.
The incidence and prevelance of PD in relatives of controls were similar
to the general population and other control groups.5, 15
Thus, it is unlikely that the results were biased by underestimating PD in
controls. The patients, however, were ascertained from a specialty clinic,
and may have had a higher proportion of familial and early-onset cases than
the general population. Therefore, the results cannot be generalized until
confirmed in population-based studies. At this point, we have demonstrated
significant familial aggregation of late-onset PD in a clinic population of
white patients residing in the Pacific Northwest.
Familial aggregation may arise from shared environment or genes. Complex
segregation analysis has suggested a genetic component for typical late-onset
PD.16 Furthermore, a risk ratio of 3, as seen
here for relatives of patients with late-onset disease vs controls, is too
high to be explained by shared environment alone.17
Thus, present results argue in favor of a genetic etiology of late-onset PD,
without ruling out the possibility of a coexisting environmental component.
AUTHOR INFORMATION
Accepted for publication December 19, 2001.
Author contributions: Study concept and design (Drs Payami and Zareparsi); acquisition of data (Dr Zareparsi); analysis and interpretation of data (Drs Payami and Zareparsi, and Ms James); drafting of the manuscript (Dr Payami); critical revision of the manuscript for important
intellectual content (Drs Payami, Nutt, and Zareparsi, and
Ms James); statistical expertise (Drs Payami and
Zareparsi); obtained funding (Dr Payami);
study supervision (Dr Payami).
Support and funding was provided by grant R01 NS36960 from the National
Institute of Neurological Disorders and Stroke (Bethesda, Md) and the National
Parkinson Foundation Inc (Miami, Fla).
We wish to thank the patients, their families, and the volunteers who
participated in this study; and Nicole Lee, BS, Melissa Gonzales McNeal, MS,
and Kim Larson, MD, for assisting with data collection.
Corresponding author and reprints: Haydeh Payami, PhD, CR131, Oregon
Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201
(e-mail: payamih{at}ohsu.edu).
From the Department of Neurology, Oregon Health Sciences University,
Portland (Drs Payami, Zareparsi, and Nutt, and Ms James); and the W. K. Kellogg
Eye Center, University of Michigan, Ann Arbor (Dr Zareparsi).
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