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Asusceptibility gene for late-onset idiopathic Parkinson's disease.

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A Susceptibility Gene for Late-Onset
Idiopathic Parkinson’s Disease
Andrew A. Hicks, PhD,1 Hjörvar Pétursson, BS,1 Thorlákur Jónsson, PhD,1 Hreinn Stefánsson, PhD,1
Hrefna S. Jóhannsdóttir, BSc,1 Jesus Sainz, PhD,1 Michael L. Frigge, PhD,1 Augustine Kong, PhD,1
Jeffrey R. Gulcher, MD, PhD,1 Kári Stefánsson, MD, PhD,1 and Sigurlaug Sveinbjörnsdóttir, MD2
Eight regions of the genome (PARK1-8) have been implicated in autosomal dominant and autosomal recessive forms of
early-onset Parkinson’s disease. These forms constitute a few of all cases. However, except for a haplotype in six families
(PARK3), no study has successfully mapped a gene or described mutations that contribute to the common late-onset
Parkinson’s disease. Some have even suggested that a genetic component does not exist. We cross-matched our nationwide genealogy database with a population-based list of Icelandic Parkinson’s disease patients to search for families with
more than one patient. We performed a genomewide scan on 117 patients and 168 of their unaffected relatives within
51 families using 781 microsatellite markers. Allele-sharing, model-independent analysis of the results showed linkage to
a region on chromosome 1p32 with a logarithm of odds score of 3.9 (Zlr ⴝ 4.2). By increasing the information content
with additional microsatellite markers in this region, we found that the logarithm of odds score increased to 4.9 (Zlr ⴝ
4.8). This result corresponds to an unadjusted p value of 1.0 ⴛ 10ⴚ6 and p < 0.005 after adjusting for a genomewide
search. We designate this region PARK10. We therefore have successfully mapped, to genomewide significance, a susceptibility gene for late-onset Parkinson’s disease using multiple families drawn across a whole population. Identification
of the susceptibility gene in this region may pave the way for a better understanding of the disease process, which, in
turn, may lead to improved diagnostics and therapeutics.
Ann Neurol 2002;52:549 –555
Parkinson’s disease is a neurodegenerative disorder of
unclear cause and pathogenesis that usually occurs in
middle age or later with an onset of symptoms typically after 60 years of age. The signs of the disease include bradykinesia, rigidity, resting tremor, and postural instability. In some rare families characterized by
early-onset and a Mendelian pattern of transmission,
the role of genetic factors has been clearly established.
In families with autosomal dominant early-onset Parkinson’s disease, the first gene to be isolated was
␣-synuclein.1 Two additional loci have been reported
in such families, including PARK3 on chromosome
2p132 and PARK4 on chromosome 4p14-16.3,3 and a
mutation in the ubiquitin carboxy-terminal hydrolase
L1 gene in one German family has been reported.4
Other families have been reported where linkage to
these regions has been excluded.5 In addition, the Parkin gene on chromosome 6q25.2-27 (PARK2) is involved in juvenile parkinsonism6 and in families demonstrating autosomal recessive inheritance as well as
some sporadic early-onset cases.7–10 Furthermore, two
loci on chromosome 1 at 1p35-p36, PARK6,11 and
1p35, PARK7,12 have been reported recently to contain
further susceptibility genes in single families with earlyonset recessive Parkinson’s disease, and a recent report
maps a susceptibility gene (PARK8) to chromosome
12p11.2-q13.1 in a single Japanese family.13
Although there is a clear role for genetic factors in
both autosomal dominant and recessive early-onset
Parkinson’s disease, these forms represent only a minor
part of the total disease spectrum. The factors contributing to the more widespread late-onset form have, until now, remained both controversial and elusive. Most
controversial is the relative role of genetic and environmental factors. The common form of Parkinson’s disease does not follow a Mendelian pattern of inheritance, and some twin studies have spawned the
conclusion that there are no genetic risk factors.14
However, we recently published a study that used a
population-based list of patients from Iceland drawn
over a 50-year period. Using a comprehensive genealogy database, we found that Parkinson’s patients in
general, and late-onset cases in particular, are more related to each other than matched controls. We further
showed that this familiality extends beyond the nuclear
family, suggesting that its basis is genetic and not only
From 1deCODE Genetics, and
Reykjavik, Iceland.
National University Hospital,
Published online Sep 20, 2002, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.10324
Received Sep 10, 2001, and in revised form Feb 14 and May 31,
2002. Accepted for publication May 31, 2002.
Address correspondence to Dr Stefánsson at deCODE Genetics,
Sturlogötu 8, Reykjavik 101, Iceland. E-mail: kstefans@decode.is
2
© 2002 Wiley-Liss, Inc.
549
shared environment.15 Although most Parkinson’s patients do not have a first-degree relative with the disease, we have found, using our genealogy database, that
for many of our Parkinson’s patients we can find an
affected relative at or within six meiotic events (six
meioses separate second-cousins).
We now extend this work by performing a genomewide scan of 117 patients in 51 extended families with
781 microsatellite markers. Our results show strong
genomewide significant linkage to chromosome 1p32.
These results are distinct from two additional genomewide scans in Parkinson’s disease,16,17 in that although
several suggestive loci were reported, nothing in these
studies was mapped to genomewide significance according to widely accepted criteria.18 This localization
(PARK10) therefore represents the first populationwide
mapping of a gene contributing to the pathogenesis of
late-onset Parkinson’s disease.
formed consent form. All personal identifiers associated with
medical information and blood samples, along with the genealogy database, were encrypted by the Data Protection
Commission of Iceland.21
Genomewide Linkage Scan
A genomewide scan was performed using a framework map
of 781 microsatellite markers.22 The marker order and positions for the framework mapping set were obtained from the
Marshfield genetic map (http://research.marshfieldclinic.org/
genetics) except for a three-marker putative inversion on
chromosome 8.23–25
We analyzed the data and determined statistical significance by applying an affected-only allele-sharing method
implemented in the Allegro program, which calculates
logarithm of odds (LOD) scores based on multipoint calculations.26 –28 Allegro28 is a linkage program developed at deCODE Genetics and available free for noncommercial use
(e-mail: allegro@decode.is). Our baseline linkage analysis
uses the Spairs scoring function,26,29 a one degree-of-freedom
alternative model constructed by exponentially tilting the
allele-sharing distribution under the null hypothesis of no
linkage27 and a family weighting scheme that is halfway, on
the log scale, between weighting each affected pair equally
and weighting each family equally. This weighting scheme is
similar to that proposed by Weeks and Lange30 as an extension of that of Hodge31 designed for sibships. In the analysis
we perform affected-only analysis in that an individual is either classified as affected or having an unknown disease status. The LOD scores reported are base 10 logarithms of likelihood ratios. The allele-sharing LOD score can be converted
to a Z-score. In particular, based on large sample theory,
Zlr ⫽ 公 [2 loge (10) LOD] is approximately distributed as
a standard normal distribution under the null hypothesis of
no linkage.27 Apart from the p value computed using normal
approximation, because of the concern with small sample behavior, we compute, using Allegro, a second p value by comparing the observed LOD score to its complete data sampling distribution under the null hypothesis.28 When a data
set consists of more than a handful of families, as here, these
two p values tend to be similar. To be conservative, we re-
Patients and Methods
Patients
This study, which used encrypted patient identifiers, was approved by the National Bioethics Committee of Iceland and
the Data Protection Commission of Iceland. Patients were
identified as previously described15,19 and, after detailed clinical examination by a neurologist specializing in movement
disorders, were considered to have Parkinson’s disease if they
had at least two of the following cardinal signs: tremor, rigidity, bradykinesia, or postural instability, whereas other
causes of parkinsonism were excluded.20 In this study, we
included 117 patients who were related to other patients at
or within six meiotic events as determined with our genealogy database, and 168 of their first-degree unaffected relatives. The patients were clustered into 51 families, and a
summary of the affected relative pairs in the families is given
in the Table. Sixty-three percent of the patients included
were men, and 81% of the 117 had at age at onset of symptoms of older than 50 years, with a mean age at onset of
65.8 years. Informed consent was obtained from all participants. See http://www.decode.com for an example of the in-
Table. A Tabulation of the Number of Various Affected Relative Pairs Found in the 51 Icelandic Families
Used in the Linkage Study
Expected Alleles Identical by Descent
Relationship
Thereof
n
Thereof
No Linkage
p ⫽ 0.4%
p ⫽ 1.7%
p ⫽ 2.8%
Siblings
Avuncular
First cousins
First cousins once removed
Second cousins
Second cousins once removed
14
4
9
10
40
8
14
4
8
10
38
4
1.00000
0.50000
0.25000
0.12500
0.06250
0.03125
1.344
0.762
0.517
0.314
0.176
0.094
1.390
0.820
0.603
0.395
0.233
0.128
1.384
0.812
0.590
0.382
0.224
0.122
Type
First-degree
Second-degree
Third-degree
Fourth-degree
Fifth-degree
Sixth-degree
Best Fitting Additive Model
For example, there are nine third-degree relative pairs, eight of them cousin pairs and the other a half-avuncular pair. For each relative type,
we give the expected number of alleles identical by descent under no linkage, and the corresponding values for the best fitting additive model
given in the article. Results for three values of the disease allele frequency ( p) are given.
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port the less significant of the two. The p values can be adjusted for multiple comparisons. An unadjusted p value of
2 ⫻ 10⫺5 corresponds approximately to a p value of 0.05
after adjusting for a genomewide scan.18
Genotypes of polymorphic markers provide incomplete
information about DNA sharing among patients. The degree
of completeness can, however, be increased by typing additional markers. The measure of information content is defined in Nicolae32 and is part of the Allegro program output.
This measure, between zero and one, is closely related to a
classic measure.33
Parametric Modeling
After obtaining a significant allele-sharing LOD score, parametric models are fitted to the data to explore the contribution of the susceptibility gene to the disease population.
When fitting parametric models, we also perform affectedonly analysis. As a result, only the ratios of penetrances are
relevant. We fit a range of single locus dominant, additive
and multiplicative models.34 For example, with a dominant
model, we assume that the risk of a person carrying one or
two copies of the at-risk allele is the same, but this risk can
be lower than one (incomplete penetrance) and the risk for a
noncarrier, whereas lower, is not necessarily zero.
Genetic and Physical Mapping
High-resolution genetic mapping and base pair resolution
physical mapping were used to locate both microsatellite
markers and genes. Additional microsatellite markers were
designed using genomic sequence from the January 9, 2001
assembly of the University of California at Santa Cruz
(http://genome.ucsc.edu). Genotype data from 146 Icelandic
nuclear families containing 872 individuals (two to seven siblings with their parents) were used to build a genetic map
over the interval of interest. The combined genetic-physical
map determined the most likely order of markers, and the
intermarker genetic distances have resolution of approximately 0.5cM.
Results
This article reports the results of our linkage scan on a
total of 117 Parkinson’s disease patients within 51
families. Figure 1 shows an example of the extended
Fig 1. An example of the extended families
used in the study, which include multiple
Parkinson’s disease patients. Gender indicators
have been shuffled for some individuals in the
top two generations, and unaffected siblings,
offspring, and mates of patients are not
shown, to protect privacy. (solid squares and
circles) Affected men and women, respectively.
The patients in this family had ages at onset
of symptoms between 66 and 78 years old.
(slashed symbols) Deceased individuals for
whom we have no DNA. Haplotypes shown
are for 10 markers from a shared region
spanning 37 markers, plus 1 marker just outside the region on either side. The shared
region is represented by a solid box.
Hicks et al: PD Susceptibility Gene
551
families used. The patients and 168 of their relatives
not diagnosed with Parkinson’s disease were genotyped
using 781 microsatellite markers. We analyzed the data
and determined significance by applying affected-only,
allele-sharing methods. These methods do not formally
specify a particular inheritance model but instead
search for genomic regions shared by affected relatives
by descent more often than expected under the baseline of no linkage. LOD scores based on multipoint
calculations, which used the information from all the
markers simultaneously, were computed using the Allegro program.28 Figure 2 presents the allele-sharing
LOD scores and the corresponding Zlr scores for the
entire genome using the markers in the framework
map. The most prominent linkage was found to chromosome 1p32. Two LOD score peaks of 3.9, separated
by approximately 13cM, were observed near D1S2652
and D1S2846, respectively. Additional LOD scores of
1.6 on chromosome 5 near D5S666, 1.2 on chromo-
some 7 near D7S661, and 1.1 on chromosome X near
DXS8080 also were observed. Although the LOD
score of 3.9 (Zlr ⫽ 4.2; p ⫽ 1.1 ⫻ 10⫺5 unadjusted)
on chromosome 1 was already genomewide significant
according to the Lander-Kruglyak criterion (single test
p value of ⬍2 ⫻ 10⫺5 which corresponds to a
genomewide adjusted p value of 0.05),18 the information content was below 60%, indicating that the
marker data was still far from capturing all the allelesharing information inherent in the material. It is more
meaningful to have a LOD score associated with high
information content. Apart from ensuring that the results are a true reflection of the information contained
in the material, it reduces the potential problem of
multiple comparisons, because multipoint LOD scores
can increase or decrease substantially as markers are
added. The information content for linkage32,33 at the
1p32 region was increased by genotyping an additional
44 markers over an approximately 44cM segment that
Fig 2. Full genome scan of all affected family members using 781 microsatellite markers. The multipoint allele-sharing logarithm of
odds (LOD) score is on the left-hand vertical axis; the corresponding Zlr score on the right-hand vertical axis and centimorgan distance from the p-terminus of the chromosome is on the horizontal axis.
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spans the region between markers D1S2884 and
D1S198.
Correct marker order and good estimates of intermarker distances are extremely important for multipoint linkage analysis.35,36 However, the microsatellite
marker maps in the public domain have limited accuracy at intermarker distances less than 2 to 3cM. Highresolution genetic and physical mapping was used to
increase the accuracy of the order of additional markers
and to provide reliable intermarker distances. With the
additional markers and our map, the LOD score peak
near marker D1S2846 dropped, whereas the LOD
score peak near D1S2652 increased to 4.9 with a corresponding Zlr score of 4.8 (Fig 3). This corresponds
to a p value of 1.0 ⫻ 10⫺6 before adjusting for multiple comparisons and a p value lower than 0.005 after
adjusting for a genomewide search. The information
content over the 20cM interval centered on the peak
exceeds 0.85 and averages 0.95. We designate this locus as PARK10. The peak is centered near marker
D1S231, with markers D1S2874 to D1S475, telomeric and centromeric, respectively, defining a decrease
of one in LOD score from the peak. We estimate this
segment to be approximately 7.6cM in genetic length
and approximately 9.5 million bases.
In an attempt to understand the contribution of this
locus to the population, we fitted a variety of parametric models to the data. By specifying allele frequencies
and penetrances that maximize the LOD score, a LOD
score between 5.3 and 5.6 can be obtained for dominant, additive, or multiplicative models. Although this
indicates that the current data do not allow us to pin
down the mode of inheritance, we can still obtain a
rough estimate of how much this susceptibility gene
Fig 3. Multipoint allele-sharing logarithm of odds (LOD) score of chromosome 1 with extra microsatellite markers within
PARK10. The multipoint LOD score is on the left-hand vertical axis, the corresponding Zlr score on the right-hand vertical axis,
and centimorgan distance from the p-terminus of the chromosome is on the horizontal axis. Several of the markers analyzed in this
region, mentioned in the text, are placed at their centimorgan location. Note that marker locations are based on our map, which is
sometimes different from the Marshfield genetic map. Thus, D1S231 is placed very close to but centromeric of the marker
D1S1661 in our map, whereas the Marshfield genetic map placed it 4.4cM telomeric of D1S1661.
Hicks et al: PD Susceptibility Gene
553
contributes to familial risk. With an additive model
that assumes that the carriers of one and two at-risk
alleles have, respectively, 30 times and 59 times the risk
of getting the disease compared with the noncarriers,
LOD scores between 5.5 and 5.6 are obtained for the
at-risk allele frequency ranging from 0.4% to 2.8%.
These models correspond to a sibling recurrence risk
ratio ranging from 3.2 to 4.6. The Table gives the expected number of alleles shared IBD for various affected relative pairs computed based on three of these
models.34 The best fitting dominant and multiplicative
models give similar numbers, which is not surprising as
the power to detect linkage with affected-only analysis
is more directly tied to the recurrence risk ratio instead
of the exact mode of inheritance.34 Compared with the
observed sibling recurrence risk ratio of 6.7 that we
reported earlier,15 the gene at this locus alone can account for a substantial fraction of the familial aggregation of late-onset Parkinson’s disease. However, given
that estimates of locus-specific effect size at genomewide LOD score peaks can produce inflated results,37 a
precise estimate of the population-attributed risk probably will not be available until the gene is cloned and
the at-risk allele(s) identified. Moreover, it needs to be
emphasized that even if this or other genetic susceptibility factors are demonstrated to have a very high
population-attributed risk, it does not rule out the possibility that environmental factors also can have a major impact on disease prevalence, as the manifestation
of the disease may require a combination of genetic
and environmental risk factors.
Discussion
Based on our previous work demonstrating a significant familial aggregation of patients with late-onset disease15 as well as several case–control38,39 and twin40
studies, a genetic contribution to the cause of the common form of Parkinson’s disease is becoming more obvious. Multiple genes may be involved together with as
yet unknown environmental factors. Until the genetic
contributions to late-onset Parkinson’s disease have
been further characterized, the extent to which diverse
genetic and environmental factors interact to cause this
disease are likely to remain a subject of debate. In fact,
it may prove difficult to find environmental factors
that contribute to the risk of Parkinson’s disease without first isolating the genetic factors, because the environmental factors may require a genetically susceptible
individual to yield the disease.
To date, there is little evidence that any of the genes
found contributing to the rare Mendelian forms of
Parkinson’s disease play a major role in the cause of the
common form of late-onset Parkinson’s disease, even
though there are reports of Lewy bodies in some patients with parkin mutations, and it has been suggested
that hemizygous mutation in parkin may play a wider
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role in susceptibility to late-onset disease.41 Two recent
genomewide linkage studies of families with patients
without unusual clinical features or age of onset demonstrate a few regions of suggestive linkage, and these
do not coincide with loci or genes mapped in the Mendelian phenocopies of Parkinson’s disease.16,17 Although neither of these scans originally presents a significant peak at chromosome 1p32, the authors of one
of these articles recently have published an article that
reanalyzes, using a different statistical approach to incorporate age at onset, their genomewide scan data,
and they now claim linkage to age at onset at 1p32,42
thus successfully reproducing the linkage result documented here. In our study, we have combined detailed
genealogical information with an extensive populationbased list of well-defined patients and used the allelesharing methods to successfully map a major gene for
late-onset Parkinson’s disease, PARK10, to genomewide
significance. Two additional loci on chromosome 1p
have been reported for Parkinson’s disease, although
they appear to be contributing to a very different form
of Parkinson’s disease from ours. Each group studied a
single extended family with early-onset autosomal recessive Parkinson’s disease. The PARK6 region11 ranges
between the markers D1S199 and D1S2885. These
markers define an approximately 9Mb span physically
located at 21 to 30Mb on the chromosome. Our locus
spans a 9Mb stretch between 56 and 64Mb and is at
least 26 million bases away from the PARK6 region.
The PARK7 locus12 ranges between markers D1S243
and D1S244, located at 1 to 11Mb. Thus, PARK7 is at
least 10Mb telomeric from PARK6, putting it at least
45 million bases away from our region. There appear
to be no overlaps between markers at the PARK6 and
PARK7 loci.12 It is highly unlikely therefore that the
same underlying genetic susceptibility at PARK10 overlaps with either PARK6 or PARK7.
From our physical map and public data, there appear to be at least 30 known or possible genes in the
region of PARK10, and a detailed description of their
functions is outside the scope of this article. Identification of the candidate gene within this region may provide further valuable insights into the molecular mechanisms that underlie this disease. The gene that
eventually is shown to be involved in the disease process could certainly offer hope for more accurate diagnosis and eventual therapeutic intervention in Parkinson’s disease.
We are indebted to the Icelandic patients, controls, and their family
members, for their generous participation in this work, to the general practitioners and clinical neurologists who contributed information, and to the Icelandic Parkinson’s Disease Society.
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idiopathic, latex, disease, genes, parkinson, onset, asusceptibility
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