Article

Complete Genomic Screen in Parkinson Disease

Center for Human Genetics, Box 3445, Duke University Medical Center, Durham, NC 27710, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 12/2001; 286(18):2239-44. DOI: 10.1001/jama.286.18.2239
Source: PubMed
ABSTRACT
The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD.
To identify genetic risk factors for idiopathic PD.
Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status.
Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis.
Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients.
Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.

Full-text

Available from: Frank Louis Mastaglia
ORIGINAL CONTRIBUTION
Complete Genomic Screen
in Parkinson Disease
Evidence for Multiple Genes
William K. Scott, PhD; Martha A.
Nance, MD; Ray L. Watts, MD; Jean
P. Hubble, MD; William C. Koller,
MD; Kelly Lyons, PhD; Rajesh
Pahwa, MD; Matthew B. Stern, MD;
Amy Colcher, MD; Bradley C. Hiner,
MD; Joseph Jankovic, MD; William
G. Ondo, MD; Fred H. Allen, Jr, MD;
Christopher G. Goetz, MD; Gary W.
Small, MD; Donna Masterman, MD;
Frank Mastaglia, MD; Nigel G. Laing,
MD; Jeffrey M. Stajich, PA-C;
Brandon Slotterbeck, BS; Michael W.
Booze, BS; Robert C. Ribble, BS;
Evadnie Rampersaud, MSPH; Sandra
G. West, BS; Rachel A. Gibson, PhD;
Lefkos T. Middleton, MD; Allen D.
Roses, MD; Jonathan L. Haines, PhD;
Burton L. Scott, PhD, MD; Jeffery M.
Vance, PhD, MD; Margaret A.
Pericak-Vance, PhD
P
ARKINSON DISEASE (PD) IS A NEU-
rodegenerative disease that af-
fects more than a half-million
people in the United States.
1
The economic, social, and emotional
burden of PD will increase as the popu-
lation ages. Controversy has sur-
rounded the etiology of PD, with evi-
dence suggesting that both genetic and
environmental factors influence dis-
ease risk. Familial aggregation of PD has
been observed for decades.
2
Data from
family studies, including a recent large
study from Iceland,
3
have shown that the
sibling recurrence risk ratio ranges from
2 to 10, suggesting that a genetic com-
ponent to PD exists. However, twin stud-
ies
4-6
have produced conflicting results
about the genetic contributions, sug-
gesting that little if any genetic contri-
bution exists in the development of PD.
Previous efforts to identify genetic
risk factors for PD have focused pri-
marily on rare, simple autosomal domi-
nant and recessive forms of the dis-
ease. Mutations in the -synuclein gene,
located on chromosome 4q, have been
shown to be rare causes of autosomal
dominant, early-onset PD.
7
Mutations
in the parkin gene, located on chromo-
some 6q, have been reported in fami-
Author Affiliations are listed at the end of this article.
Corresponding Author and Reprints: Margaret A. Peri-
cak-Vance, PhD, Center for Human Genetics, Box
3445, Duke University Medical Center, Durham, NC
27710 (e-mail: mpv@chg.mc.duke.edu).
Context The relative contribution of genes vs environment in idiopathic Parkinson
disease (PD) is controversial. Although genetic studies have identified 2 genes in which
mutations cause rare single-gene variants of PD and observational studies have sug-
gested a genetic component, twin studies have suggested that little genetic contribu-
tion exists in the common forms of PD.
Objective To identify genetic risk factors for idiopathic PD.
Design, Setting, and Participants Genetic linkage study conducted 1995-2000
in which a complete genomic screen (n=344 markers) was performed in 174 families
with multiple individuals diagnosed as having idiopathic PD, identified through pro-
bands in 13 clinic populations in the continental United States and Australia. A total of
870 family members were studied: 378 diagnosed as having PD, 379 unaffected by
PD, and 113 with unclear status.
Main Outcome Measures Logarithm of odds (lod) scores generated from para-
metric and nonparametric genetic linkage analysis.
Results Two-point parametric maximum parametric lod score (MLOD) and multi-
point nonparametric lod score (LOD) linkage analysis detected significant evidence
for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene
(MLOD=5.07; LOD=5.47) in families with at least 1 individual with PD onset at younger
than 40 years, chromosomes 17q (MLOD=2.28; LOD=2.62), 8p (MLOD=2.01;
LOD=2.22), and 5q (MLOD=2.39; LOD=1.50) overall and in families with late-
onset PD, and chromosome 9q (MLOD=1.52; LOD=2.59) in families with both
levodopa-responsive and levodopa-nonresponsive patients.
Conclusions Our data suggest that the parkin gene is important in early-onset PD
and that multiple genetic factors may be important in the development of idiopathic
late-onset PD.
JAMA. 2001;286:2239-2244 www.jama.com
See also pp 2245 and 2324.
©2001 American Medical Association. All rights reserved. (Reprinted) JAMA, November 14, 2001—Vol 286, No. 18 2239
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Page 1
lies with rare autosomal recessive ju-
venile parkinsonism and autosomal
recessive early-onset PD.
8,9
Linkage of
several large families with autosomal
dominant PD to chromosome 2 has
been reported,
10
but a disease-causing
gene remains to be identified. Collec-
tively, these studies have demon-
strated genetic effects only for rare
single-gene variants of PD. To exam-
ine the broader issue of genetic effects
in idiopathic PD, we performed a com-
plete genomic screen for linkage analy-
sis in 174 families with PD containing
at least 1 affected relative pair.
METHODS
Family Data
In 1995-2000, we coordinated a 13-
center effort selecting multiplex (2 in-
dividuals diagnosed as having PD) fami-
lies for genetic studies of PD. History
of PD was documented for each fam-
ily by conducting a standard inter-
view with the proband or a knowl-
edgable family informant. Diagnostic
and exclusion criteria, based on previ-
ously published diagnostic criteria for
PD,
11-13
were adopted by all participat-
ing clinicians before beginning selec-
tion of families.
All participants were examined be-
fore enrollment in the study by a board-
certified neurologist or a physician as-
sistant trained in neurologic disease and
supervised by a neurologist. Partici-
pants were classified as affected, un-
clear, or unaffected based on neuro-
logic examination findings and clinical
history. Affected individuals had at least
2 cardinal signs of PD (eg, rest tremor,
bradykinesia, and rigidity) and no atypi-
cal clinical features or other causes of
parkinsonism. Individuals with un-
clear status had only 1 sign of PD, a his-
tory of atypical clinical features, or both.
Unaffected individuals had no signs of
PD. Excluded from participation were
individuals with a history of encepha-
litis, neuroleptic therapy within the year
before diagnosis, evidence of normal
pressure hydrocephalus, or a clinical
course with unusual features sugges-
tive of atypical or secondary parkin-
sonism.
Age at onset of PD was self-reported
and defined as the age at which the af-
fected individual could first recall notic-
ing one of the primary signs of PD. Be-
cause a positive response to levodopa
therapy was considered supportive of a
diagnosis of idiopathic PD, physician and
patient observations of whether symp-
toms of PD were significantly improved
by levodopa therapy were used to clas-
sify individuals as responsive or nonre-
sponsive to levodopa.
12,13
Individuals for
whom levodopa was of uncertain ben-
efit or who never received levodopa
therapy were classified as having un-
known levodopa response. Within-
family variation in response to le-
vodopa was considered a marker of
potential phenotypic and thus geno-
typic heterogeneity.
To ensure diagnostic consistency
across sites, clinical data for all partici-
pants were reviewed by a clinical ad-
judication board, which consisted of a
board-certified neurologist with fellow-
ship training in movement disorders
(B.L.S.), a dually board-certified neu-
rologist and medical geneticist (J.M.V.),
and a certified physician assistant
(J.M.S.). Forms with missing data or
data inconsistent with the diagnosis as-
signed to the individual were referred
back to the collaborating site for clari-
fication. All participants gave written
informed consent before venipunc-
ture and data collection according to
protocols approved by each center’s in-
stitutional review board.
DNA Analysis
Genomic DNA was extracted from
whole blood using the Puregene sys-
tem (Gentra Systems, Minneapolis,
Minn). Analysis was performed on 344
microsatellite markers with an aver-
age spacing of 10 cM (centimorgans).
Genotyping was performed by the
FAAST method.
14
All samples in the
laboratory were identified only by a se-
quential 6-digit identification num-
ber, which was given to the sample
when it was received in the DNA-
Bank. No names or family relation-
ships were provided to any laboratory
technician.
Systematic genotyping errors were
minimized using a system of quality
control checks with duplicated samples.
For each 96-well polymerase chain re-
action plate, 2 standard samples from
Centre d’Etude du Polymorphisme Hu-
main (Paris, France) families were in-
cluded and 6 samples were duplicated
either on that plate or another plate in
the screen. Laboratory technicians not
involved in the determination of geno-
types performed the placement of these
duplicated quality control samples.
Thus, the laboratory technicians who
read the genotypes were blinded to the
location of the matching partner for
each quality control sample to avoid
bias in interpretation of results. Statis-
tical analysts used automated com-
puter scripts to check each set of geno-
types submitted by the technician for
mismatches between the duplicated
samples; mismatches are indicative of
potential genotype reading errors, mis-
loading of samples, and sample mix-
ups. These mismatches were then sent
as one of a large group of surrounding
genotypes for rechecking. Thus, the
technician had no knowledge of the ac-
tual genotype in question. As an addi-
tional quality control measure, poten-
tial pedigree errors were checked using
the program RELPAIR,
15
which infers
likely relationships between pairs of
relatives using identical by descent–
sharing estimates from a set of micro-
satellite markers.
Statistical Analysis
Data analysis used a multianalytical ap-
proach consisting of both parametric
lod score and nonparametric affected
relative pair methods. Maximum para-
metric lod scores (MLODs) for each
marker were calculated using the
VITESSE and HOMOG program pack-
ages.
16,17
The MLOD is the lod score maxi-
mized over the 2 genetic models tested,
allowing for genetic heterogeneity.
Dominant and recessive low-pen-
etrance (affecteds-only) models were
considered. Only individuals with a
clear diagnosis of PD were considered
affected in these analyses. Estimates of
GENOMIC SCREEN IN PARKINSON DISEASE
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prevalence of PD range from 0.3% in
individuals 40 years or older to 2.5%
in individuals 70 years or older.
1
Based
on these prevalence estimates and al-
lowing for age-dependent or incom-
plete penetrance, disease allele frequen-
cies of 0.001 for the dominant model
and 0.20 for the recessive model were
used. Marker allele frequencies were
generated from more than 150 unre-
lated white individuals.
Multipoint nonparametric lod scores
(LODs) were calculated using GENE-
HUNTER-PLUS.
18
Sex-averaged inter-
marker distances from the Marshfield
Center for Medical Genetics, Marsh-
field, Wis, genetic linkage maps (http://
www.marshfieldclinic.org/research
/genetics/map_markers/maps
/indexmapframes.html) were used in
these analyses. In contrast to nonpara-
metric linkage approaches that con-
sider allele sharing in pairs of affected
siblings,
19
GENEHUNTER-PLUS con-
siders allele sharing across pairs of af-
fected relatives (or all affected rela-
tives in a family) in moderately sized
pedigrees. We selected this program be-
cause of the additional power contrib-
uted to the sample by the 75 affected
relative pairs that would be excluded
by an affected sibpair analysis. Be-
cause of computational constraints on
pedigree size, 27 unaffected individu-
als from 12 families were omitted from
this analysis.
Because of the potential genetic het-
erogeneity in this sample, a priori we
stratified the data set into 3 subsets. The
early-onset PD subset included 18 fami-
lies with at least 1 member with early-
onset PD (40 years
20
) (range, 12-66
years). The levodopa-nonresponsive
subset included 9 families with late-
onset PD that contained at least 1 af-
fected individual who was determined
to be nonresponsive to levodopa
therapy. The late-onset idiopathic PD
subset contained 147 families with late-
onset PD.
Traditionally in linkage analysis (par-
ticularly of mendelian traits), a LOD of
more than 3 (corresponding to 1000:1
odds in favor of linkage) is considered
strong evidence for linkage. However,
such a threshold is likely too stringent
for initial efforts to find complex dis-
ease genes; using a lower threshold
(such as a LOD of 1) in an initial ge-
nomic screen may help ensure that
genes with modest effects are not
missed.
21
Recent genomic screens have
used reduced thresholds for declaring
results interesting for further
study.
22,23
In this study, only regions
generating both MLODs and LODs of
more than 1.5 were classified as hav-
ing interesting results. Although this ap-
proach may increase the number of
false-positive results that are sub-
jected to more detailed examination, it
decreases the more serious possibility
of missing a true genetic effect.
RESULTS
All individuals potentially informative
for linkage were considered for selec-
tion in each family, and all family mem-
bers sampled at the time of the study
were included in this analysis. The fami-
lies contained an average of 2.3 af-
fected individuals and an average of 1.5
affected relative pairs per family. Al-
though most affected relative pairs were
affected sibpairs (185/260), there were
75 other affected relative pairs (19 avun-
cular, 51 cousin, and 5 parent-child
pairs) in the data set, indicating that
families were often multigenerational in
structure and that the study was not lim-
ited to affected sibpairs.
All families studied were white and in-
cluded 870 individuals (an average of 5
per family). Of these individuals, 378
(43%) were diagnosed as having PD, 379
(44%) were unaffected, and 113 (13%)
had unclear status. In affected individu-
als, the mean (SD) age at onset of PD was
59.9 (12.6) years (range, 12-90 years),
and the mean (SD) age at examination
was 69.9 (10.2) years (range, 33-90
years). Mean (SD) age at examination in
unaffected individuals was 67.1 (12.9)
years (range, 31-96 years), and mean
(SD) age at examination in those with
unclear PD status was 72.1 (11.6) years
(range, 49-90 years). Mean age at onset
in the families with early-onset PD was
39.7 years (range, 12-66 years), whereas
mean age at onset in the families with
late-onset PD was 62.7 years (range,
40-90 years). The 2 age-of-onset groups
were similar with respect to average fam-
ily size and structure.
Analysis of the clinical parameters of
the collected data set did not differ sig-
nificantly from the patient data col-
lected for other studies in which the fo-
cus was on the enrollment of patients
with PD for clinical trials.
24
Genetic re-
gions generating both MLODs and
LODs of greater than 1.5 are listed in
the T
ABLE. Markers on chromosomes
5q, 8p, and 17q generated interesting
2-point and multipoint lod scores
(MLODs and LODs of more than 1.5)
in the overall sample of 174 families
(F
IGURE 1). The strongest evidence for
linkage in the overall data set was on
chromosome 8p (MLOD =2.01 at
D8S520; LOD=2.22). Other regions
with interesting 2-point and multi-
point results were 5q (MLOD= 2.39
Table. Regions Generating 2-Point MLODs and Multipoint LODs Greater Than 1.5
*
Chromosome Set
Peak
Marker
2-Point MLOD
Multipoint LOD
MLOD Location, cM† Peak LOD Location, cM†
3q LDNR D3S2460 1.62 135 1.54 134
5q Overall D5S816 2.39 139 1.50 139
6q EOPD D6S305 5.07 166 5.47 166
8p Overall D8S520 2.01 21 2.22 27
LOPD D8S520 1.92 21 1.69 27
9q LDNR D9S301 1.52 66 2.59 140
17q Overall D17S921 1.92 36 2.02 56
LOPD D17S1293 2.28 56 2.62 56
*
MLOD indicates maximum parametric lod score; LOD, nonparametric lod score; LDNR, levodopa nonresponsive;
EOPD, early-onset Parkinson disease; and LOPD, late-onset Parkinson disease.
†Location is presented in centimorgans (cM) from the p telomere, based on the Marshfield Clinic sex-averaged maps.
GENOMIC SCREEN IN PARKINSON DISEASE
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at D5S816; LOD= 1.5) and 17q
(MLOD= 1.92 at D17S921; LOD =2.02).
F
IGURE 2 presents the 2-point MLOD
results for the data stratified by age at
onset and levodopa response. In the
subset of 18 families with early-onset
PD, a significant MLOD was obtained
at D6S305, located in intron 7 of the
parkin gene (MLOD=5.07). Multi-
point analysis confirmed these find-
ings, resulting in a LOD of 5.47. No
other regions of the genome gener-
ated both MLODs and LODs 1.5 in
the early-onset subset.
The strongest linkage result ob-
tained in the subset containing 147
families with late-onset idiopathic PD
was on 17q (MLOD=2.28 at D17S1293;
LOD= 2.62). A second region of inter-
est was located on 8p (MLOD=1.92 at
D8S520; LOD= 1.69).
The 9 levodopa-nonresponsive fami-
lies produced novel results on chro-
mosome 9q (MLOD =1.52 at D9S301;
LOD= 2.59). An additional region of in-
terest was detected on 3q (MLOD= 1.62
at D3S2460; LOD= 1.54).
COMMENT
The results of this study, to our knowl-
edge the largest complete genomic
screen in idiopathic PD, suggest that ge-
netic factors are involved in the etiol-
ogy of both early- and late-onset PD.
These results are in contrast to find-
ings of the twin study by Tanner and
colleagues.
6
In that study of 161 twin
pairs, the authors found similar con-
cordance rates in identical (15.5%) and
fraternal (11.1%) twin pairs and con-
cluded that there was no role for ge-
netics in late-onset PD. However, the
authors acknowledged that there were
limitations to the twin study design,
4
including sample size and time to fol-
low-up.
25
Our results suggest that these
concerns are warranted.
Analysis of 18 families with at least
1 early-onset PD case resulted in strong
evidence for linkage to D6S305, which
is located in intron 7 of the parkin gene.
Parkin was originally described as the
gene responsible for only autosomal re-
cessive juvenile parkinsonism
8
and later
was implicated in other autosomal re-
cessive, early-onset PD.
9
The 18 fami-
lies with early-onset PD were pheno-
typically similar to the overall data set,
with the only notable difference being
earlier age at onset of PD symptoms in
at least 1 individual. The 18 families
with early-onset PD did not have a rec-
ognizable mode of inheritance, con-
tained a wide range of ages at onset
(12-66 years), and were a mixture of af-
fected sibpairs and other affected rela-
tive pairs in multiple generations.
Through examination of the parkin
gene in these 174 families and an ad-
ditional 134 multiplex and singleton
families, we discovered parkin muta-
tions in 11 early-onset and 7 late-
onset idiopathic PD families.
26
These
Figure 1. Two-Point Maximum Parametric Lod Scores (MLODs) for the Overall Data Set
(n=174)
MLOD Score
3
123456789
Chromosome
10 11 12 13 14 15 16 17 18 19 20 2122 X
1
2
0
0 500 1500
2000 2500 3000 35001000
Map Position, cM
Each square represents the MLOD at 1 of the 344 markers analyzed in the genomic screen. Regions of interest
(see the “Methods” section) are located above the dotted horizontal line (MLOD 1.5). cM indicates centi-
morgans.
Figure 2. Two-Point Maximum Parametric Lod Scores (MLODs) Stratified by Age at Onset
of PD and Levodopa Response
MLOD Score
5
3
123456789
Chromosome
10 11 12 13 14 15 16 17 18 19 20 2122 X
1
2
0
0 500 1500 2000 2500 3000 35001000
Map Position, cM
Early-Onset PD (n
=
18)
Late-Onset PD (n
=
147)
Levodopa Nonresponsive (n
=
9)
Each point represents the MLOD at 1 of the 344 markers analyzed in each subset. Regions of interest (see the
“Methods” section) are located above the dotted horizontal line (MLOD 1.5). cM indicates centimorgans;
PD, Parkinson disease.
GENOMIC SCREEN IN PARKINSON DISEASE
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linkage and mutation results indicate
that parkin is an important genetic fac-
tor in PD and mutations are more preva-
lent than previously reported. Parkin
mutations were not identified in 10
families with early-onset PD included
in the genomic screen, indicating that
additional loci underlying early-onset
PD may exist.
In the 147 families with late-onset
PD, the strongest overall evidence for
linkage was on chromosome 17q at
marker D17S1293, which is about 8 cM
from the tau gene. The tau gene en-
codes a microtubule-associated pro-
tein that is expressed in the brain and
forms paired helical filaments found in
Alzheimer disease and other neurode-
generative disorders.
27
Mutations in the
tau gene cause frontotemporal demen-
tia with parkinsonism (FTDP),
28
and a
haplotype of single nucleotide poly-
morphisms (SNPs) in the gene has been
associated with progressive supra-
nuclear palsy (PSP).
29
The strict clinical criteria developed
for use in this study ensured that these
families have idiopathic PD and not
atypical forms of parkinsonism. For
example, to exclude potential cases of
PSP from the sample, individuals with
PD had to have asymmetrical motor
symptoms at onset, no postural insta-
bility with falls early in the disease
course, and no supranuclear down- or
lateral-gaze palsy. Subjects with poten-
tial FTDP were excluded from the PD
affected group by requiring the absence
of dementia at onset and the presence
of asymmetrical onset of motor symp-
toms. Cognitive status testing was not
performed during the initial clinical
examinations in these families, and
therefore we cannot determine if link-
age to this region is associated with
development of dementia later in the
disease. These data are being collected
during follow-up evaluations of these
families and will be examined in future
studies. Therefore, the evidence for link-
age of late-onset PD to chromosome 17q
suggests a possible genetic link between
FTDP, PSP, and idiopathic PD. We
examined intragenic SNPs in tau for
association with PD and found that a
haplotype of 4 SNPs in the tau gene is
significantly associated with increased
risk of developing PD.
30
Association of
PD with a haplotype of tau and evi-
dence for linkage to that region of chro-
mosome 17q suggest that tau or a gene
in linkage disequilibrium with tau is a
genetic risk factor for PD.
Stratification by levodopa response
identified additional regions of inter-
est. In particular, multipoint LODs on
chromosome 9q were stronger in these
9 families compared with the other
families with late-onset idiopathic PD.
Each family included both levodopa-
responsive and nonresponsive mem-
bers, indicating that variable response
to levodopa within the family might be
part of the phenotype associated with
a susceptibility locus in this region. This
region of 9q contains the torsinA gene,
deletions in which are responsible for
causing idiopathic torsion dystonia, an-
other movement disorder that is not re-
sponsive to levodopa therapy.
31
These
data suggest a potential etiologic con-
nection between dystonia and non
levodopa-responsive parkinsonism.
Family-based genetic linkage stud-
ies are frequently used as initial at-
tempts to identify susceptibility genes
in complex diseases. This study de-
sign requires a selected sample of fami-
lies with multiple related individuals di-
agnosed as having the disease. Only
10% to 20% of individuals with PD re-
port a family history of the disease, and
only a subset have a living relative with
PD. Because of this ascertainment
scheme, these multiplex families may
not be representative of all cases of PD.
Therefore, the results of this study may
not apply to all PD cases and cannot be
used to calculate the relative contribu-
tion of each gene to the overall risk of
PD. However, we found no significant
differences in the clinical presentation
of patients in this data set and those seen
in a general PD clinic population.
24
Once susceptibility genes underlying
each of these regions of linkage are
identified, investigations of population-
based random samples will be neces-
sary to determine the contribution of
each to the overall risk of idiopathic PD.
These results provide strong evi-
dence that the parkin gene is influen-
tial in the development of early-onset
PD, that several genes may influence
the development of late-onset PD, and
that age at onset and levodopa
response pattern may be useful dis-
criminators for genetic etiology. Like
many complex traits, it is likely that
PD is caused by an interaction of
genetic and environmental risk fac-
tors, in which specific genetic tem-
plates are more susceptible to the
influences of environmental expo-
sures. Further studies to identify the
molecular pathways affected by the
responsible genes will provide valu-
able insight into this complex etiology
and potential treatment for PD.
Author Affiliations: Department of Medicine and Cen-
ter for Human Genetics, Institute for Genome Sci-
ences and Policy, Duke University Medical Center,
Durham, NC (Drs W. K. Scott, B. L. Scott, Vance, and
Pericak-Vance, Messrs Stajich, Slotterbeck, Booze, and
Ribble, and Mss Rampersaud and West); Struthers Par-
kinson Center, Golden Valley, Minn (Dr Nance); De-
partment of Neurology, Emory University School of
Medicine, Atlanta, Ga (Dr Watts); Department of Neu-
rology, Ohio State University, Columbus (Dr Hubble);
Department of Neurology, University of Miami School
of Medicine, Miami, Fla (Drs Koller and Lyons); De-
partment of Neurology, University of Kansas Medi-
cal Center, Kansas City (Dr Pahwa); Department of
Neurology, University of Pennsylvania Health Sys-
tem, Philadelphia (Drs Stern and Colcher); Depart-
ment of Neurology, Marshfield Clinic, Marshfield, Wis
(Dr Hiner); Department of Neurology, Baylor Col-
lege of Medicine, Houston, Tex (Drs Jankovic and
Ondo); Carolina Neurologic Clinic, Charlotte, NC (Dr
Allen); Department of Neurological Sciences, Rush-
Presbyterian-St Lukes Hospital, Chicago, Ill (Dr Goetz);
Departments of Psychiatry and Behavioral Science
and Neurology, University of California, Los Angeles
(Drs Small and Masterman); Centre for Neuromus-
cular and Neurological Disorders, University of
Western Australia, Perth (Drs Mastaglia and Laing);
GlaxoSmithKline Research and Development, Green-
ford, Middlesex, England (Drs Gibson and Middle-
ton); GlaxoSmithKline Research and Development, Re-
search Triangle Park, NC (Dr Roses); and Program in
Human Genetics, Vanderbilt University Medical Cen-
ter, Nashville, Tenn (Dr Haines).
Author Contributions: Dr Pericak-Vance had full ac-
cess to all of the data in this study and takes respon-
sibility for the integrity of the data and the accuracy
of the data analysis.
Study concept and design: W. K. Scott, Nance, Hubble,
Koller, Stern, Hiner, Jankovic, Goetz, Roses, Pericak-
Vance.
Acquisition of data: W. K. Scott, Nance, Watts, Hubble,
Koller, Lyons, Pahwa, Stern, Colcher, Hiner, Janko-
vic, Ondo, Allen, Goetz, Small, Masterman, Masta-
glia, Laing, Stajich, Slotterbeck, Booze, Ribble, Ram-
persaud, West, Middleton, Roses, Haines, B. L. Scott,
Vance.
Analysis and interpretation of data: W. K. Scott, Kol-
ler, Booze, Ribble.
Drafting of the manuscript: W. K. Scott, Koller, Booze,
Ribble, Gibson, Haines.
GENOMIC SCREEN IN PARKINSON DISEASE
©2001 American Medical Association. All rights reserved. (Reprinted) JAMA, November 14, 2001Vol 286, No. 18 2243
at Medical Library of the PLA, on August 12, 2007 www.jama.comDownloaded from
Page 5
Critical revision of the manuscript for important in-
tellectual content: W. K. Scott, Nance, Watts, Hubble,
Koller, Lyons, Pahwa, Stern, Colcher, Hiner, Janko-
vic, Ondo, Allen, Goetz, Small, Masterman, Masta-
glia, Laing, Stajich, Slotterbeck, Booze, Rampersaud,
West, Middleton, Roses, Haines, B. L. Scott, Vance,
Pericak-Vance.
Statistical expertise: W. K. Scott, Haines.
Obtained funding: Roses, Pericak-Vance.
Administrative, technical, or material support: Watts,
Hubble, Koller, Lyons, Pahwa, Stern, Hiner, Ondo,
Small, Mastaglia, Laing, Slotterbeck, Booze, Ribble,
Rampersaud, West, Middleton, Roses, Vance, Pericak-
Vance.
Study supervision: W. K. Scott, Koller, Hiner, Booze,
Pericak-Vance.
Clinical expertise: Goetz.
Funding/Support: This research was supported in part
by National Institutes of Health grants P01 NS26630
(Dr Pericak-Vance) and P50 NS39764 (Dr Vance) and
funding from GlaxoSmithKline Inc.
Acknowledgment: We thank all the families whose par-
ticipation made this project possible. We gratefully ac-
knowledge the contributions of the study personnel at
each of the collaborating sites and at the Center for Hu-
man Genetics, Institute for Genome Sciences and Policy,
Duke University Medical Center, Durham, NC.
REFERENCES
1. Tanner CM, Goldman SM. Epidemiology of Par-
kinsons disease. Neurol Clin. 1996;14:317-335.
2. Allan W. Inheritance of the shaking palsy. Arch In-
tern Med. 1937;60:424-436.
3. Sveinbjornsdottir S, Hicks A, Jonsson T, et al. Fa-
milial aggregation of Parkinsons disease in Iceland.
N Engl J Med. 2000;343:1765-1770.
4. Johnson WG, Hodge SE, Duvoisin RC. Twin stud-
ies and the genetics of Parkinsons disease: a reap-
praisal. Mov Disord. 1990;5:187-194.
5. Vieregge P, Schiffke KA, Friedrich HJ, Mu¨ ller B,
Ludin HP. Parkinsons disease in twins. Neurology.
1992;42:1453-1461.
6. Tanner CM, Ottman R, Goldman SM, et al. Par-
kinson disease in twins: an etiologic study. JAMA. 1999;
281:341-346.
7. Polymeropoulos MH, Lavedan C, Leroy E, et al.
Mutation in the -synuclein gene identified in fami-
lies with Parkinsons disease. Science. 1997;276:
2045-2047.
8. Kitada T, Asakawa S, Hattori N, et al. Mutations
in the parkin gene cause autosomal recessive juvenile
parkinsonism. Nature. 1998;392:605-608.
9. Abbas N, Lucking CB, Ricard S, et al. A wide va-
riety of mutations in the Parkin gene are responsible
for autosomal recessive parkinsonism in Europe. Hum
Mol Genet. 1999;8:567-574.
10. Gasser T, Mu¨ ller-Myhsok B, Wszolek ZK, et al. A
susceptibility locus for Parkinsons disease maps to chro-
mosome 2p13. Nat Genet. 1998;18:262-265.
11. Ward CD, Gibb WR. Research diagnostic criteria for
Parkinsons disease. Adv Neurol. 1990;53:245-249.
12. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accu-
racy of clinical diagnosis of idiopathic Parkinsons dis-
ease: a clinico-pathological study of 100 cases. J Neu-
rol Neurosurg Psychiatry. 1992;55:181-184.
13. Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ.
What features improve the accuracy of clinical diag-
nosis in Parkinsons disease: a clinicopathological study.
Neurology. 1992;42:1142-1146.
14. Vance JM, Ben Othmane K. Methods of geno-
typing. In: Haines JL, Pericak-Vance MA, eds. Ap-
proaches to Gene Mapping in Complex Human Dis-
eases. New York, NY: Wiley-Liss; 1998:213-228.
15. Boehnke M, Cox NJ. Accurate inference of rela-
tionships in sib-pair linkage studies. Am J Hum Genet.
1997;61:423-429.
16. OConnell JR, Weeks DE. The VITESSE algo-
rithm for rapid exact multilocus linkage analysis via
genotype set-recoding and fuzzy inheritance. Nat
Genet. 1995;11:402-408.
17. Ott J. Analysis of Human Genetic Linkage. 3rd
ed. Baltimore, Md: The Johns Hopkins University Press;
1999.
18. Kong A, Cox NJ. Allele-sharing models: LOD scores
and accurate linkage tests. Am J Hum Genet. 1997;
61:1179-1188.
19. Risch N. Linkage strategies for genetically com-
plex traits I: multilocus models. Am J Hum Genet. 1990;
46:222-228.
20. Golbe LI. Young-onset Parkinsons disease: a clini-
cal review. Neurology. 1991;41:168-173.
21. Weeks DE, Lathrop GM. Polygenic disease: meth-
ods for mapping complex disease traits. Trends Genet.
1995;11:513-519.
22. Weeks DE, Conley YP, Mah TS, et al. A full ge-
nome scan for age-related maculopathy. Hum Mol
Genet. 2000;9:1329-1349.
23. Pericak-Vance MA, Bass MP, Yamaoka LH, et al.
Complete genomic screen in late-onset familial Alz-
heimer disease: evidence for a new locus on chromo-
some 12. JAMA. 1997;278:1237-1241.
24. Hubble JP, Weeks CC, Nance M, et al. Parkin-
sons disease: clinical features in sibships [abstract].
Neurology. 1999;52:A13.
25. Langston JW. Epidemiology versus genetics in Par-
kinsons disease: progress in resolving an age-old de-
bate. Ann Neurol. 1998;44(suppl 1):S45-S52.
26. Scott WK, Rogala AR, Rampersaud E, et al. Par-
kin mutations and idiopathic Parkinson disease (PD)
[abstract]. Am J Hum Genet. 2000;67(suppl):19.
27. Poorkaj P, Bird T, Wijsman E, et al. Tau is a can-
didate gene for chromosome 17 frontotemporal de-
mentia. Ann Neurol. 1998;43:815-825.
28. Hutton M, Lendon CL, Rizzu P, et al. Association
of missense and 5-splice-site mutations in tau with
the inherited dementia FTDP-17. Nature. 1998;393:
702-705.
29. Baker M, Litvan I, Houlden H, et al. Association
of an extended haplotype in the tau gene with pro-
gressive supranuclear palsy. Hum Mol Genet. 1999;
8:711-715.
30. Martin ER, Scott WK, Nance MA, et al. Associa-
tion of single-nucleotide polymorphisms of the tau gene
with late-onset Parkinson disease. JAMA. 2001;286:
2245-2250.
31. Ozelius LJ, Hewett JW, Page CE, et al. The early-
onset torsion dystonia gene (DYT1) encodes an ATP-
binding protein. Nat Genet. 1997;17:40-48.
GENOMIC SCREEN IN PARKINSON DISEASE
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  • Source
    • "Although the etiology of nigrostriatal pathway degeneration in PD is still unclear, research indicates that PD can represent the final common pathway of different conditions . It is suggested that PD can result from the combination of genetic and environmental factors that can interact in the development of the modification in the brain cells leading to the disease (Ben-Shlomo, 1996; de Rijk et al., 1997; Gasser et al., 1998; Hellenbrand et al., 1997; Jarman & Wood, 1999; Lazzarini et al., 1994; Scott et al., 2001). Evidence deriving from epidemiological studies supports the hypothesis that environmental factors play an important role in the genesis of the disease in addition to genetic factors (Behari et al., 2001; Tanner & Goldman, 1996), as subjects belonging to same ethnic groups but living in different countries show the same incidence rates of their acquired country (Shoenberg, 1987 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Dietary protein content can reduce the effectiveness of levodopa treatment in Parkinson's disease (PD)-affected patients, as the large neutral amino acids (LNAA) and levodopa, a prodrug of dopamine, share the same saturable carrier system. Moreover, the importance of some dietary risk factors for PD has been postulated in recent decades. A plant-food (vegan) diet, easily restricting total protein intake to the RDA while redistributing the total daily protein amount, can be effective in minimizing diet interference on levodopa treatment. This appears to be useful in the management of PD patients, improving levodopa efficacy, possibly reducing total Levodopa schedule, and optimizing neurological performance. These effects can slow the appearance of motor impairment and of the complications related to levodopa chronic therapy. Moreover, the composition of a plant-based diet can hypothetically contrast some risk factors for PD, contributing to slow the progression of the dopaminergic system degeneration underlying the disease.
    Full-text · Chapter · Dec 2015
    • "Initially, we evaluated 396 unrelated cases with PD (non-Hispanic/Latino Caucasians, range of age-at-onset (AAO): 10–85 year, average AAO: 53.6 year) and 12 cases of essential tremor with Parkinsonism (ETP) (Rocca et al., 1998). Patients were collected by 1 of 13 ascertainment centres in the PD Genetics Collaboration (Scott et al., 2001) or by the Morris K. Udall Parkinson Disease Center of Excellence (PI: Vance JM) ascertainment core. These participants were recruited primarily by participating movement disorder and neurology clinics. "
    [Show abstract] [Hide abstract] ABSTRACT: We set out to determine whether expansions in the C9ORF72 repeat found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) families are associated with Parkinson disease (PD). We determined the repeat size in a total of 889 clinically ascertained patients (including PD and essential tremor plus Parkinsonism (ETP)) and 1144 controls using a repeat-primed PCR assay. We found that large C9ORF72 repeat expansions (>30 repeats) were not contributing to PD risk. However, PD and ETP cases had a significant increase in intermediate (>20 to 30+) repeat copies compared to controls. Overall, 14 cases (13 PD, 1 ETP) and three controls had >20 repeat copies (Fisher's exact test p = 0.002). Further, seven cases and no controls had >23 repeat copies (p = 0.003). Our results suggest that intermediate copy numbers of the C9ORF72 repeat contribute to risk for PD and ETP. This also suggests that PD, ALS and FTD share some pathophysiological mechanisms of disease. Further studies are needed to elucidate the contribution of the C9ORF72 repeat in the overall PD population and to determine whether other common genetic risk factors exist between these neurodegenerative disorders.
    No preview · Article · Jul 2013 · Annals of Human Genetics
  • Source
    • "Importantly, a gene-specific screen conducted on PD patients identified two novel variants in mtHSP70, namely R126W and P509S, which are suggested to be involved in PD pathogenesis. Recently, another separate large-scale genomic screen involving PD patients revealed a strong association of genes present on the long arm of chromosome 5 to be involved in the overall PD pathogenesis (49,50). This region includes the gene locus of HSPA9 (mtHSP70), thus supporting a likely involvement of mtHsp70 in PD pathology (49,50). "
    [Show abstract] [Hide abstract] ABSTRACT: Parkinson's disease (PD) is the second most prevalent progressive neurological disorder commonly associated with impaired mitochondrial function in dopaminergic neurons. Although familial PD is multifactorial in nature, a recent genetic screen involving PD patients identified two mitochondrial Hsp70 variants (P509S and R126W) that are suggested in PD pathogenesis. However, molecular mechanisms underlying how mtHsp70 PD variants are centrally involved in PD progression is totally elusive. In this article, we provide mechanistic insights into the mitochondrial dysfunction associated with human mtHsp70 PD variants. Biochemically, the R126W variant showed severely compromised protein stability and was found highly susceptible to aggregation at physiological conditions. Strikingly, on the other hand, the P509S variant exhibits significantly enhanced interaction with J-protein cochaperones involved in folding and import machinery, thus altering the overall regulation of chaperone-mediated folding cycle and protein homeostasis. To assess the impact of mtHsp70 PD mutations at the cellular level, we developed yeast as a model system by making analogous mutations in Ssc1 ortholog. Interestingly, PD mutations in yeast (R103W and P486S) exhibit multiple in vivo phenotypes, which are associated with 'mitochondrial dysfunction', including compromised growth, impairment in protein translocation, reduced functional mitochondrial mass, mitochondrial DNA loss, respiratory incompetency and increased susceptibility to oxidative stress. In addition to that, R103W protein is prone to aggregate in vivo due to reduced stability, whereas P486S showed enhanced interaction with J-proteins, thus remarkably recapitulating the cellular defects that are observed in human PD variants. Taken together, our findings provide evidence in favor of direct involvement of mtHsp70 as a susceptibility factor in PD.
    Full-text · Article · Apr 2012 · Human Molecular Genetics
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