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Genes influencing Parkinson
disease onset
Replication of PARK3 and identification of novel loci
N. Pankratz, PhD; S.K. Uniacke, BS; C.A. Halter, MS; A. Rudolph, PhD; C.W. Shults, MD;
P.M. Conneally, PhD; T. Foroud, PhD; W.C. Nichols, PhD; and the Parkinson Study Group*
Abstract—A genome screen to identify genes influencing the age at Parkinson disease (PD) onset was completed using 276
families without parkin mutations. Significant evidence of linkage to chromosome 2p near the PARK3 locus (logarithm of odds
[lod] ⫽ 4.8) was observed. Evidence of linkage was also detected to chromosomes 1q (lod ⫽ 3.0) and 8q (lod ⫽ 2.6). These data
suggest that the genes influencing age at PD onset likely differ from those that contribute to PD susceptibility.
NEUROLOGY 2004;62:1616 –1618
Parkinson disease (PD) age at onset has wide variability, ranging anywhere from juvenile to very late
(80s to 90s), with an average age at onset of 60 years.
Although few families include both juvenile- and
late-onset PD, wide disparity in age at onset, even
within the same family, has been found. An important question is whether the genes that contribute to
PD susceptibility also contribute to age at disease
onset or whether different genes are involved. As
large multiplex PD datasets are ascertained to identify PD susceptibility genes, it has become possible to
directly answer this question. Evidence of linkage for
age at onset of PD to chromosomes 1, 6, and 101 and
chromosomes 2, 9, 20, and 212 has been reported.
Materials and methods. Subjects. Three hundred sixty-six
families (n ⫽ 788 individuals), consisting of at least one pair of
living siblings diagnosed with PD, were recruited through 59 Parkinson Study Group sites located throughout North America. The
average age at onset of the PD subjects was 60.9 years, with a
range of 18 to 87 years. DNA samples were obtained from all
individuals after appropriate written informed consent approved
by each individual institution’s institutional review board was
completed.
As previously described,3 all study participants completed a
rigorous clinical evaluation (including Unified Parkinson’s Disease Rating Scale Parts II and III), and the Diagnostic Checklist
developed for this project was used to classify participants as
either verified PD or nonverified PD. Families with at least two
individuals meeting criteria for verified PD were included in the
more restrictive primary analyses (Model I), whereas all families
were employed in the more inclusive Model II analyses.
Parkin screening. Thirty-one different parkin mutations were
previously identified in 39 of the 173 families analyzed,3 after both
direct sequencing and fluorescent dosage analysis were performed. As it has previously been shown that PD patients with
parkin mutations have significantly earlier age at onset than
those without parkin mutations,4 all genetic analyses were performed excluding the families with a parkin mutation.
Genome screen. Genotyping was performed using 400 dinucleotide repeat markers from the ABI Prism Linkage Mapping Set
(Applied Biosystems, Foster City, CA), as previously described.3
The average marker heterozygosity was 79%, and the average
intermarker spacing was 8.6 cM. Marker allele frequencies were
estimated using all 1,576 chromosomes, and the genotypic data
were evaluated for Mendelian inheritance of marker alleles and to
verify the full sibling relationships among the subjects. Four halfsibling pairs were identified owing to significantly lower than
expected sharing of marker alleles identical by descent, and the
pedigrees were modified to reflect this.
Statistical analysis. Multipoint, nonparametric linkage analysis was performed using the computer program SOLAR5 to identify genes contributing to the quantitative trait, age at onset of
PD. Linkage analyses were performed using Models I and II.
Results. Sample. Some families could not be used because age at onset was not available for the minimum of
two affected individuals. After removing all families with a
known parkin mutation, there were 276 families (n ⫽ 567
affected individuals) with two or more members having a
reported age at PD onset (table 1).
Analysis of age-at-onset data. The distribution of the
age at PD onset in this sample did not significantly deviate
from normality, though it was slightly skewed toward
early onset (skewness ⫽ ⫺0.77). A high degree of kurtosis
may increase the number of false-positive results.6 The
kurtosis of our distribution was relatively low (0.47) and
should not substantially increase the false-positive rate.
Inclusion of gender as a covariate did not significantly
improve the fit of the polygenic model (p ⫽ 0.34).
Genome screen. Genome-wide linkage analysis identified several chromosomal regions providing evidence of
linkage to the phenotype age at onset of PD symptoms
(table 2). A significant logarithm-of-odds (lod) score of 4.8
*See the Appendix on page 1618 for a list of Group members.
From the Department of Medical and Molecular Genetics (Drs. Pankratz, Conneally, and Foroud, C.A. Halter), Indiana University Medical Center,
Indianapolis, IN; Division of Human Genetics (Dr. Nichols, S.K. Uniacke), Cincinnati Children’s Hospital Medical Center, OH; Department of Neurology (Dr.
Rudolph), University of Rochester, NY; and Department of Neurosciences (Dr. Shults), University of California, La Jolla, and VA San Diego Healthcare
System, CA.
Supported by NS37167.
Received September 16, 2003. Accepted in final form December 30, 2003.
Address correspondence and reprint requests to Dr. W.C. Nichols, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet
Ave., 1469 TCHRF, Cincinnati, OH 45229; e-mail: [email protected]
1616
Copyright © 2004 by AAN Enterprises, Inc.
Table 1 Study sample
ceptibility.8 The PARK3 locus was originally
identified as a causative gene in families of German
descent, segregating PD in an autosomal dominant
pattern,9 and it is interesting that it appears to act
in a different fashion in our sample. Whereas neurodegeneration occurs in all individuals, particularly
as they age, the rate at which cells are lost is likely
to be quite variable and may not be a linear process.
Thus, all individuals, if they were to survive indefinitely, would have sufficient neuronal loss to elicit
symptoms of PD; however, because of the variable
rate of neurodegeneration, some individuals will
never manifest symptoms.
It is intriguing to speculate that mutations that
increase the rate of normal neuronal loss may predispose an individual to PD. If these mutations are,
in fact, in the same gene, this mechanism may account for the linkage to both PD susceptibility and
PD age at onset. A mutation in a gene that dramatically alters the rate of neuronal loss may manifest
clinically as a high-penetrance PD mutation, as was
observed in several German families. Subtle polymorphisms in the same gene, which may be present
in our sample, may still lead to variation in the rate
of neurodegeneration and thus alter age at onset of
PD. In this instance, other loci must also be contributing to PD susceptibility.
No. of
Subjects
Families
% male
Age at onset, y;
mean ⫾ SD
I: verified PD
308
151
62
61.9 ⫾ 10.4
II: full sample
567
276
61
62.8 ⫾ 10.6
Model
PD ⫽ Parkinson disease.
was observed on chromosome 2p when only those individuals meeting the stricter disease definition of verified PD
were included in the analyses (Model I; figure). The maximum lod score occurred at marker D2S337, which is
within 8 cM of the recently refined PARK3 locus (D2S2113
to D2S1394).7 As the evidence of linkage in our sample
spans 15 cM in this chromosomal region, our region on
chromosome 2p overlaps with the PARK3 locus, which was
recently implicated in another study mapping genes determining age at onset in PD.2 Two other regions on chromosomes 1q (lod ⫽ 3.0; Model I) and 8q (lod ⫽ 2.6; Model II)
also produced suggestive evidence of linkage.
Discussion. Strong evidence for a gene contributing to age at onset was detected in our sample on
chromosome 2p in a region encompassing the PARK3
locus and that is distinct from our previously reported linkage to chromosome 2q36-37 for PD susTable 2 Regions with lod scores of ⱖ2.2
Model I lod scores
Chromosome
Position,*
cM
Nearest
marker
Two point
Model II lod scores
Multipoint
Two point
Multipoint
1
257
D1S2800
3.1
3.0
1.9
1.2
2
81
D2S337
4.9
4.8
3.4
3.5
8
57
D8S1771
1.6
1.6
2.2
2.6
* Multipoint map distances are based on the sex-averaged genetic maps from Marshfield Genetic Laboratory.
lod ⫽ logarithm of the odds.
Figure. (A) Multipoint logarithm-ofthe-odds (lod) score graph summarizing
the results of the genome screen for
chromosomes 1 to 22 using only those
families meeting criteria for Model I
(narrow) definition of Parkinson disease (PD) diagnosis. (B) Multipoint lod
score graph summarizing the results of
the genome screen for chromosomes 1 to
22 using all families and Model II
(broad) definition of PD diagnosis.
May (1 of 2) 2004
NEUROLOGY 62
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Analysis of 14 genes within the PARK3 region did
not reveal any potentially pathogenic mutations.7
Subsequently, suggestive linkage to this chromosomal region was detected in another PD sample,
employing the phenotype of age at onset of PD (lod ⫽
2.1).2 This convergence of linkage evidence from
three different studies employing different phenotypes—PD susceptibility and age at PD onset—
suggests that perhaps mutations in a single gene at
the PARK3 locus may cause PD and also influence
the age at symptom onset.
An important advantage of our study was the
identification and exclusion of 39 parkin mutationpositive families prior to the genome screen analyses. Combining samples with differing genetic
etiologies may reduce the power to detect genes contributing to the age at onset of PD. The only other
regions in our study that exceeded Kruglyak and
Lander’s threshold for suggestive linkage (lod ⱖ
2.2)10 were on chromosomes 1q and 8q. Other studies
seeking to identify genes contributing to PD age at
onset did not report evidence of linkage to these two
regions,1,2 nor are they within 40 cM of any regions
so far implicated in PD susceptibility.3
Appendix
Parkinson Study Group investigators. Steering Committee: Lawrence
Golbe, MD, UMDNJ/Robert Wood Johnson Medical Center, New Brunswick, NJ; William Koller, MD, Mount Sinai, New York; Kelly Lyons, PhD,
University of Kansas, Kansas City; Karen Marder, MD, Columbia–Presbyterian Medical Center, New York; Frederick Marshall, MD, University of
Rochester, NY; David Oakes, PhD, University of Rochester, NY; Alice Rudolph, PhD, University of Rochester, NY; Clifford W. Shults, MD, University of California, San Diego; Aileen Shinaman, JD, University of
Rochester, NY; Eric Siemers, MD, Eli Lilly & Company, Indianapolis, IN.
Participating investigators and coordinators (affiliation at time of data
collection): Joanne Wojcieszek, MD, Jo Belden, RN, Indiana University
School of Medicine, Indianapolis; Julie Carter, RN, MN, ANP, Richard
Camicioli, MD, Pam Andrews, RN, Oregon Health & Science University,
Portland; Michel Panisset, MD, Jean Hall, RN, McGill Centre for Studies in
Aging, Verdun, Quebec, Canada; Jean Hubble, MD, Magali Fernandez, MD,
Carson Reider, PhD, Ohio State University, Columbus; Ali Rajput, MD,
Alex Rajput, MD, Theresa Shirley, RN, Saskatoon Health District Board,
Saskatchewan, Canada; Tilak Mendis, MD, David A. Grimes, MD, Peggy
Gray, RN, BSCN, Ottawa Civic Hospital, Ontario, Canada; Carmen Serrano Ramos, MD, Sandra Roque, RN, University of Puerto Rico School of
Medicine, San Juan; Ronald Pfeiffer, MD, Brenda Pfeiffer, RN, BSN, University of Tennessee–Memphis; Lawrence Elmer, MD, PhD, Kathy Davis,
RN, MSN, Medical College of Ohio, Toledo; Joseph Friedman, MD, Hubert
Fernandez, MD, Margaret Lannon, RN, MS, Brown University, Pawtucket,
RI; Stephen Reich, MD, Becky Dunlop, RN, Johns Hopkins University,
Baltimore, MD; Lauren Seeberger, MD, Christopher O’Brien, MD, Deborah
Judd, RN, Colorado Neurologic Institute, Englewood; Robert Hauser, MD,
Theresa Zesiewicz, MD, Holly Delgado, RN, University of South Florida,
Tampa; Clifford Shults, MD, Deborah Fontaine, RNC, GNP, University of
California San Diego; Danna Jennings, MD, Kenneth Marek, MD, Susan
Mendick, MPH, Institute for Neurodegenerative Disorders, New Haven,
CT; Michael Aminoff, MD, FRCP, Mariann DiMinno, University of California San Francisco; Peter Lewitt, MD, Maryan DeAngelis, RN, Clinical Neuroscience Center, West Bloomfield, MI; Rajesh Pahwa, MD, Stephanie
Thomas, LPN, Kansas University Medical Center, Kansas City; Daniel
Truong, MD, Mayank Pathak, MD, An Tran, RN, Parkinson’s and Movement Disorder Institute, Fountain Valley, CA; Robert Rodnitzky, MD, Judith Dobson, RN, University of Iowa, Iowa City; William Koller, MD,
William Weiner, MD, Kelly Lyons, PhD, University of Miami, FL; Roger
Kurlan, MD, Debra Berry, MSN, NP, University of Rochester, NY; John
Bertoni, MD, PhD, Carolyn Peterson, RN, Creighton University, Omaha,
NE; Wayne Martin, MD, Marguerite Wieler, BSC, PT, University of Alberta, Edmonton, Canada; Paul Tuite, MD, Robyn Schacherer, RN, University of Minnesota Fairview University Medical Center, Minneapolis; Karen
1618
NEUROLOGY 62
May (1 of 2) 2004
Marder, MD, Juliette Harris, MS, PhD, Columbia–Presbyterian Medical
Center, New York; Joseph Jankovic, MD, Christine Hunter, RN, Baylor
College of Medicine, Houston, TX; Anthony Lang, MD, Galit Kleimer–
Fisman, MD, Anette Nieves, MD, Julie So, RN, Toronto Western Hospital,
Ontario, Canada; Stewart Factor, DO, Sharon Evans, LPN, Albany Medical
College, NY; Bala Manyam, MD, Brian Wulbrecht, Scott & White Hospital/
Texas A&M University, Temple, TX; Francis Walker, MD, Victoria Hunt,
RN, Wake Forest University School of Medicine, Winston–Salem, NC; Mark
F. Gordon, MD, Joanna Hamman, Long Island Jewish Medical Center, New
Hyde Park, NY; Un Jung Kang, MD, Joan Young, University of Chicago, IL;
Karen Blindauer, MD, Jeannine Petit, CNRN, GNPC, Medical College of
Wisconsin, Milwaukee; Jayaraman Rao, MD, Maureen Cook, RN, BSN,
Louisiana State University Medical Center, New Orleans; Mark Stacy, MD,
Kelli Williamson, RN, Barrow Neurologic Institute, Phoenix, AZ; Rachel
Saunders Pullman, MD, Karyn Boyar, RNC, MS, FNP, Beth Israel Medical
Center, New York; Maureen Leehey, MD, Theresa Derian, RN, University
of Colorado Health Sciences Center, Denver; Paul Gordon, MD, Joan
Werner, University of New Mexico, Albuquerque; Brad Racette, MD, Laura
Good, RN, Washington University, St. Louis, MO; David Simon, MD, Lisa
Scollins, RN, Beth Israel Deaconess Medical Center, Boston, MA; Arif
Dalvi, MD, Donna Schwieterman, MA, CCRC, University of Cincinnati
Medical Center, OH; Richard Dewey, MD, Melinda Meacham, RN, BSN,
University of Texas Southwestern Medical Center, Dallas; James Sutton,
MD, Brad Hutchinson, California Medical Clinic for Movement Disorders,
Oxnard; Mandar Jog, MD, PhD, Cheryl Horn, London Health Sciences
Center, Ontario, Canada; Kapil Sethi, MD, Joan Carpenter, RN, Medical
College of Georgia, Augusta; Paul Atchison, MD, Susan Rolli, RN, University of Alabama Birmingham; Lewis Sudarsky, MD, Claire Joubert, PAC,
BS, Brigham & Women’s Hospital, Boston, MA; Miodrag Velickovic, MD,
Sabrina Phipps, Mount Sinai Medical Center, New York; Tanya Simuni,
MD, Annette Kaczmarek, BS, Northwestern University Medical School,
Chicago, IL; Neal Hermanowicz, MD, Shari Niswonger, RN, University of
California Irvine; Andrew Feigin, MD, Barbara Shannon, RN, North Shore
University Hospital, Manhasset, NY; Vincent Calabresse, MD, Peggy Roberge, RN, Hunter Homes McGuire Veterans Medical Center, Richmond, VA;
Lisa Shulman, MD, Kelly Dustin, RN, University of Maryland School of
Medicine, Baltimore; Todd Ajax, MD, Janet Mannetter, RN, McFarland
Clinic, Mary Greely Hospital, Ames, IA; G. David Podskalny, MD, Lisa
Giffin, LPN, UMDNJ/School of Osteopathic Medicine, Stratford, NJ; Ryan
Uitti, MD, Margaret Foster Turk, RN, Mayo Clinic Jacksonville, FL.
Biostatistics and Clinical Trials Coordination Centers staff: David
Oakes, PhD, Arthur Watts, BS, Antai Wang, MA, Tori Ross, MA, Susan
Bennett, AAS, Elaine Julian–Baros, Susan Daigneault, University of Rochester, NY.
Acknowledgment
The authors thank the subjects for their participation in this
research study.
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