* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Genes influencing Parkinson disease onset - progeni
Artificial gene synthesis wikipedia , lookup
Genomic imprinting wikipedia , lookup
Population genetics wikipedia , lookup
Epigenetics of human development wikipedia , lookup
Gene expression profiling wikipedia , lookup
Gene expression programming wikipedia , lookup
Heritability of IQ wikipedia , lookup
Minimal genome wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
Point mutation wikipedia , lookup
X-inactivation wikipedia , lookup
Quantitative trait locus wikipedia , lookup
Biology and consumer behaviour wikipedia , lookup
Medical genetics wikipedia , lookup
Neuronal ceroid lipofuscinosis wikipedia , lookup
Genome evolution wikipedia , lookup
Designer baby wikipedia , lookup
Microevolution wikipedia , lookup
Epigenetics of neurodegenerative diseases wikipedia , lookup
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 1617 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. References 1. Li YJ, Scott WK, Hedges DJ et al. Age at onset in two common neurodegenerative diseases is genetically controlled. Am J Hum Genet 2002; 70:985–993. 2. DeStefano AL, Lew MF, Golbe LI et al. PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study. Am J Hum Genet 2002;70:1089 –1095. 3. Pankratz N, Nichols WC, Uniacke SK et al. Significant linkage of Parkinson disease to chromosome 2q36 –37. Am J Hum Genet 2003;72: 1053–1057. 4. Foroud T, Uniacke SK, Liu L, et al. Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology 2003; 60:796 – 801. 5. Almasy L, Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998;62:1198 –1211. 6. Pankratz N, Mukhopadhyay N, Huang S, Foroud T, Kirkwood SC. Identification of genes for complex disease using longitudinal phenotypes. BMC Genet 2003;4(suppl 1):558. 7. West AB, Zimprich A, Lockhart PJ, et al. Refinement of the PARK3 locus on chromosome 2p13 and the analysis of 14 candidate genes. Eur J Hum Genet 2001;9:659 – 666. 8. Pankratz N, Nichols WC, Uniacke SK, et al. Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Hum Mol Genet 2003b;12:2599 – 2608. 9. Gasser T, Muller–Myhsok B, Wszolek ZK, et al. A susceptibility locus for Parkinson’s disease maps to chromosome 2p13. Nat Genet 1998;18: 262–265. 10. Kruglyak L, Lander ES. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet 1995;57:439 – 454.