Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations

Nathan Pankratz, William C. Nichols, Sean K. Uniacke, Cheryl Halter, Alice Rudolph, Cliff Shults, P. Michael Conneally, Tatiana Foroud, Lawrence Golbe, William Koller, Karen Marder, Frederick Marshall, David Oakes, Aileen Shinaman, Eric Siemers, Julie Carter, Richard Camicioli, Pamela Andrews, Joanne Wojcieszek, Joann BeldenMagali Frenandez, Jean Hubble, Carson Reider, Ali Rajput, Alex Rajput, Theresa Shirley, Michael Panisset, Jean Hall, Tilak Mendis, David A. Grimes, Peggy Gray, Carmen Serrano Ramos, Sandra Roque, Stephen Reich, Becky Dunlop, Robert Hauser, Juan Sanchez-Ramos, Theresa Zesiewicz, Holly Delgado, Ronald Pfeiffer, Brenda Pfeiffer, Joseph Friedman, Hubert Fernandez, Margaret Lannon, Deborah Fontaine, Lauren Seeberger, Christopher O'Brien, Deborah Judd, Rajesh Pahwa, Stephanie Thomas, Lawrence Elmer, Kathy Davis, Darma Jennings, Kenneth Marek, Susan Mendick, Daniel Truong, Mayank Pathak, Anhoa Tran, Robert Rodnitzyk, Judith Dobson, Roger Kurlan, Debra Berry, Paul Tuite, Robyn Schacher, Michael Aminoff, Mariann DiMinno, Karen Marder, Juliette Harris, Peter Lewitt, Maryan DeAngelis, William Koller, William Weiner, Kelly Lyons, Wayne Martin, Marguerite Wieler, Joseph Jankovic, Christine Hunter, John Bertoni, Carolyn Peterson, Stewart Factor, Sharon Evans, Francis Walker, Victoria Hunt, Jung Kang Un, Shirley Uy, Mark Stacy, Kelli Williamson, David Simon, Lisa Scollins, Karen Brindauer, Jeannine Petit, Bala Manyam, Patricia Simpson, Anette Nieves, Julie So, Miodrag Velickovic, Sabrina Phipps, Mark F. Gordon, Joanna Hamann

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Parkinson disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity, and postural instability, as well as by a clinically significant response to treatment with levodopa. Mutations in the α-synuclein gene have been found to result in autosomal dominant PD, and mutations in the parkin gene produce autosomal recessive juvenile-onset PD. We have studied 203 sibling pairs with PD who were evaluated by a rigorous neurological assessment based on (a) inclusion criteria consisting of clinical features highly associated with autopsy-confirmed PD and (b) exclusion criteria highly associated with other, non-PD pathological diagnoses. Families with positive LOD scores for a marker in an intron of the parkin gene were prioritized for parkin-gene testing, and mutations in the parkin gene were identified in 22 families. To reduce genetic heterogeneity, these families were not included in subsequent genome-screen analysis. Thus, a total of 160 multiplex families without evidence of a parkin mutation were used in multipoint nonparametric linkage analysis to identify PD-susceptibility genes. Two models of PD affection status were considered: model I included only those individuals with a more stringent diagnosis of verified PD (96 sibling pairs from 90 families), whereas model II included all examined individuals as affected, regardless of their final diagnostic classification (170 sibling pairs from 160 families). Under model I, the highest LOD scores were observed on chromosome X (LOD score 2.1) and on chromosome 2 (LOD score 1.9). Analyses performed with all available sibling pairs (model II) found even greater evidence of linkage to chromosome X (LOD score 2.7) and to chromosome 2 (LOD score 2.5). Evidence of linkage was also found to chromosomes 4, 5, and 13 (LOD scores >1.5). Our findings are consistent with those of other linkage studies that have reported linkage to chromosomes 5 and X.

Original languageEnglish (US)
Pages (from-to)124-135
Number of pages12
JournalAmerican Journal of Human Genetics
Volume71
Issue number1
DOIs
StatePublished - 2002

Fingerprint

Parkinson Disease
Genome
Mutation
Genes
Chromosomes, Human, Pair 5
Chromosomes, Human, Pair 2
X Chromosome
Synucleins
Muscle Rigidity
Chromosomes, Human, Pair 13
Hypokinesia
Chromosomes, Human, Pair 4
Genetic Heterogeneity
Disease Susceptibility
Parkinsonian Disorders
Levodopa
Tremor
Neurodegenerative Diseases
Introns
Autopsy

ASJC Scopus subject areas

  • Genetics

Cite this

Pankratz, N., Nichols, W. C., Uniacke, S. K., Halter, C., Rudolph, A., Shults, C., ... Hamann, J. (2002). Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations. American Journal of Human Genetics, 71(1), 124-135. https://doi.org/10.1086/341282

Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations. / Pankratz, Nathan; Nichols, William C.; Uniacke, Sean K.; Halter, Cheryl; Rudolph, Alice; Shults, Cliff; Conneally, P. Michael; Foroud, Tatiana; Golbe, Lawrence; Koller, William; Marder, Karen; Marshall, Frederick; Oakes, David; Shinaman, Aileen; Siemers, Eric; Carter, Julie; Camicioli, Richard; Andrews, Pamela; Wojcieszek, Joanne; Belden, Joann; Frenandez, Magali; Hubble, Jean; Reider, Carson; Rajput, Ali; Rajput, Alex; Shirley, Theresa; Panisset, Michael; Hall, Jean; Mendis, Tilak; Grimes, David A.; Gray, Peggy; Ramos, Carmen Serrano; Roque, Sandra; Reich, Stephen; Dunlop, Becky; Hauser, Robert; Sanchez-Ramos, Juan; Zesiewicz, Theresa; Delgado, Holly; Pfeiffer, Ronald; Pfeiffer, Brenda; Friedman, Joseph; Fernandez, Hubert; Lannon, Margaret; Fontaine, Deborah; Seeberger, Lauren; O'Brien, Christopher; Judd, Deborah; Pahwa, Rajesh; Thomas, Stephanie; Elmer, Lawrence; Davis, Kathy; Jennings, Darma; Marek, Kenneth; Mendick, Susan; Truong, Daniel; Pathak, Mayank; Tran, Anhoa; Rodnitzyk, Robert; Dobson, Judith; Kurlan, Roger; Berry, Debra; Tuite, Paul; Schacher, Robyn; Aminoff, Michael; DiMinno, Mariann; Marder, Karen; Harris, Juliette; Lewitt, Peter; DeAngelis, Maryan; Koller, William; Weiner, William; Lyons, Kelly; Martin, Wayne; Wieler, Marguerite; Jankovic, Joseph; Hunter, Christine; Bertoni, John; Peterson, Carolyn; Factor, Stewart; Evans, Sharon; Walker, Francis; Hunt, Victoria; Un, Jung Kang; Uy, Shirley; Stacy, Mark; Williamson, Kelli; Simon, David; Scollins, Lisa; Brindauer, Karen; Petit, Jeannine; Manyam, Bala; Simpson, Patricia; Nieves, Anette; So, Julie; Velickovic, Miodrag; Phipps, Sabrina; Gordon, Mark F.; Hamann, Joanna.

In: American Journal of Human Genetics, Vol. 71, No. 1, 2002, p. 124-135.

Research output: Contribution to journalArticle

Pankratz, N, Nichols, WC, Uniacke, SK, Halter, C, Rudolph, A, Shults, C, Conneally, PM, Foroud, T, Golbe, L, Koller, W, Marder, K, Marshall, F, Oakes, D, Shinaman, A, Siemers, E, Carter, J, Camicioli, R, Andrews, P, Wojcieszek, J, Belden, J, Frenandez, M, Hubble, J, Reider, C, Rajput, A, Rajput, A, Shirley, T, Panisset, M, Hall, J, Mendis, T, Grimes, DA, Gray, P, Ramos, CS, Roque, S, Reich, S, Dunlop, B, Hauser, R, Sanchez-Ramos, J, Zesiewicz, T, Delgado, H, Pfeiffer, R, Pfeiffer, B, Friedman, J, Fernandez, H, Lannon, M, Fontaine, D, Seeberger, L, O'Brien, C, Judd, D, Pahwa, R, Thomas, S, Elmer, L, Davis, K, Jennings, D, Marek, K, Mendick, S, Truong, D, Pathak, M, Tran, A, Rodnitzyk, R, Dobson, J, Kurlan, R, Berry, D, Tuite, P, Schacher, R, Aminoff, M, DiMinno, M, Marder, K, Harris, J, Lewitt, P, DeAngelis, M, Koller, W, Weiner, W, Lyons, K, Martin, W, Wieler, M, Jankovic, J, Hunter, C, Bertoni, J, Peterson, C, Factor, S, Evans, S, Walker, F, Hunt, V, Un, JK, Uy, S, Stacy, M, Williamson, K, Simon, D, Scollins, L, Brindauer, K, Petit, J, Manyam, B, Simpson, P, Nieves, A, So, J, Velickovic, M, Phipps, S, Gordon, MF & Hamann, J 2002, 'Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations', American Journal of Human Genetics, vol. 71, no. 1, pp. 124-135. https://doi.org/10.1086/341282
Pankratz, Nathan ; Nichols, William C. ; Uniacke, Sean K. ; Halter, Cheryl ; Rudolph, Alice ; Shults, Cliff ; Conneally, P. Michael ; Foroud, Tatiana ; Golbe, Lawrence ; Koller, William ; Marder, Karen ; Marshall, Frederick ; Oakes, David ; Shinaman, Aileen ; Siemers, Eric ; Carter, Julie ; Camicioli, Richard ; Andrews, Pamela ; Wojcieszek, Joanne ; Belden, Joann ; Frenandez, Magali ; Hubble, Jean ; Reider, Carson ; Rajput, Ali ; Rajput, Alex ; Shirley, Theresa ; Panisset, Michael ; Hall, Jean ; Mendis, Tilak ; Grimes, David A. ; Gray, Peggy ; Ramos, Carmen Serrano ; Roque, Sandra ; Reich, Stephen ; Dunlop, Becky ; Hauser, Robert ; Sanchez-Ramos, Juan ; Zesiewicz, Theresa ; Delgado, Holly ; Pfeiffer, Ronald ; Pfeiffer, Brenda ; Friedman, Joseph ; Fernandez, Hubert ; Lannon, Margaret ; Fontaine, Deborah ; Seeberger, Lauren ; O'Brien, Christopher ; Judd, Deborah ; Pahwa, Rajesh ; Thomas, Stephanie ; Elmer, Lawrence ; Davis, Kathy ; Jennings, Darma ; Marek, Kenneth ; Mendick, Susan ; Truong, Daniel ; Pathak, Mayank ; Tran, Anhoa ; Rodnitzyk, Robert ; Dobson, Judith ; Kurlan, Roger ; Berry, Debra ; Tuite, Paul ; Schacher, Robyn ; Aminoff, Michael ; DiMinno, Mariann ; Marder, Karen ; Harris, Juliette ; Lewitt, Peter ; DeAngelis, Maryan ; Koller, William ; Weiner, William ; Lyons, Kelly ; Martin, Wayne ; Wieler, Marguerite ; Jankovic, Joseph ; Hunter, Christine ; Bertoni, John ; Peterson, Carolyn ; Factor, Stewart ; Evans, Sharon ; Walker, Francis ; Hunt, Victoria ; Un, Jung Kang ; Uy, Shirley ; Stacy, Mark ; Williamson, Kelli ; Simon, David ; Scollins, Lisa ; Brindauer, Karen ; Petit, Jeannine ; Manyam, Bala ; Simpson, Patricia ; Nieves, Anette ; So, Julie ; Velickovic, Miodrag ; Phipps, Sabrina ; Gordon, Mark F. ; Hamann, Joanna. / Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations. In: American Journal of Human Genetics. 2002 ; Vol. 71, No. 1. pp. 124-135.
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abstract = "Parkinson disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity, and postural instability, as well as by a clinically significant response to treatment with levodopa. Mutations in the α-synuclein gene have been found to result in autosomal dominant PD, and mutations in the parkin gene produce autosomal recessive juvenile-onset PD. We have studied 203 sibling pairs with PD who were evaluated by a rigorous neurological assessment based on (a) inclusion criteria consisting of clinical features highly associated with autopsy-confirmed PD and (b) exclusion criteria highly associated with other, non-PD pathological diagnoses. Families with positive LOD scores for a marker in an intron of the parkin gene were prioritized for parkin-gene testing, and mutations in the parkin gene were identified in 22 families. To reduce genetic heterogeneity, these families were not included in subsequent genome-screen analysis. Thus, a total of 160 multiplex families without evidence of a parkin mutation were used in multipoint nonparametric linkage analysis to identify PD-susceptibility genes. Two models of PD affection status were considered: model I included only those individuals with a more stringent diagnosis of verified PD (96 sibling pairs from 90 families), whereas model II included all examined individuals as affected, regardless of their final diagnostic classification (170 sibling pairs from 160 families). Under model I, the highest LOD scores were observed on chromosome X (LOD score 2.1) and on chromosome 2 (LOD score 1.9). Analyses performed with all available sibling pairs (model II) found even greater evidence of linkage to chromosome X (LOD score 2.7) and to chromosome 2 (LOD score 2.5). Evidence of linkage was also found to chromosomes 4, 5, and 13 (LOD scores >1.5). Our findings are consistent with those of other linkage studies that have reported linkage to chromosomes 5 and X.",
author = "Nathan Pankratz and Nichols, {William C.} and Uniacke, {Sean K.} and Cheryl Halter and Alice Rudolph and Cliff Shults and Conneally, {P. Michael} and Tatiana Foroud and Lawrence Golbe and William Koller and Karen Marder and Frederick Marshall and David Oakes and Aileen Shinaman and Eric Siemers and Julie Carter and Richard Camicioli and Pamela Andrews and Joanne Wojcieszek and Joann Belden and Magali Frenandez and Jean Hubble and Carson Reider and Ali Rajput and Alex Rajput and Theresa Shirley and Michael Panisset and Jean Hall and Tilak Mendis and Grimes, {David A.} and Peggy Gray and Ramos, {Carmen Serrano} and Sandra Roque and Stephen Reich and Becky Dunlop and Robert Hauser and Juan Sanchez-Ramos and Theresa Zesiewicz and Holly Delgado and Ronald Pfeiffer and Brenda Pfeiffer and Joseph Friedman and Hubert Fernandez and Margaret Lannon and Deborah Fontaine and Lauren Seeberger and Christopher O'Brien and Deborah Judd and Rajesh Pahwa and Stephanie Thomas and Lawrence Elmer and Kathy Davis and Darma Jennings and Kenneth Marek and Susan Mendick and Daniel Truong and Mayank Pathak and Anhoa Tran and Robert Rodnitzyk and Judith Dobson and Roger Kurlan and Debra Berry and Paul Tuite and Robyn Schacher and Michael Aminoff and Mariann DiMinno and Karen Marder and Juliette Harris and Peter Lewitt and Maryan DeAngelis and William Koller and William Weiner and Kelly Lyons and Wayne Martin and Marguerite Wieler and Joseph Jankovic and Christine Hunter and John Bertoni and Carolyn Peterson and Stewart Factor and Sharon Evans and Francis Walker and Victoria Hunt and Un, {Jung Kang} and Shirley Uy and Mark Stacy and Kelli Williamson and David Simon and Lisa Scollins and Karen Brindauer and Jeannine Petit and Bala Manyam and Patricia Simpson and Anette Nieves and Julie So and Miodrag Velickovic and Sabrina Phipps and Gordon, {Mark F.} and Joanna Hamann",
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T1 - Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations

AU - Pankratz, Nathan

AU - Nichols, William C.

AU - Uniacke, Sean K.

AU - Halter, Cheryl

AU - Rudolph, Alice

AU - Shults, Cliff

AU - Conneally, P. Michael

AU - Foroud, Tatiana

AU - Golbe, Lawrence

AU - Koller, William

AU - Marder, Karen

AU - Marshall, Frederick

AU - Oakes, David

AU - Shinaman, Aileen

AU - Siemers, Eric

AU - Carter, Julie

AU - Camicioli, Richard

AU - Andrews, Pamela

AU - Wojcieszek, Joanne

AU - Belden, Joann

AU - Frenandez, Magali

AU - Hubble, Jean

AU - Reider, Carson

AU - Rajput, Ali

AU - Rajput, Alex

AU - Shirley, Theresa

AU - Panisset, Michael

AU - Hall, Jean

AU - Mendis, Tilak

AU - Grimes, David A.

AU - Gray, Peggy

AU - Ramos, Carmen Serrano

AU - Roque, Sandra

AU - Reich, Stephen

AU - Dunlop, Becky

AU - Hauser, Robert

AU - Sanchez-Ramos, Juan

AU - Zesiewicz, Theresa

AU - Delgado, Holly

AU - Pfeiffer, Ronald

AU - Pfeiffer, Brenda

AU - Friedman, Joseph

AU - Fernandez, Hubert

AU - Lannon, Margaret

AU - Fontaine, Deborah

AU - Seeberger, Lauren

AU - O'Brien, Christopher

AU - Judd, Deborah

AU - Pahwa, Rajesh

AU - Thomas, Stephanie

AU - Elmer, Lawrence

AU - Davis, Kathy

AU - Jennings, Darma

AU - Marek, Kenneth

AU - Mendick, Susan

AU - Truong, Daniel

AU - Pathak, Mayank

AU - Tran, Anhoa

AU - Rodnitzyk, Robert

AU - Dobson, Judith

AU - Kurlan, Roger

AU - Berry, Debra

AU - Tuite, Paul

AU - Schacher, Robyn

AU - Aminoff, Michael

AU - DiMinno, Mariann

AU - Marder, Karen

AU - Harris, Juliette

AU - Lewitt, Peter

AU - DeAngelis, Maryan

AU - Koller, William

AU - Weiner, William

AU - Lyons, Kelly

AU - Martin, Wayne

AU - Wieler, Marguerite

AU - Jankovic, Joseph

AU - Hunter, Christine

AU - Bertoni, John

AU - Peterson, Carolyn

AU - Factor, Stewart

AU - Evans, Sharon

AU - Walker, Francis

AU - Hunt, Victoria

AU - Un, Jung Kang

AU - Uy, Shirley

AU - Stacy, Mark

AU - Williamson, Kelli

AU - Simon, David

AU - Scollins, Lisa

AU - Brindauer, Karen

AU - Petit, Jeannine

AU - Manyam, Bala

AU - Simpson, Patricia

AU - Nieves, Anette

AU - So, Julie

AU - Velickovic, Miodrag

AU - Phipps, Sabrina

AU - Gordon, Mark F.

AU - Hamann, Joanna

PY - 2002

Y1 - 2002

N2 - Parkinson disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity, and postural instability, as well as by a clinically significant response to treatment with levodopa. Mutations in the α-synuclein gene have been found to result in autosomal dominant PD, and mutations in the parkin gene produce autosomal recessive juvenile-onset PD. We have studied 203 sibling pairs with PD who were evaluated by a rigorous neurological assessment based on (a) inclusion criteria consisting of clinical features highly associated with autopsy-confirmed PD and (b) exclusion criteria highly associated with other, non-PD pathological diagnoses. Families with positive LOD scores for a marker in an intron of the parkin gene were prioritized for parkin-gene testing, and mutations in the parkin gene were identified in 22 families. To reduce genetic heterogeneity, these families were not included in subsequent genome-screen analysis. Thus, a total of 160 multiplex families without evidence of a parkin mutation were used in multipoint nonparametric linkage analysis to identify PD-susceptibility genes. Two models of PD affection status were considered: model I included only those individuals with a more stringent diagnosis of verified PD (96 sibling pairs from 90 families), whereas model II included all examined individuals as affected, regardless of their final diagnostic classification (170 sibling pairs from 160 families). Under model I, the highest LOD scores were observed on chromosome X (LOD score 2.1) and on chromosome 2 (LOD score 1.9). Analyses performed with all available sibling pairs (model II) found even greater evidence of linkage to chromosome X (LOD score 2.7) and to chromosome 2 (LOD score 2.5). Evidence of linkage was also found to chromosomes 4, 5, and 13 (LOD scores >1.5). Our findings are consistent with those of other linkage studies that have reported linkage to chromosomes 5 and X.

AB - Parkinson disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity, and postural instability, as well as by a clinically significant response to treatment with levodopa. Mutations in the α-synuclein gene have been found to result in autosomal dominant PD, and mutations in the parkin gene produce autosomal recessive juvenile-onset PD. We have studied 203 sibling pairs with PD who were evaluated by a rigorous neurological assessment based on (a) inclusion criteria consisting of clinical features highly associated with autopsy-confirmed PD and (b) exclusion criteria highly associated with other, non-PD pathological diagnoses. Families with positive LOD scores for a marker in an intron of the parkin gene were prioritized for parkin-gene testing, and mutations in the parkin gene were identified in 22 families. To reduce genetic heterogeneity, these families were not included in subsequent genome-screen analysis. Thus, a total of 160 multiplex families without evidence of a parkin mutation were used in multipoint nonparametric linkage analysis to identify PD-susceptibility genes. Two models of PD affection status were considered: model I included only those individuals with a more stringent diagnosis of verified PD (96 sibling pairs from 90 families), whereas model II included all examined individuals as affected, regardless of their final diagnostic classification (170 sibling pairs from 160 families). Under model I, the highest LOD scores were observed on chromosome X (LOD score 2.1) and on chromosome 2 (LOD score 1.9). Analyses performed with all available sibling pairs (model II) found even greater evidence of linkage to chromosome X (LOD score 2.7) and to chromosome 2 (LOD score 2.5). Evidence of linkage was also found to chromosomes 4, 5, and 13 (LOD scores >1.5). Our findings are consistent with those of other linkage studies that have reported linkage to chromosomes 5 and X.

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