Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families

Nathan Pankratz, William C. Nichols, Sean K. Uniacke, Cheryl Halter, Jill Murrell, Alice Rudolph, Clifford W. Shults, P. Michael Conneally, Tatiana Foroud, Daniel Truong, Mayank Pathak, An Tran, Robert Rodnitzky, Judith Dobson, William Koller, William Weiner, Kelly Lyons, Roger Kurlan, Debra Berry, John Bertoni & 71 others Carolyn Peterson, Wayne Martin, Marguerite Wieler, Paul Tuite, Robyn Schacherer, Karen Marder, Juliette Harris, Joseph Jankovic, Christine Hunter, Anthony Lang, Galit Kleimer-Fisman, Anette Nieves, Julie So, Stewart Factor, Sharon Evans, Bala Manyam, Brian Wulbrecht, Francis Walker, Victoria Hunt, Mark F. Gordon, Joanna Hamman, Un Jang Kang, Joan Young, Karen Blindauer, Jeannine Petit, Jayaraman Rao, Maureen Cook, Mark Stacy, Kelli Williamson, Kapil Dev Sethi, Karyn Boyar, Maureen Leehey, Theresa Derian, Paul Gordon, Joan Werner, Brad Racette, Laura Good, David Simon, Lisa Scollins, Donna Schwieterman, Richard Dewey, Melinda Meacham, James Sutton, Brad Hutchinson, Mandar Jog, Cheryl Horn, Kapil Sethi, Joan Carpenter, Paul Atchison, Susan Rolli, Lewis Sudarsky, Claire Corwin, Miodrag Velickovic, Sabrina Phipps, Tanya Simuni, Annette Kaczmarek, Neal Hermanowicz, Shari Niswonger, Andrew Feigin, Barbara Shannon, Vincent Calabrese, Peggy Roberge, Hunter Homes, Lisa Shulman, Kelly Dustin, Todd Ajax, Janet Mannetter, G. David Podskalny, Lisa Giffin, Ryan Uitti, Margaret Foster Turk

Research output: Contribution to journalArticle

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Abstract

Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, non-parametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD = 2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD = 4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD = 2.4) and X (LOD = 3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.

Original languageEnglish (US)
Pages (from-to)2599-2608
Number of pages10
JournalHuman Molecular Genetics
Volume12
Issue number20
DOIs
StatePublished - Oct 15 2003

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Parkinson Disease
Genome
Genes
Chromosomes, Human, Pair 2
Siblings
Chromosomes, Human, Pair 10
Disease Susceptibility
Genetic Epistasis
Chromosomes, Human, Pair 14
X Chromosome
Neurodegenerative Diseases
Alleles
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Pankratz, N., Nichols, W. C., Uniacke, S. K., Halter, C., Murrell, J., Rudolph, A., ... Turk, M. F. (2003). Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. Human Molecular Genetics, 12(20), 2599-2608. https://doi.org/10.1093/hmg/ddg270

Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. / Pankratz, Nathan; Nichols, William C.; Uniacke, Sean K.; Halter, Cheryl; Murrell, Jill; Rudolph, Alice; Shults, Clifford W.; Conneally, P. Michael; Foroud, Tatiana; Truong, Daniel; Pathak, Mayank; Tran, An; Rodnitzky, Robert; Dobson, Judith; Koller, William; Weiner, William; Lyons, Kelly; Kurlan, Roger; Berry, Debra; Bertoni, John; Peterson, Carolyn; Martin, Wayne; Wieler, Marguerite; Tuite, Paul; Schacherer, Robyn; Marder, Karen; Harris, Juliette; Jankovic, Joseph; Hunter, Christine; Lang, Anthony; Kleimer-Fisman, Galit; Nieves, Anette; So, Julie; Factor, Stewart; Evans, Sharon; Manyam, Bala; Wulbrecht, Brian; Walker, Francis; Hunt, Victoria; Gordon, Mark F.; Hamman, Joanna; Kang, Un Jang; Young, Joan; Blindauer, Karen; Petit, Jeannine; Rao, Jayaraman; Cook, Maureen; Stacy, Mark; Williamson, Kelli; Sethi, Kapil Dev; Boyar, Karyn; Leehey, Maureen; Derian, Theresa; Gordon, Paul; Werner, Joan; Racette, Brad; Good, Laura; Simon, David; Scollins, Lisa; Schwieterman, Donna; Dewey, Richard; Meacham, Melinda; Sutton, James; Hutchinson, Brad; Jog, Mandar; Horn, Cheryl; Sethi, Kapil; Carpenter, Joan; Atchison, Paul; Rolli, Susan; Sudarsky, Lewis; Corwin, Claire; Velickovic, Miodrag; Phipps, Sabrina; Simuni, Tanya; Kaczmarek, Annette; Hermanowicz, Neal; Niswonger, Shari; Feigin, Andrew; Shannon, Barbara; Calabrese, Vincent; Roberge, Peggy; Homes, Hunter; Shulman, Lisa; Dustin, Kelly; Ajax, Todd; Mannetter, Janet; Podskalny, G. David; Giffin, Lisa; Uitti, Ryan; Turk, Margaret Foster.

In: Human Molecular Genetics, Vol. 12, No. 20, 15.10.2003, p. 2599-2608.

Research output: Contribution to journalArticle

Pankratz, N, Nichols, WC, Uniacke, SK, Halter, C, Murrell, J, Rudolph, A, Shults, CW, Conneally, PM, Foroud, T, Truong, D, Pathak, M, Tran, A, Rodnitzky, R, Dobson, J, Koller, W, Weiner, W, Lyons, K, Kurlan, R, Berry, D, Bertoni, J, Peterson, C, Martin, W, Wieler, M, Tuite, P, Schacherer, R, Marder, K, Harris, J, Jankovic, J, Hunter, C, Lang, A, Kleimer-Fisman, G, Nieves, A, So, J, Factor, S, Evans, S, Manyam, B, Wulbrecht, B, Walker, F, Hunt, V, Gordon, MF, Hamman, J, Kang, UJ, Young, J, Blindauer, K, Petit, J, Rao, J, Cook, M, Stacy, M, Williamson, K, Sethi, KD, Boyar, K, Leehey, M, Derian, T, Gordon, P, Werner, J, Racette, B, Good, L, Simon, D, Scollins, L, Schwieterman, D, Dewey, R, Meacham, M, Sutton, J, Hutchinson, B, Jog, M, Horn, C, Sethi, K, Carpenter, J, Atchison, P, Rolli, S, Sudarsky, L, Corwin, C, Velickovic, M, Phipps, S, Simuni, T, Kaczmarek, A, Hermanowicz, N, Niswonger, S, Feigin, A, Shannon, B, Calabrese, V, Roberge, P, Homes, H, Shulman, L, Dustin, K, Ajax, T, Mannetter, J, Podskalny, GD, Giffin, L, Uitti, R & Turk, MF 2003, 'Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families', Human Molecular Genetics, vol. 12, no. 20, pp. 2599-2608. https://doi.org/10.1093/hmg/ddg270
Pankratz, Nathan ; Nichols, William C. ; Uniacke, Sean K. ; Halter, Cheryl ; Murrell, Jill ; Rudolph, Alice ; Shults, Clifford W. ; Conneally, P. Michael ; Foroud, Tatiana ; Truong, Daniel ; Pathak, Mayank ; Tran, An ; Rodnitzky, Robert ; Dobson, Judith ; Koller, William ; Weiner, William ; Lyons, Kelly ; Kurlan, Roger ; Berry, Debra ; Bertoni, John ; Peterson, Carolyn ; Martin, Wayne ; Wieler, Marguerite ; Tuite, Paul ; Schacherer, Robyn ; Marder, Karen ; Harris, Juliette ; Jankovic, Joseph ; Hunter, Christine ; Lang, Anthony ; Kleimer-Fisman, Galit ; Nieves, Anette ; So, Julie ; Factor, Stewart ; Evans, Sharon ; Manyam, Bala ; Wulbrecht, Brian ; Walker, Francis ; Hunt, Victoria ; Gordon, Mark F. ; Hamman, Joanna ; Kang, Un Jang ; Young, Joan ; Blindauer, Karen ; Petit, Jeannine ; Rao, Jayaraman ; Cook, Maureen ; Stacy, Mark ; Williamson, Kelli ; Sethi, Kapil Dev ; Boyar, Karyn ; Leehey, Maureen ; Derian, Theresa ; Gordon, Paul ; Werner, Joan ; Racette, Brad ; Good, Laura ; Simon, David ; Scollins, Lisa ; Schwieterman, Donna ; Dewey, Richard ; Meacham, Melinda ; Sutton, James ; Hutchinson, Brad ; Jog, Mandar ; Horn, Cheryl ; Sethi, Kapil ; Carpenter, Joan ; Atchison, Paul ; Rolli, Susan ; Sudarsky, Lewis ; Corwin, Claire ; Velickovic, Miodrag ; Phipps, Sabrina ; Simuni, Tanya ; Kaczmarek, Annette ; Hermanowicz, Neal ; Niswonger, Shari ; Feigin, Andrew ; Shannon, Barbara ; Calabrese, Vincent ; Roberge, Peggy ; Homes, Hunter ; Shulman, Lisa ; Dustin, Kelly ; Ajax, Todd ; Mannetter, Janet ; Podskalny, G. David ; Giffin, Lisa ; Uitti, Ryan ; Turk, Margaret Foster. / Genome-wide linkage analysis and evidence of gene-by-gene interactions in a sample of 362 multiplex Parkinson disease families. In: Human Molecular Genetics. 2003 ; Vol. 12, No. 20. pp. 2599-2608.
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abstract = "Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, non-parametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD = 2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD = 4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD = 2.4) and X (LOD = 3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.",
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AU - Pankratz, Nathan

AU - Nichols, William C.

AU - Uniacke, Sean K.

AU - Halter, Cheryl

AU - Murrell, Jill

AU - Rudolph, Alice

AU - Shults, Clifford W.

AU - Conneally, P. Michael

AU - Foroud, Tatiana

AU - Truong, Daniel

AU - Pathak, Mayank

AU - Tran, An

AU - Rodnitzky, Robert

AU - Dobson, Judith

AU - Koller, William

AU - Weiner, William

AU - Lyons, Kelly

AU - Kurlan, Roger

AU - Berry, Debra

AU - Bertoni, John

AU - Peterson, Carolyn

AU - Martin, Wayne

AU - Wieler, Marguerite

AU - Tuite, Paul

AU - Schacherer, Robyn

AU - Marder, Karen

AU - Harris, Juliette

AU - Jankovic, Joseph

AU - Hunter, Christine

AU - Lang, Anthony

AU - Kleimer-Fisman, Galit

AU - Nieves, Anette

AU - So, Julie

AU - Factor, Stewart

AU - Evans, Sharon

AU - Manyam, Bala

AU - Wulbrecht, Brian

AU - Walker, Francis

AU - Hunt, Victoria

AU - Gordon, Mark F.

AU - Hamman, Joanna

AU - Kang, Un Jang

AU - Young, Joan

AU - Blindauer, Karen

AU - Petit, Jeannine

AU - Rao, Jayaraman

AU - Cook, Maureen

AU - Stacy, Mark

AU - Williamson, Kelli

AU - Sethi, Kapil Dev

AU - Boyar, Karyn

AU - Leehey, Maureen

AU - Derian, Theresa

AU - Gordon, Paul

AU - Werner, Joan

AU - Racette, Brad

AU - Good, Laura

AU - Simon, David

AU - Scollins, Lisa

AU - Schwieterman, Donna

AU - Dewey, Richard

AU - Meacham, Melinda

AU - Sutton, James

AU - Hutchinson, Brad

AU - Jog, Mandar

AU - Horn, Cheryl

AU - Sethi, Kapil

AU - Carpenter, Joan

AU - Atchison, Paul

AU - Rolli, Susan

AU - Sudarsky, Lewis

AU - Corwin, Claire

AU - Velickovic, Miodrag

AU - Phipps, Sabrina

AU - Simuni, Tanya

AU - Kaczmarek, Annette

AU - Hermanowicz, Neal

AU - Niswonger, Shari

AU - Feigin, Andrew

AU - Shannon, Barbara

AU - Calabrese, Vincent

AU - Roberge, Peggy

AU - Homes, Hunter

AU - Shulman, Lisa

AU - Dustin, Kelly

AU - Ajax, Todd

AU - Mannetter, Janet

AU - Podskalny, G. David

AU - Giffin, Lisa

AU - Uitti, Ryan

AU - Turk, Margaret Foster

PY - 2003/10/15

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N2 - Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, non-parametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD = 2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD = 4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD = 2.4) and X (LOD = 3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.

AB - Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, non-parametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD = 2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD = 4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD = 2.4) and X (LOD = 3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.

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