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

Parkinson Study Group

Research output: Contribution to journalArticle

142 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 - Jan 1 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
  • Genetics(clinical)

Cite this

Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations. / Parkinson Study Group.

In: American Journal of Human Genetics, Vol. 71, No. 1, 01.01.2002, p. 124-135.

Research output: Contribution to journalArticle

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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 = "{Parkinson Study Group} and 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 Sethi, {Kapil Dev}",
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