TY - JOUR
T1 - Genome screen to identify susceptibility genes for Parkinson disease in a sample without parkin mutations
AU - Parkinson Study Group
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 - Dewey, Richard
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
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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U2 - 10.1086/341282
DO - 10.1086/341282
M3 - Article
C2 - 12058349
AN - SCOPUS:18444364221
VL - 71
SP - 124
EP - 135
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -