Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease

Jessie Theuns; Aline Verstraeten; Kristel Sleegers; Eline Wauters; Ilse Gijselinck; Stefanie Smolders; David Crosiers; Ellen Corsmit; Ellen Elinck; Manu Sharma; Rejko Krüger; Suzanne Lesage; Alexis Brice; Sun Ju Chung; Mi-Jung Kim; Young Jin Kim; Owen A Ross; Zbigniew K Wszolek; Ekaterina Rogaeva; Zhengrui Xi; Anthony E Lang; Christine Klein; Anne Weissbach; George D Mellick; Peter A Silburn; Georgios M Hadjigeorgiou; Efthimios Dardiotis; Nobutaka Hattori; Kotaro Ogaki; Eng-King Tan; Yi Zhao; Jan Aasly; Enza Maria Valente; Simona Petrucci; Grazia Annesi; Aldo Quattrone; Carlo Ferrarese; Laura Brighina; Angela Deutschländer; Andreas Puschmann; Christer Nilsson; Gaëtan Garraux; Mark S LeDoux; Ronald F Pfeiffer; Magdalena Boczarska-Jedynak; Grzegorz Opala; Demetrius M Maraganore; Sebastiaan Engelborghs; Peter Paul De Deyn; Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium; Karen Morrison

doi:10.1212/WNL.0000000000001012

Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease

Jessie Theuns, Aline Verstraeten, Kristel Sleegers, Eline Wauters, Ilse Gijselinck, Stefanie Smolders, David Crosiers, Ellen Corsmit, Ellen Elinck, Manu Sharma, Rejko Krüger, Suzanne Lesage, Alexis Brice, Sun Ju Chung, Mi-Jung Kim, Young Jin Kim, Owen A Ross, Zbigniew K Wszolek, Ekaterina Rogaeva, Zhengrui XiAnthony E Lang, Christine Klein, Anne Weissbach, George D Mellick, Peter A Silburn, Georgios M Hadjigeorgiou, Efthimios Dardiotis, Nobutaka Hattori, Kotaro Ogaki, Eng-King Tan, Yi Zhao, Jan Aasly, Enza Maria Valente, Simona Petrucci, Grazia Annesi, Aldo Quattrone, Carlo Ferrarese, Laura Brighina, Angela Deutschländer, Andreas Puschmann, Christer Nilsson, Gaëtan Garraux, Mark S LeDoux, Ronald F Pfeiffer, Magdalena Boczarska-Jedynak, Grzegorz Opala, Demetrius M Maraganore, Sebastiaan Engelborghs, Peter Paul De Deyn, Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium, Karen Morrison

Research output: Contribution to journal › Article › peer-review

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Abstract

OBJECTIVES: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort.

METHODS: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia.

RESULTS: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low.

CONCLUSIONS: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.

Original language	English
Pages (from-to)	1906-13
Number of pages	8
Journal	Neurology
Volume	83
Issue number	21
DOIs	https://doi.org/10.1212/WNL.0000000000001012
Publication status	Published - 18 Nov 2014

Bibliographical note

Keywords

Cohort Studies
DNA Repeat Expansion
Female
Humans
Internationality
Male
Middle Aged
Parkinson Disease
Proteins

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10.1212/WNL.0000000000001012

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Theuns, J., Verstraeten, A., Sleegers, K., Wauters, E., Gijselinck, I., Smolders, S., Crosiers, D., Corsmit, E., Elinck, E., Sharma, M., Krüger, R., Lesage, S., Brice, A., Chung, S. J., Kim, M.-J., Kim, Y. J., Ross, O. A., Wszolek, Z. K., Rogaeva, E., ... Morrison, K. (2014). Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology, 83(21), 1906-13. https://doi.org/10.1212/WNL.0000000000001012

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title = "Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease",

abstract = "OBJECTIVES: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort.METHODS: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia.RESULTS: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low.CONCLUSIONS: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.",

keywords = "Cohort Studies, DNA Repeat Expansion, Female, Humans, Internationality, Male, Middle Aged, Parkinson Disease, Proteins",

author = "Jessie Theuns and Aline Verstraeten and Kristel Sleegers and Eline Wauters and Ilse Gijselinck and Stefanie Smolders and David Crosiers and Ellen Corsmit and Ellen Elinck and Manu Sharma and Rejko Kr{\"u}ger and Suzanne Lesage and Alexis Brice and Chung, {Sun Ju} and Mi-Jung Kim and Kim, {Young Jin} and Ross, {Owen A} and Wszolek, {Zbigniew K} and Ekaterina Rogaeva and Zhengrui Xi and Lang, {Anthony E} and Christine Klein and Anne Weissbach and Mellick, {George D} and Silburn, {Peter A} and Hadjigeorgiou, {Georgios M} and Efthimios Dardiotis and Nobutaka Hattori and Kotaro Ogaki and Eng-King Tan and Yi Zhao and Jan Aasly and Valente, {Enza Maria} and Simona Petrucci and Grazia Annesi and Aldo Quattrone and Carlo Ferrarese and Laura Brighina and Angela Deutschl{\"a}nder and Andreas Puschmann and Christer Nilsson and Ga{\"e}tan Garraux and LeDoux, {Mark S} and Pfeiffer, {Ronald F} and Magdalena Boczarska-Jedynak and Grzegorz Opala and Maraganore, {Demetrius M} and Sebastiaan Engelborghs and {De Deyn}, {Peter Paul} and {Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium} and Karen Morrison",

note = "{\textcopyright} 2014 American Academy of Neurology.",

year = "2014",

month = nov,

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doi = "10.1212/WNL.0000000000001012",

language = "English",

volume = "83",

pages = "1906--13",

journal = "Neurology",

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Theuns, J, Verstraeten, A, Sleegers, K, Wauters, E, Gijselinck, I, Smolders, S, Crosiers, D, Corsmit, E, Elinck, E, Sharma, M, Krüger, R, Lesage, S, Brice, A, Chung, SJ, Kim, M-J, Kim, YJ, Ross, OA, Wszolek, ZK, Rogaeva, E, Xi, Z, Lang, AE, Klein, C, Weissbach, A, Mellick, GD, Silburn, PA, Hadjigeorgiou, GM, Dardiotis, E, Hattori, N, Ogaki, K, Tan, E-K, Zhao, Y, Aasly, J, Valente, EM, Petrucci, S, Annesi, G, Quattrone, A, Ferrarese, C, Brighina, L, Deutschländer, A, Puschmann, A, Nilsson, C, Garraux, G, LeDoux, MS, Pfeiffer, RF, Boczarska-Jedynak, M, Opala, G, Maraganore, DM, Engelborghs, S, De Deyn, PP, Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium & Morrison, K 2014, 'Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease', Neurology, vol. 83, no. 21, pp. 1906-13. https://doi.org/10.1212/WNL.0000000000001012

TY - JOUR

T1 - Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease

AU - Theuns, Jessie

AU - Verstraeten, Aline

AU - Sleegers, Kristel

AU - Wauters, Eline

AU - Gijselinck, Ilse

AU - Smolders, Stefanie

AU - Crosiers, David

AU - Corsmit, Ellen

AU - Elinck, Ellen

AU - Sharma, Manu

AU - Krüger, Rejko

AU - Lesage, Suzanne

AU - Brice, Alexis

AU - Chung, Sun Ju

AU - Kim, Mi-Jung

AU - Kim, Young Jin

AU - Ross, Owen A

AU - Wszolek, Zbigniew K

AU - Rogaeva, Ekaterina

AU - Xi, Zhengrui

AU - Lang, Anthony E

AU - Klein, Christine

AU - Weissbach, Anne

AU - Mellick, George D

AU - Silburn, Peter A

AU - Hadjigeorgiou, Georgios M

AU - Dardiotis, Efthimios

AU - Hattori, Nobutaka

AU - Ogaki, Kotaro

AU - Tan, Eng-King

AU - Zhao, Yi

AU - Aasly, Jan

AU - Valente, Enza Maria

AU - Petrucci, Simona

AU - Annesi, Grazia

AU - Quattrone, Aldo

AU - Ferrarese, Carlo

AU - Brighina, Laura

AU - Deutschländer, Angela

AU - Puschmann, Andreas

AU - Nilsson, Christer

AU - Garraux, Gaëtan

AU - LeDoux, Mark S

AU - Pfeiffer, Ronald F

AU - Boczarska-Jedynak, Magdalena

AU - Opala, Grzegorz

AU - Maraganore, Demetrius M

AU - Engelborghs, Sebastiaan

AU - De Deyn, Peter Paul

AU - Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium

AU - Morrison, Karen

PY - 2014/11/18

Y1 - 2014/11/18

N2 - OBJECTIVES: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort.METHODS: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia.RESULTS: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low.CONCLUSIONS: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.

AB - OBJECTIVES: The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort.METHODS: C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia.RESULTS: A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low.CONCLUSIONS: Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.

KW - Cohort Studies

KW - DNA Repeat Expansion

KW - Female

KW - Humans

KW - Internationality

KW - Male

KW - Middle Aged

KW - Parkinson Disease

KW - Proteins

U2 - 10.1212/WNL.0000000000001012

DO - 10.1212/WNL.0000000000001012

M3 - Article

C2 - 25326098

SN - 0028-3878

VL - 83

SP - 1906

EP - 1913

JO - Neurology

JF - Neurology

IS - 21

ER -

Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease

Abstract

Bibliographical note

Keywords

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Cite this