A comprehensive screening of copy number variability in dementia with Lewy bodies

Celia Kun-Rodrigues; Tatiana Orme; Susana Carmona; Dena G. Hernandez; Owen A. Ross; John D. Eicher; Claire Shepherd; Laura Parkkinen; Lee Darwent; Michael G. Heckman; Sonja W. Scholz; Juan C. Troncoso; Olga Pletnikova; Ted Dawson; Liana Rosenthal; Olaf Ansorge; Jordi Clarimon; Alberto Lleo; Estrella Morenas-Rodriguez; Lorraine Clark; Lawrence S. Honig; Karen Marder; Afina Lemstra; Ekaterina Rogaeva; Peter St. George-Hyslop; Elisabet Londos; Henrik Zetterberg; Imelda Barber; Anne Braae; Kristelle Brown; Kevin Morgan; Claire Troakes; Safa Al-Sarraj; Tammaryn Lashley; Janice Holton; Yaroslau Compta; Vivianna Van Deerlin; Geidy E. Serrano; Thomas G. Beach; Suzanne Lesage; Douglas Galasko; Eliezer Masliah; Isabel Santana; Pau Pastor; Monica Diez-Fairen; Miquel Aguilar; Pentti J. Tienari; Liisa Myllykangas; Minna Oinas; Tamas Revesz; Andrew Lees; Brad F. Boeve; Ronald C. Petersen; Tanis J. Ferman; Valentina Escott-Price; Neill Graff-Radford; Nigel J. Cairns; John C. Morris; Stuart Pickering-Brown; David Mann; Glenda M. Halliday; John Hardy; John Q. Trojanowski; Dennis W. Dickson; Andrew Singleton; David J. Stone; Rita Guerreiro; Jose Bras

doi:10.1016/j.neurobiolaging.2018.10.019

A comprehensive screening of copy number variability in dementia with Lewy bodies

Celia Kun-Rodrigues, Tatiana Orme, Susana Carmona, Dena G. Hernandez, Owen A. Ross, John D. Eicher, Claire Shepherd, Laura Parkkinen, Lee Darwent, Michael G. Heckman, Sonja W. Scholz, Juan C. Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Lorraine ClarkLawrence S. Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St. George-Hyslop, Elisabet Londos, Henrik Zetterberg, Imelda Barber, Anne Braae, Kristelle Brown, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, Geidy E. Serrano, Thomas G. Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F. Boeve, Ronald C. Petersen, Tanis J. Ferman, Valentina Escott-Price, Neill Graff-Radford, Nigel J. Cairns, John C. Morris, Stuart Pickering-Brown, David Mann, Glenda M. Halliday, John Hardy, John Q. Trojanowski, Dennis W. Dickson, Andrew Singleton, David J. Stone, Rita Guerreiro, Jose Bras

School of Medicine

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

10 Scopus citations

Abstract

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.

Original language	English (US)
Pages (from-to)	223.e1-223.e10
Journal	Neurobiology of aging
Volume	75
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.10.019
State	Published - Mar 2019

Keywords

Copy number variants
Dementia with Lewy bodies
Genome-wide
MAPT
SNCA

ASJC Scopus subject areas

General Neuroscience
Aging
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

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10.1016/j.neurobiolaging.2018.10.019

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Kun-Rodrigues, C., Orme, T., Carmona, S., Hernandez, D. G., Ross, O. A., Eicher, J. D., Shepherd, C., Parkkinen, L., Darwent, L., Heckman, M. G., Scholz, S. W., Troncoso, J. C., Pletnikova, O., Dawson, T., Rosenthal, L., Ansorge, O., Clarimon, J., Lleo, A., Morenas-Rodriguez, E., ... Bras, J. (2019). A comprehensive screening of copy number variability in dementia with Lewy bodies. Neurobiology of aging, 75, 223.e1-223.e10. https://doi.org/10.1016/j.neurobiolaging.2018.10.019

Kun-Rodrigues, C, Orme, T, Carmona, S, Hernandez, DG, Ross, OA, Eicher, JD, Shepherd, C, Parkkinen, L, Darwent, L, Heckman, MG, Scholz, SW, Troncoso, JC, Pletnikova, O, Dawson, T , Rosenthal, L, Ansorge, O, Clarimon, J, Lleo, A, Morenas-Rodriguez, E, Clark, L, Honig, LS, Marder, K, Lemstra, A, Rogaeva, E, St. George-Hyslop, P, Londos, E, Zetterberg, H, Barber, I, Braae, A, Brown, K, Morgan, K, Troakes, C, Al-Sarraj, S, Lashley, T, Holton, J, Compta, Y, Van Deerlin, V, Serrano, GE, Beach, TG, Lesage, S, Galasko, D, Masliah, E, Santana, I, Pastor, P, Diez-Fairen, M, Aguilar, M, Tienari, PJ, Myllykangas, L, Oinas, M, Revesz, T, Lees, A, Boeve, BF, Petersen, RC, Ferman, TJ, Escott-Price, V, Graff-Radford, N, Cairns, NJ, Morris, JC, Pickering-Brown, S, Mann, D, Halliday, GM, Hardy, J, Trojanowski, JQ, Dickson, DW, Singleton, A, Stone, DJ, Guerreiro, R & Bras, J 2019, 'A comprehensive screening of copy number variability in dementia with Lewy bodies', Neurobiology of aging, vol. 75, pp. 223.e1-223.e10. https://doi.org/10.1016/j.neurobiolaging.2018.10.019

@article{64cfd7dbf3564362a9a3f3c491495ab2,

title = "A comprehensive screening of copy number variability in dementia with Lewy bodies",

abstract = "The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.",

keywords = "Copy number variants, Dementia with Lewy bodies, Genome-wide, MAPT, SNCA",

author = "Celia Kun-Rodrigues and Tatiana Orme and Susana Carmona and Hernandez, {Dena G.} and Ross, {Owen A.} and Eicher, {John D.} and Claire Shepherd and Laura Parkkinen and Lee Darwent and Heckman, {Michael G.} and Scholz, {Sonja W.} and Troncoso, {Juan C.} and Olga Pletnikova and Ted Dawson and Liana Rosenthal and Olaf Ansorge and Jordi Clarimon and Alberto Lleo and Estrella Morenas-Rodriguez and Lorraine Clark and Honig, {Lawrence S.} and Karen Marder and Afina Lemstra and Ekaterina Rogaeva and {St. George-Hyslop}, Peter and Elisabet Londos and Henrik Zetterberg and Imelda Barber and Anne Braae and Kristelle Brown and Kevin Morgan and Claire Troakes and Safa Al-Sarraj and Tammaryn Lashley and Janice Holton and Yaroslau Compta and {Van Deerlin}, Vivianna and Serrano, {Geidy E.} and Beach, {Thomas G.} and Suzanne Lesage and Douglas Galasko and Eliezer Masliah and Isabel Santana and Pau Pastor and Monica Diez-Fairen and Miquel Aguilar and Tienari, {Pentti J.} and Liisa Myllykangas and Minna Oinas and Tamas Revesz and Andrew Lees and Boeve, {Brad F.} and Petersen, {Ronald C.} and Ferman, {Tanis J.} and Valentina Escott-Price and Neill Graff-Radford and Cairns, {Nigel J.} and Morris, {John C.} and Stuart Pickering-Brown and David Mann and Halliday, {Glenda M.} and John Hardy and Trojanowski, {John Q.} and Dickson, {Dennis W.} and Andrew Singleton and Stone, {David J.} and Rita Guerreiro and Jose Bras",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = mar,

doi = "10.1016/j.neurobiolaging.2018.10.019",

language = "English (US)",

volume = "75",

pages = "223.e1--223.e10",

journal = "Neurobiology of aging",

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AU - Kun-Rodrigues, Celia

AU - Orme, Tatiana

AU - Carmona, Susana

AU - Hernandez, Dena G.

AU - Ross, Owen A.

AU - Eicher, John D.

AU - Shepherd, Claire

AU - Parkkinen, Laura

AU - Darwent, Lee

AU - Heckman, Michael G.

AU - Scholz, Sonja W.

AU - Troncoso, Juan C.

AU - Pletnikova, Olga

AU - Dawson, Ted

AU - Rosenthal, Liana

AU - Ansorge, Olaf

AU - Clarimon, Jordi

AU - Lleo, Alberto

AU - Morenas-Rodriguez, Estrella

AU - Clark, Lorraine

AU - Honig, Lawrence S.

AU - Marder, Karen

AU - Lemstra, Afina

AU - Rogaeva, Ekaterina

AU - St. George-Hyslop, Peter

AU - Londos, Elisabet

AU - Zetterberg, Henrik

AU - Barber, Imelda

AU - Braae, Anne

AU - Brown, Kristelle

AU - Morgan, Kevin

AU - Troakes, Claire

AU - Al-Sarraj, Safa

AU - Lashley, Tammaryn

AU - Holton, Janice

AU - Compta, Yaroslau

AU - Van Deerlin, Vivianna

AU - Serrano, Geidy E.

AU - Beach, Thomas G.

AU - Lesage, Suzanne

AU - Galasko, Douglas

AU - Masliah, Eliezer

AU - Santana, Isabel

AU - Pastor, Pau

AU - Diez-Fairen, Monica

AU - Aguilar, Miquel

AU - Tienari, Pentti J.

AU - Myllykangas, Liisa

AU - Oinas, Minna

AU - Revesz, Tamas

AU - Lees, Andrew

AU - Boeve, Brad F.

AU - Petersen, Ronald C.

AU - Ferman, Tanis J.

AU - Escott-Price, Valentina

AU - Graff-Radford, Neill

AU - Cairns, Nigel J.

AU - Morris, John C.

AU - Pickering-Brown, Stuart

AU - Mann, David

AU - Halliday, Glenda M.

AU - Hardy, John

AU - Trojanowski, John Q.

AU - Dickson, Dennis W.

AU - Singleton, Andrew

AU - Stone, David J.

AU - Guerreiro, Rita

AU - Bras, Jose

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N2 - The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.

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KW - Dementia with Lewy bodies

KW - Genome-wide

KW - MAPT

KW - SNCA

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SN - 0197-4580

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JO - Neurobiology of aging

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ER -

A comprehensive screening of copy number variability in dementia with Lewy bodies

Abstract

Keywords

ASJC Scopus subject areas

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