Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

Jose Bras; Rita Guerreiro; Lee Darwent; Laura Parkkinen; Olaf Ansorge; Valentina Escott-Price; Dena G. Hernandez; Michael A. Nalls; Lorraine N. Clark; Lawrence S. Honig; Karen Marder; Wiesje M. Van Der Flier; Afina Lemstra; Philip Scheltens; Ekaterina Rogaeva; Peter St George-Hyslop; Elisabet Londos; Henrik Zetterberg; Sara Ortega-Cubero; Pau Pastor; Tanis J. Ferman; Neill R. Graff-Radford; Owen A. Ross; Imelda Barber; Anne Braae; Kristelle Brown; Kevin Morgan; Walter Maetzler; Daniela Berg; Claire Troakes; Safa Al-Sarraj; Tammaryn Lashley; Yaroslau Compta; Tamas Revesz; Andrew Lees; Nigel Cairns; Glenda M. Halliday; David Mann; Stuart Pickering-Brown; Dennis W. Dickson; Andrew Singleton; John Hardy

doi:10.1093/hmg/ddu334

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

Jose Bras, Rita Guerreiro, Lee Darwent, Laura Parkkinen, Olaf Ansorge, Valentina Escott-Price, Dena G. Hernandez, Michael A. Nalls, Lorraine N. Clark, Lawrence S. Honig, Karen Marder, Wiesje M. Van Der Flier, Afina Lemstra, Philip Scheltens, Ekaterina Rogaeva, Peter St George-Hyslop, Elisabet Londos, Henrik Zetterberg, Sara Ortega-Cubero, Pau PastorTanis J. Ferman, Neill R. Graff-Radford, Owen A. Ross, Imelda Barber, Anne Braae, Kristelle Brown, Kevin Morgan, Walter Maetzler, Daniela Berg, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Yaroslau Compta, Tamas Revesz, Andrew Lees, Nigel Cairns, Glenda M. Halliday, David Mann, Stuart Pickering-Brown, Dennis W. Dickson, Andrew Singleton, John Hardy

Basic and Clinical Neuroscience

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

171 Citations (Scopus)

Abstract

Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

Original language	English
Pages (from-to)	6139-6146
Number of pages	8
Journal	Human Molecular Genetics
Volume	23
Issue number	23
DOIs	https://doi.org/10.1093/hmg/ddu334
Publication status	Published - 1 Dec 2014

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Bras, J., Guerreiro, R., Darwent, L., Parkkinen, L., Ansorge, O., Escott-Price, V., Hernandez, D. G., Nalls, M. A., Clark, L. N., Honig, L. S., Marder, K., Van Der Flier, W. M., Lemstra, A., Scheltens, P., Rogaeva, E., St George-Hyslop, P., Londos, E., Zetterberg, H., Ortega-Cubero, S., ... Hardy, J. (2014). Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Human Molecular Genetics, 23(23), 6139-6146. https://doi.org/10.1093/hmg/ddu334

@article{1899879cdfd342f6a09182ab79002489,

title = "Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies",

abstract = "Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available. ",

author = "Jose Bras and Rita Guerreiro and Lee Darwent and Laura Parkkinen and Olaf Ansorge and Valentina Escott-Price and Hernandez, {Dena G.} and Nalls, {Michael A.} and Clark, {Lorraine N.} and Honig, {Lawrence S.} and Karen Marder and {Van Der Flier}, {Wiesje M.} and Afina Lemstra and Philip Scheltens and Ekaterina Rogaeva and {St George-Hyslop}, Peter and Elisabet Londos and Henrik Zetterberg and Sara Ortega-Cubero and Pau Pastor and Ferman, {Tanis J.} and Graff-Radford, {Neill R.} and Ross, {Owen A.} and Imelda Barber and Anne Braae and Kristelle Brown and Kevin Morgan and Walter Maetzler and Daniela Berg and Claire Troakes and Safa Al-Sarraj and Tammaryn Lashley and Yaroslau Compta and Tamas Revesz and Andrew Lees and Nigel Cairns and Halliday, {Glenda M.} and David Mann and Stuart Pickering-Brown and Dickson, {Dennis W.} and Andrew Singleton and John Hardy",

year = "2014",

month = dec,

day = "1",

doi = "10.1093/hmg/ddu334",

language = "English",

volume = "23",

pages = "6139--6146",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "23",

}

Bras, J, Guerreiro, R, Darwent, L, Parkkinen, L, Ansorge, O, Escott-Price, V, Hernandez, DG, Nalls, MA, Clark, LN, Honig, LS, Marder, K, Van Der Flier, WM, Lemstra, A, Scheltens, P, Rogaeva, E, St George-Hyslop, P, Londos, E, Zetterberg, H, Ortega-Cubero, S, Pastor, P, Ferman, TJ, Graff-Radford, NR, Ross, OA, Barber, I, Braae, A, Brown, K, Morgan, K, Maetzler, W, Berg, D, Troakes, C , Al-Sarraj, S, Lashley, T, Compta, Y, Revesz, T, Lees, A, Cairns, N, Halliday, GM, Mann, D, Pickering-Brown, S, Dickson, DW, Singleton, A & Hardy, J 2014, 'Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies', Human Molecular Genetics, vol. 23, no. 23, pp. 6139-6146. https://doi.org/10.1093/hmg/ddu334

TY - JOUR

T1 - Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

AU - Bras, Jose

AU - Guerreiro, Rita

AU - Darwent, Lee

AU - Parkkinen, Laura

AU - Ansorge, Olaf

AU - Escott-Price, Valentina

AU - Hernandez, Dena G.

AU - Nalls, Michael A.

AU - Clark, Lorraine N.

AU - Honig, Lawrence S.

AU - Marder, Karen

AU - Van Der Flier, Wiesje M.

AU - Lemstra, Afina

AU - Scheltens, Philip

AU - Rogaeva, Ekaterina

AU - St George-Hyslop, Peter

AU - Londos, Elisabet

AU - Zetterberg, Henrik

AU - Ortega-Cubero, Sara

AU - Pastor, Pau

AU - Ferman, Tanis J.

AU - Graff-Radford, Neill R.

AU - Ross, Owen A.

AU - Barber, Imelda

AU - Braae, Anne

AU - Brown, Kristelle

AU - Morgan, Kevin

AU - Maetzler, Walter

AU - Berg, Daniela

AU - Troakes, Claire

AU - Al-Sarraj, Safa

AU - Lashley, Tammaryn

AU - Compta, Yaroslau

AU - Revesz, Tamas

AU - Lees, Andrew

AU - Cairns, Nigel

AU - Halliday, Glenda M.

AU - Mann, David

AU - Pickering-Brown, Stuart

AU - Dickson, Dennis W.

AU - Singleton, Andrew

AU - Hardy, John

PY - 2014/12/1

Y1 - 2014/12/1

N2 - Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

AB - Clinical and neuropathological similarities between dementia with Lewy bodies (DLB), Parkinson's and Alzheimer's diseases (PD and AD, respectively) suggest that these disorders may share etiology. To test this hypothesis, we have performed an association study of 54 genomic regions, previously implicated in PD or AD, in a large cohort of DLB cases and controls. The cohort comprised 788 DLB cases and 2624 controls. To minimize the issue of potential misdiagnosis, we have also performed the analysis including only neuropathologically proven DLB cases (667 cases). The results show that the APOE is a strong genetic risk factor for DLB, confirming previous findings, and that the SNCA and SCARB2 loci are also associated after a study-wise Bonferroni correction, although these have a different association profile than the associations reported for the same loci in PD. We have previously shown that the p.N370S variant in GBA is associated with DLB, which, together with the findings at the SCARB2 locus, suggests a role for lysosomal dysfunction in this disease. These results indicate that DLB has a unique genetic risk profile when compared with the two most common neurodegenerative diseases and that the lysosome may play an important role in the etiology of this disorder. We make all these data available.

UR - http://www.scopus.com/inward/record.url?scp=84908296281&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddu334

DO - 10.1093/hmg/ddu334

M3 - Article

C2 - 24973356

AN - SCOPUS:84908296281

SN - 0964-6906

VL - 23

SP - 6139

EP - 6146

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 23

ER -

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

Abstract

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