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 Jill 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

Research output: Contribution to journalArticle

104 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 languageEnglish (US)
Pages (from-to)6139-6146
Number of pages8
JournalHuman Molecular Genetics
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2014

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Lewy Body Disease
Lysosomes
Diagnostic Errors
Neurodegenerative Diseases
Parkinson Disease
Dementia
Alzheimer Disease

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bras, J., Guerreiro, R., Darwent, L., Parkkinen, L., Ansorge, O., Escott-Price, V., ... 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

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

In: Human Molecular Genetics, Vol. 23, No. 23, 01.12.2014, p. 6139-6146.

Research output: Contribution to journalArticle

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
Bras, Jose ; Guerreiro, Rita ; Darwent, Lee ; Parkkinen, Laura ; Ansorge, Olaf ; Escott-Price, Valentina ; Hernandez, Dena G. ; Nalls, Michael A. ; Clark, Lorraine N. ; Honig, Lawrence S. ; Marder, Karen ; Van Der Flier, Wiesje M. ; Lemstra, Afina ; Scheltens, Philip ; Rogaeva, Ekaterina ; St George-Hyslop, Peter ; Londos, Elisabet ; Zetterberg, Henrik ; Ortega-Cubero, Sara ; Pastor, Pau ; Ferman, Tanis Jill ; Graff Radford, Neill R ; Ross, Owen A ; Barber, Imelda ; Braae, Anne ; Brown, Kristelle ; Morgan, Kevin ; Maetzler, Walter ; Berg, Daniela ; Troakes, Claire ; Al-Sarraj, Safa ; Lashley, Tammaryn ; Compta, Yaroslau ; Revesz, Tamas ; Lees, Andrew ; Cairns, Nigel ; Halliday, Glenda M. ; Mann, David ; Pickering-Brown, Stuart ; Dickson, Dennis W ; Singleton, Andrew ; Hardy, John. / Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 23. pp. 6139-6146.
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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.",
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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 Jill

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

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