Abstract

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 × 10−8). One additional genetic locus previously linked to psychosis in Alzheimer’s disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 × 10−6. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

Details

Title
GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study
Author
Rongve Arvid 1   VIAFID ORCID Logo  ; Witoelar Aree 2 ; Ruiz, Agustín 3 ; Athanasiu Lavinia 2 ; Abdelnour Carla 3 ; Clarimon Jordi 4 ; Heilmann-Heimbach Stefanie 5 ; Hernández, Isabel 3 ; Moreno-Grau, Sonia 3 ; de Rojas Itziar 3 ; Morenas-Rodríguez Estrella 4 ; Fladby Tormod 6 ; Sando, Sigrid B 7 ; Bråthen Geir 8   VIAFID ORCID Logo  ; Blanc Frédéric 9 ; Bousiges Olivier 10 ; Lemstra, Afina W 11 ; Inger, van Steenoven 11 ; Londos Elisabet 12 ; Almdahl, Ina S 13   VIAFID ORCID Logo  ; Pålhaugen Lene 6 ; Eriksen, Jon A 2 ; Djurovic Srdjan 14   VIAFID ORCID Logo  ; Stordal Eystein 15   VIAFID ORCID Logo  ; Saltvedt Ingvild 16 ; Ulstein, Ingun D 17 ; Bettella Francesco 18   VIAFID ORCID Logo  ; Desikan, Rahul S 19 ; Ane-Victoria, Idland 20 ; Toft Mathias 21   VIAFID ORCID Logo  ; Pihlstrøm Lasse 22   VIAFID ORCID Logo  ; Snaedal Jon 23 ; Tárraga Lluís 3 ; Boada Mercè 3 ; Lleó Alberto 4 ; Hreinn, Stefánsson 24   VIAFID ORCID Logo  ; Stefánsson Kári 24   VIAFID ORCID Logo  ; Ramírez, Alfredo 25   VIAFID ORCID Logo  ; Aarsland Dag 26 ; Andreassen, Ole A 2 

1  Haugesund Hospital, Helse Fonna, Department of Research and Innovation, Haugesund, Norway (GRID:grid.413782.b); The University of Bergen, Department of Clinical Medicine (K1), Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443) 
2  NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, Institute of Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
3  Universitat Internacional de Catalunya (UIC), Memory Clinic and Research Center of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain (GRID:grid.410675.1) (ISNI:0000 0001 2325 3084) 
4  Universitat Autònoma de Barcelona, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (GRID:grid.7080.f); Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid and Barcelona, Spain (GRID:grid.7080.f) 
5  University of Bonn, Institute of Human Genetics, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300); University of Bonn, Department of Genomics, Life & Brain Center, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300) 
6  Akershus University Hospital, Department of Neurology, Lørenskog, Norway (GRID:grid.411279.8) (ISNI:0000 0000 9637 455X); University of Oslo, AHUS Campus, Oslo, Norway (GRID:grid.411279.8) 
7  Norwegian University of Science and Technology, Department of Neuromedicine and Movement Science, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393) 
8  St Olav’s Hospital, Department of Neurology, Trondheim, Norway (GRID:grid.52522.32) (ISNI:0000 0004 0627 3560) 
9  University Hospital of Strasbourg, CMRR (Memory Resources and Research Centre), Geriatrics Department, Strasbourg, France (GRID:grid.412220.7) (ISNI:0000 0001 2177 138X); University of Strasbourg and CNRS, ICube laboratory and FMTS, team IMIS/Neurocrypto, Strasbourg, France (GRID:grid.11843.3f) (ISNI:0000 0001 2157 9291) 
10  University Hospital of Strasbourg, CMRR (Memory Resources and Research Centre), Laboratory of Biochemistry and Molecular Biology, Strasbourg, France (GRID:grid.412220.7) (ISNI:0000 0001 2177 138X) 
11  University of Strasbourg and CNRS, Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), UMR7364, Strasbourg, France (GRID:grid.463959.4) (ISNI:0000 0004 0367 7674); Alzheimercenter & Department of Neurology VU University Medical Center, Amsterdam, the Netherlands (GRID:grid.16872.3a) (ISNI:0000 0004 0435 165X) 
12  Lund University, Skane University Hospital, Institute of Clinical Sciences, Malmö, Sweden (GRID:grid.16872.3a) 
13  University of Oslo, AHUS Campus, Oslo, Norway (GRID:grid.16872.3a); Oslo University Hospital, Department of Geriatric Psychiatry, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
14  Oslo University Hospital, Department of Medical Genetics, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Bergen, NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443) 
15  Namsos Hospital, Department of Psychiatry, Namsos, Norway (GRID:grid.461096.c) (ISNI:0000 0004 0627 3042); Norwegian University of Science and Technology, Department of Mental Health, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393) 
16  Norwegian University of Science and Technology, Department of Neuromedicine and Movement Science, Trondheim, Norway (GRID:grid.5947.f) (ISNI:0000 0001 1516 2393); St. Olav’s Hospital, Department of Geriatrics, Trondheim, Norway (GRID:grid.52522.32) (ISNI:0000 0004 0627 3560) 
17  University of Oslo, Institute of Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Oslo University Hospital, Department of Geriatric Psychiatry, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
18  NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
19  Neurology and Pediatrics, UCSF, Departments of Radiology and Biomedical Imaging, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
20  University of Oslo, Oslo Delirium Research Group, Department of Geriatric Medicine, Institute of Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); University of Oslo, Research Group for Lifespan Changes in Brain and Cognition, Department of Psychology, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); University of Oslo, Institute of Basic Medical Sciences, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
21  University of Oslo, Institute of Clinical Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Oslo University Hospital, Department of Neurology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
22  Oslo University Hospital, Department of Neurology, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
23  Landspitali University Hospital, Reykjavik, Iceland (GRID:grid.410540.4) (ISNI:0000 0000 9894 0842) 
24  DeCODE genetics, Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889) 
25  University of Cologne, Division for Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, Cologne, Germany (GRID:grid.6190.e) (ISNI:0000 0000 8580 3777); University of Bonn, Department for Neurodegenerative Diseases and Geriatric Psychiatry, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300) 
26  Psychology and Neuroscience, King’s College London, Institute of Psychiatry, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); Stavanger University Hospital, Center for Age-Related Diseases, Stavanger, Norway (GRID:grid.412835.9) (ISNI:0000 0004 0627 2891) 
Publication year
2019
Publication date
2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-43458-2
ProQuest document ID
2221219251
Copyright
© The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.