Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study
Rita Guerreiro
(1, 2, 3)
,
Owen Ross
(4)
,
Celia Kun-Rodrigues
(2)
,
Dena Hernandez
(5, 6)
,
Tatiana Orme
(2)
,
John Eicher
,
Claire Shepherd
(7, 8)
,
Laura Parkkinen
(9)
,
Lee Darwent
(2)
,
Michael Heckman
(4)
,
Sonja Scholz
(10)
,
Juan Troncoso
(11)
,
Olga Pletnikova
(11)
,
Olaf Ansorge
(9)
,
Jordi Clarimon
(12, 13)
,
Alberto Lleo
(12, 13)
,
Estrella Morenas-Rodriguez
(12, 13)
,
Lorraine Clark
(14)
,
Lawrence Honig
(14)
,
Karen Marder
(14)
,
Afina Lemstra
(15)
,
Ekaterina Rogaeva
(16)
,
Peter St George-Hyslop
(16, 17, 18)
,
Elisabet Londos
(19)
,
Henrik Zetterberg
(1, 2, 20)
,
Imelda Barber
(21)
,
Anne Braae
(21)
,
Kristelle Brown
(21)
,
Kevin Morgan
(21)
,
Claire Troakes
(22)
,
Safa Al-Sarraj
(22)
,
Tammaryn Lashley
(22)
,
Janice Holton
(22)
,
Yaroslau Compta
(2, 23)
,
Vivianna van Deerlin
(24)
,
Geidy Serrano
(24)
,
Thomas Beach
,
Suzanne Lesage
(25)
,
Douglas Galasko
(26)
,
Eliezer Masliah
(5)
,
Isabel Santana
,
Pau Pastor
(13)
,
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 Stone
,
Jose Bras
(1, 2, 3)
1
UK DRI -
UK Dementia Research Institute
2 UCL Queen Square Institute of Neurology
3 CIDMA - University of Aveiro
4 Mayo Clinic [Jacksonville]
5 NIA - National Institute on Aging [Bethesda, USA]
6 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
7 NeuRA - Neuroscience Research Australia
8 UNSW - University of New South Wales [Sydney]
9 Nuffield Department of Clinical Neurosciences [Oxford]
10 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
11 Johns Hopkins University School of Medicine [Baltimore]
12 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
13 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
14 CUMC - Columbia University Medical Center
15 VU University Medical Center [Amsterdam]
16 Tanz Center Research in Neurodegenerative Diseases [Toronto]
17 University of Toronto
18 CIMR - Cambridge Institute for Medical Research
19 Lund University
20 Sahlgrenska Academy at University of Gothenburg [Göteborg]
21 UON - University of Nottingham, UK
22 King‘s College London
23 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
24 Perelman School of Medicine
25 ICM - Institut du Cerveau = Paris Brain Institute
26 UC San Diego - University of California [San Diego]
2 UCL Queen Square Institute of Neurology
3 CIDMA - University of Aveiro
4 Mayo Clinic [Jacksonville]
5 NIA - National Institute on Aging [Bethesda, USA]
6 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
7 NeuRA - Neuroscience Research Australia
8 UNSW - University of New South Wales [Sydney]
9 Nuffield Department of Clinical Neurosciences [Oxford]
10 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
11 Johns Hopkins University School of Medicine [Baltimore]
12 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
13 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
14 CUMC - Columbia University Medical Center
15 VU University Medical Center [Amsterdam]
16 Tanz Center Research in Neurodegenerative Diseases [Toronto]
17 University of Toronto
18 CIMR - Cambridge Institute for Medical Research
19 Lund University
20 Sahlgrenska Academy at University of Gothenburg [Göteborg]
21 UON - University of Nottingham, UK
22 King‘s College London
23 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
24 Perelman School of Medicine
25 ICM - Institut du Cerveau = Paris Brain Institute
26 UC San Diego - University of California [San Diego]
John Eicher
- Function : Author
Thomas Beach
- Function : Author
Isabel Santana
- Function : Author
Monica Diez-Fairen
- Function : Author
Miquel Aguilar
- Function : Author
Pentti J Tienari
- Function : Author
Liisa Myllykangas
- Function : Author
Minna Oinas
- Function : Author
Tamas Revesz
- Function : Author
Andrew Lees
- Function : Author
Brad F Boeve
- Function : Author
Ronald C Petersen
- Function : Author
Tanis J Ferman
- Function : Author
Valentina Escott-Price
- Function : Author
Neill Graff-Radford
- Function : Author
Nigel J Cairns
- Function : Author
John C Morris
- Function : Author
Stuart Pickering-Brown
- Function : Author
David Mann
- Function : Author
Glenda M Halliday
- Function : Author
John Hardy
- Function : Author
John Q Trojanowski
- Function : Author
Dennis W Dickson
- Function : Author
Andrew Singleton
- Function : Author
David Stone
- Function : Author
Abstract
Background: Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder.
Methods: In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage.
Findings: This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14-2·70; p=1·05 × 10-48), SNCA (rs7681440; OR 0·73, 0·66-0·81; p=6·39 × 10-10), an GBA (rs35749011; OR 2·55, 1·88-3·46; p=1·78 × 10-9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27-1·79; p=2·32 × 10-6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%.
Interpretation: Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.