Heritability and genetic variance of dementia with Lewy bodies
Rita Guerreiro
(1)
,
Valentina Escott-Price
(2)
,
Dena Hernandez
(3)
,
Celia Kun-Rodrigues
(1)
,
Owen Ross
(4)
,
Tatiana Orme
(1)
,
Joao Luis Neto
(1)
,
Susana Carmona
(1)
,
Nadia Dehghani
(1)
,
John Eicher
(1, 5)
,
Claire Shepherd
(6)
,
Laura Parkkinen
(7)
,
Lee Darwent
(2)
,
Michael Heckman
(4)
,
Sonja Scholz
(8, 9)
,
Juan Troncoso
(9)
,
Olga Pletnikova
(9)
,
Ted Dawson
(9)
,
Liana Rosenthal
(9)
,
Olaf Ansorge
(7)
,
Jordi Clarimon
(10, 11)
,
Alberto Lleo
(10, 11)
,
Estrella Morenas-Rodriguez
(10, 11, 12)
,
Lorraine Clark
(13)
,
Lawrence Honig
(13)
,
Karen Marder
(13)
,
Afina Lemstra
(14)
,
Ekaterina Rogaeva
(15, 16)
,
Peter St George-Hyslop
(15, 16, 17)
,
Elisabet Londos
(18)
,
Henrik Zetterberg
(2, 19)
,
Imelda Barber
(20)
,
Anne Braae
(20)
,
Kristelle Brown
(20)
,
Kevin Morgan
(20)
,
Claire Troakes
(21)
,
Safa Al-Sarraj
(21)
,
Tammaryn Lashley
(22)
,
Janice Holton
(22)
,
Yaroslau Compta
(22, 23)
,
Vivianna van Deerlin
(24)
,
Geidy Serrano
,
Thomas Beach
,
Suzanne Lesage
(25)
,
Douglas Galasko
,
Eliezer Masliah
,
Isabel Santana
,
Pau Pastor
,
Monica Diez-Fairen
,
Miquel Aguilar
,
Pentti Tienari
,
Liisa Myllykangas
,
Minna Oinas
,
Tamas Revesz
,
Andrew Lees
,
Brad Boeve
,
Ronald Petersen
,
Tanis Ferman
,
Neill Graff-Radford
,
Nigel Cairns
,
John Morris
,
Stuart Pickering-Brown
,
David Mann
,
Glenda Halliday
,
John Hardy
,
John Trojanowski
(24)
,
Dennis Dickson
,
Andrew Singleton
,
David Stone
,
Jose Bras
,
Peter St. George-Hyslop
1
UCL Institute of Neurology, Queen Square [London]
2 UK DRI - UK Dementia Research Institute
3 NIA - National Institute on Aging [Bethesda, USA]
4 Mayo Clinic [Jacksonville]
5 Merck Research Laboratories
6 UNSW - University of New South Wales [Sydney]
7 Nuffield Department of Clinical Neurosciences [Oxford]
8 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
9 Johns Hopkins University School of Medicine [Baltimore]
10 Hospital de la Santa Creu i Sant Pau
11 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
12 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
13 Columbia University [New York]
14 VU University Medical Center [Amsterdam]
15 Tanz Center Research in Neurodegenerative Diseases [Toronto]
16 University of Toronto
17 CIMR - Cambridge Institute for Medical Research
18 Lund University
19 Sahlgrenska Academy at University of Gothenburg [Göteborg]
20 UON - University of Nottingham, UK
21 King‘s College London
22 UCL Queen Square Institute of Neurology
23 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
24 Perelman School of Medicine
25 ICM - Institut du Cerveau = Paris Brain Institute
2 UK DRI - UK Dementia Research Institute
3 NIA - National Institute on Aging [Bethesda, USA]
4 Mayo Clinic [Jacksonville]
5 Merck Research Laboratories
6 UNSW - University of New South Wales [Sydney]
7 Nuffield Department of Clinical Neurosciences [Oxford]
8 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
9 Johns Hopkins University School of Medicine [Baltimore]
10 Hospital de la Santa Creu i Sant Pau
11 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
12 CIBERNED - Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas
13 Columbia University [New York]
14 VU University Medical Center [Amsterdam]
15 Tanz Center Research in Neurodegenerative Diseases [Toronto]
16 University of Toronto
17 CIMR - Cambridge Institute for Medical Research
18 Lund University
19 Sahlgrenska Academy at University of Gothenburg [Göteborg]
20 UON - University of Nottingham, UK
21 King‘s College London
22 UCL Queen Square Institute of Neurology
23 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
24 Perelman School of Medicine
25 ICM - Institut du Cerveau = Paris Brain Institute
Valentina Escott-Price
- Function : Author
- PersonId : 1305604
- ORCID : 0000-0003-1784-5483
Geidy Serrano
- Function : Author
Thomas Beach
- Function : Author
Douglas Galasko
- Function : Author
Eliezer Masliah
- Function : Author
Isabel Santana
- Function : Author
Pau Pastor
- Function : Author
- PersonId : 1377660
- ORCID : 0000-0002-2573-6378
Monica Diez-Fairen
- Function : Author
Miquel Aguilar
- Function : Author
Pentti Tienari
- Function : Author
Liisa Myllykangas
- Function : Author
Minna Oinas
- Function : Author
Tamas Revesz
- Function : Author
Andrew Lees
- Function : Author
Brad Boeve
- Function : Author
Ronald Petersen
- Function : Author
Tanis Ferman
- Function : Author
Neill Graff-Radford
- Function : Author
Nigel Cairns
- Function : Author
John Morris
- Function : Author
Stuart Pickering-Brown
- Function : Author
David Mann
- Function : Author
Glenda Halliday
- Function : Author
John Hardy
- Function : Author
Dennis Dickson
- Function : Author
Andrew Singleton
- Function : Author
David Stone
- Function : Author
Jose Bras
- Function : Author
- PersonId : 1359609
- ORCID : 0000-0001-8186-0333
Peter St. George-Hyslop
- Function : Author
Abstract
Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.