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Heritability and genetic variance of dementia with Lewy bodies

Guerreiro, Rita; Escott-Price, Valentina; Hernandez, Dena; Kun-Rodrigues, Celia; Ross, Owen; Orme, Tatiana; Neto, Joao Luis; Carmona, Susana; Dehghani, Nadia; Eicher, John D; Shepherd, Claire; Parkkinen, Laura; Darwent, Lee; Heckman, Michael G; Scholz, Sonja; Troncoso, Juan; Pletnikova, Olga; Dawson, Ted; Rosenthal, Liana; Ansorge, Olaf; Clarimon, Jordi; Lleo, Alberto; Morenas-Rodriguez, Estrella; Clark, Lorraine; Honig, Lawrence; Marder, Karen; Lemstra, Afina; Rogaeva, Ekaterina; St. George-Hyslop, Peter; Londos, Elisabet; Zetterberg, Henrik; Barber, Imelda; Braae, Anne; Brown, Kristelle; Morgan, Kevin; Troakes, Claire; Al-Sarraj, Safa; Lashley, Tammaryn; Holton, Janice; Compta, Yaroslau; Van Deerlin, Vivianna; Serrano, Geidy; Beach, Thomas; Lesage, Suzanne; Galasko, Douglas; Masliah, Eliezer; Santana, Isabel; Pastor, Pau; Diez-Fairen, Monica; Aguilar, Miquel; Tienari, Pentti; Myllykangas, Liisa; Oinas, Minna; Revesz, Tamas; Lees, Andrew; Boeve, Brad; Petersen, Ronald; Ferman, Tanis; Graff-Radford, Neill; Cairns, Nigel; Morris, John; Pickering-Brown, Stuart; Mann, David; Halliday, Glenda; Hardy, John; Trojanowski, John Q; Dickson, Dennis; Singleton, Andrew; Stone, David; Bras, Jose

Authors

Rita Guerreiro

Valentina Escott-Price

Dena Hernandez

Celia Kun-Rodrigues

Owen Ross

Tatiana Orme

Joao Luis Neto

Susana Carmona

Nadia Dehghani

John D Eicher

Claire Shepherd

Laura Parkkinen

Lee Darwent

Michael G Heckman

Sonja Scholz

Juan Troncoso

Olga Pletnikova

Ted Dawson

Liana Rosenthal

Olaf Ansorge

Jordi Clarimon

Alberto Lleo

Estrella Morenas-Rodriguez

Lorraine Clark

Lawrence Honig

Karen Marder

Afina Lemstra

Ekaterina Rogaeva

Peter St. George-Hyslop

Elisabet Londos

Henrik Zetterberg

Imelda Barber

Anne Braae

KEVIN MORGAN kevin.morgan@nottingham.ac.uk
Professor of Human Genomics and Molecular Genetics

Claire Troakes

Safa Al-Sarraj

Tammaryn Lashley

Janice Holton

Yaroslau Compta

Vivianna Van Deerlin

Geidy Serrano

Thomas Beach

Suzanne Lesage

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 Q Trojanowski

Dennis Dickson

Andrew Singleton

David Stone

Jose Bras



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.

Journal Article Type Article
Publication Date Jul 31, 2019
Journal Neurobiology of Disease
Print ISSN 0969-9961
Electronic ISSN 1095-953X
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 127
Pages 492-501
APA6 Citation Guerreiro, R., Escott-Price, V., Hernandez, D., Kun-Rodrigues, C., Ross, O., Orme, T., …Bras, J. (2019). Heritability and genetic variance of dementia with Lewy bodies. Neurobiology of Disease, 127, 492-501. https://doi.org/10.1016/j.nbd.2019.04.004
DOI https://doi.org/10.1016/j.nbd.2019.04.004
Publisher URL https://www.sciencedirect.com/science/article/pii/S0969996119300956

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