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;...

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.

Citation

Guerreiro, R., Escott-Price, V., Hernandez, D., Kun-Rodrigues, C., Ross, O., Orme, T., Neto, J. L., Carmona, S., Dehghani, N., Eicher, J. D., Shepherd, C., Parkkinen, L., Darwent, L., Heckman, M. G., Scholz, S., Troncoso, J., Pletnikova, O., Dawson, T., Rosenthal, L., Ansorge, O., …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

• Journal Article Type: Article
• Acceptance Date: Apr 3, 2019
• Online Publication Date: Apr 2, 2019
• Publication Date: Jul 31, 2019
• Deposit Date: Nov 1, 2018
• Publicly Available Date: Apr 3, 2020
• Journal: Neurobiology of Disease
• Print ISSN: 0969-9961
• Electronic ISSN: 1095-953X
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 127
• Pages: 492-501
• DOI: https://doi.org/10.1016/j.nbd.2019.04.004
• Public URL: https://nottingham-repository.worktribe.com/output/1215394
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0969996119300956
• Contract Date: Nov 1, 2018