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Heritability and genetic variance of dementia with Lewy bodies

Guerreiro, Rita, Escott-Price, Valentina, Hernandez, Dena G., Kun-Rodrigues, Celia, Ross, Owen A., Orme, Tatiana, Neto, Joao Luis, Carmona, Susana, Dehghani, Nadia, Eicher, John D., Shepherd, Claire, Parkkinen, Laura, Darwent, Lee, Heckman, Michael G., Scholz, Sonja W., Troncoso, Juan C., Pletnikova, Olga, Dawson, Ted, Rosenthal, Liana, Ansorge, Olaf, Clarimon, Jordi, Lleo, Alberto, Morenas-Rodriguez, Estrella, Clark, Lorraine, Honig, Lawrence S., 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 E., Beach, Thomas G., Lesage, Suzanne, Galasko, Douglas, Masliah, Eliezer, Santana, Isabel, Pastor, Pau, Diez-Fairen, Monica, Aguilar, Miquel, Tienari, Pentti J., Myllykangas, Liisa, Oinas, Minna, Revesz, Tamas, Lees, Andrew, Boeve, Brad F., Petersen, Ronald C., Ferman, Tanis J., Graff-Radford, Neill, Cairns, Nigel J., Morris, John C., Pickering-Brown, Stuart, Mann, David, Halliday, Glenda M., Hardy, John, Trojanowski, John Q., Dickson, Dennis W., Singleton, Andrew, Stone, David J. and Bras, Jose 2019. Heritability and genetic variance of dementia with Lewy bodies. Neurobiology of Disease 127 , pp. 492-501. 10.1016/j.nbd.2019.04.004

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Elsevier
ISSN: 0969-9961
Date of First Compliant Deposit: 14 May 2019
Date of Acceptance: 2 April 2019
Last Modified: 04 Apr 2020 06:10

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