Heritability and genetic variance of dementia with Lewy bodies

for the International Parkinson's Disease Genomics Consortium

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)492-501
Number of pages10
JournalNeurobiology of Disease
Volume127
DOIs
StatePublished - Jul 1 2019

Fingerprint

Lewy Body Disease
Alzheimer Disease
Single Nucleotide Polymorphism
Parkinson Disease
Inborn Genetic Diseases
Genome-Wide Association Study
Linkage Disequilibrium
Gene Frequency
Genome
Phenotype
Education

Keywords

  • Dementia
  • Genetic correlation
  • Genetic variance
  • Lewy bodies

ASJC Scopus subject areas

  • Neurology

Cite this

for the International Parkinson's Disease Genomics Consortium (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

Heritability and genetic variance of dementia with Lewy bodies. / for the International Parkinson's Disease Genomics Consortium.

In: Neurobiology of Disease, Vol. 127, 01.07.2019, p. 492-501.

Research output: Contribution to journalArticle

for the International Parkinson's Disease Genomics Consortium 2019, 'Heritability and genetic variance of dementia with Lewy bodies', Neurobiology of Disease, vol. 127, pp. 492-501. https://doi.org/10.1016/j.nbd.2019.04.004
for the International Parkinson's Disease Genomics Consortium. Heritability and genetic variance of dementia with Lewy bodies. Neurobiology of Disease. 2019 Jul 1;127:492-501. https://doi.org/10.1016/j.nbd.2019.04.004
for the International Parkinson's Disease Genomics Consortium. / Heritability and genetic variance of dementia with Lewy bodies. In: Neurobiology of Disease. 2019 ; Vol. 127. pp. 492-501.
@article{15759129009248d5bd56462e25442d89,
title = "Heritability and genetic variance of dementia with Lewy bodies",
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.",
keywords = "Dementia, Genetic correlation, Genetic variance, Lewy bodies",
author = "{for the International Parkinson's Disease Genomics Consortium} and Rita Guerreiro and Valentina Escott-Price and Hernandez, {Dena G.} and Celia Kun-Rodrigues and Ross, {Owen A.} and Tatiana Orme and Neto, {Joao Luis} and Susana Carmona and Nadia Dehghani and Eicher, {John D.} and Claire Shepherd and Laura Parkkinen and Lee Darwent and Heckman, {Michael G.} and Scholz, {Sonja W.} and Troncoso, {Juan C} and Olga Pletnikova and Dawson, {Ted M} and Rosenthal, {Liana Isa Shapiro} and Olaf Ansorge and Jordi Clarimon and Alberto Lleo and Estrella Morenas-Rodriguez and Lorraine Clark and Honig, {Lawrence S.} and Karen Marder and Afina Lemstra and Ekaterina Rogaeva and {St. George-Hyslop}, Peter and Elisabet Londos and Henrik Zetterberg and Imelda Barber and Anne Braae and Kristelle Brown and Kevin Morgan and Claire Troakes and Safa Al-Sarraj and Tammaryn Lashley and Janice Holton and Yaroslau Compta and {Van Deerlin}, Vivianna and Serrano, {Geidy E.} and Beach, {Thomas G.} and Suzanne Lesage and Douglas Galasko and Eliezer Masliah and Isabel Santana and Pau Pastor and Monica Diez-Fairen and Miquel Aguilar",
year = "2019",
month = "7",
day = "1",
doi = "10.1016/j.nbd.2019.04.004",
language = "English (US)",
volume = "127",
pages = "492--501",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Heritability and genetic variance of dementia with Lewy bodies

AU - for the International Parkinson's Disease Genomics Consortium

AU - Guerreiro, Rita

AU - Escott-Price, Valentina

AU - Hernandez, Dena G.

AU - Kun-Rodrigues, Celia

AU - Ross, Owen A.

AU - Orme, Tatiana

AU - Neto, Joao Luis

AU - Carmona, Susana

AU - Dehghani, Nadia

AU - Eicher, John D.

AU - Shepherd, Claire

AU - Parkkinen, Laura

AU - Darwent, Lee

AU - Heckman, Michael G.

AU - Scholz, Sonja W.

AU - Troncoso, Juan C

AU - Pletnikova, Olga

AU - Dawson, Ted M

AU - Rosenthal, Liana Isa Shapiro

AU - Ansorge, Olaf

AU - Clarimon, Jordi

AU - Lleo, Alberto

AU - Morenas-Rodriguez, Estrella

AU - Clark, Lorraine

AU - Honig, Lawrence S.

AU - Marder, Karen

AU - Lemstra, Afina

AU - Rogaeva, Ekaterina

AU - St. George-Hyslop, Peter

AU - Londos, Elisabet

AU - Zetterberg, Henrik

AU - Barber, Imelda

AU - Braae, Anne

AU - Brown, Kristelle

AU - Morgan, Kevin

AU - Troakes, Claire

AU - Al-Sarraj, Safa

AU - Lashley, Tammaryn

AU - Holton, Janice

AU - Compta, Yaroslau

AU - Van Deerlin, Vivianna

AU - Serrano, Geidy E.

AU - Beach, Thomas G.

AU - Lesage, Suzanne

AU - Galasko, Douglas

AU - Masliah, Eliezer

AU - Santana, Isabel

AU - Pastor, Pau

AU - Diez-Fairen, Monica

AU - Aguilar, Miquel

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

KW - Dementia

KW - Genetic correlation

KW - Genetic variance

KW - Lewy bodies

UR - http://www.scopus.com/inward/record.url?scp=85064074557&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064074557&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2019.04.004

DO - 10.1016/j.nbd.2019.04.004

M3 - Article

VL - 127

SP - 492

EP - 501

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

ER -