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The contributions of rare inherited and polygenic risk to ASD in multiplex families

Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome se...

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Autores principales: Cirnigliaro, Matilde, Chang, Timothy S., Arteaga, Stephanie A., Pérez-Cano, Laura, Ruzzo, Elizabeth K., Gordon, Aaron, Bicks, Lucy K., Jung, Jae-Yoon, Lowe, Jennifer K., Wall, Dennis P., Geschwind, Daniel H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400943/
https://www.ncbi.nlm.nih.gov/pubmed/37506195
http://dx.doi.org/10.1073/pnas.2215632120
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author Cirnigliaro, Matilde
Chang, Timothy S.
Arteaga, Stephanie A.
Pérez-Cano, Laura
Ruzzo, Elizabeth K.
Gordon, Aaron
Bicks, Lucy K.
Jung, Jae-Yoon
Lowe, Jennifer K.
Wall, Dennis P.
Geschwind, Daniel H.
author_facet Cirnigliaro, Matilde
Chang, Timothy S.
Arteaga, Stephanie A.
Pérez-Cano, Laura
Ruzzo, Elizabeth K.
Gordon, Aaron
Bicks, Lucy K.
Jung, Jae-Yoon
Lowe, Jennifer K.
Wall, Dennis P.
Geschwind, Daniel H.
author_sort Cirnigliaro, Matilde
collection PubMed
description Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD.
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spelling pubmed-104009432023-08-05 The contributions of rare inherited and polygenic risk to ASD in multiplex families Cirnigliaro, Matilde Chang, Timothy S. Arteaga, Stephanie A. Pérez-Cano, Laura Ruzzo, Elizabeth K. Gordon, Aaron Bicks, Lucy K. Jung, Jae-Yoon Lowe, Jennifer K. Wall, Dennis P. Geschwind, Daniel H. Proc Natl Acad Sci U S A Biological Sciences Autism spectrum disorder (ASD) has a complex genetic architecture involving contributions from both de novo and inherited variation. Few studies have been designed to address the role of rare inherited variation or its interaction with common polygenic risk in ASD. Here, we performed whole-genome sequencing of the largest cohort of multiplex families to date, consisting of 4,551 individuals in 1,004 families having two or more autistic children. Using this study design, we identify seven previously unrecognized ASD risk genes supported by a majority of rare inherited variants, finding support for a total of 74 genes in our cohort and a total of 152 genes after combined analysis with other studies. Autistic children from multiplex families demonstrate an increased burden of rare inherited protein-truncating variants in known ASD risk genes. We also find that ASD polygenic score (PGS) is overtransmitted from nonautistic parents to autistic children who also harbor rare inherited variants, consistent with combinatorial effects in the offspring, which may explain the reduced penetrance of these rare variants in parents. We also observe that in addition to social dysfunction, language delay is associated with ASD PGS overtransmission. These results are consistent with an additive complex genetic risk architecture of ASD involving rare and common variation and further suggest that language delay is a core biological feature of ASD. National Academy of Sciences 2023-07-28 2023-08-01 /pmc/articles/PMC10400943/ /pubmed/37506195 http://dx.doi.org/10.1073/pnas.2215632120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Cirnigliaro, Matilde
Chang, Timothy S.
Arteaga, Stephanie A.
Pérez-Cano, Laura
Ruzzo, Elizabeth K.
Gordon, Aaron
Bicks, Lucy K.
Jung, Jae-Yoon
Lowe, Jennifer K.
Wall, Dennis P.
Geschwind, Daniel H.
The contributions of rare inherited and polygenic risk to ASD in multiplex families
title The contributions of rare inherited and polygenic risk to ASD in multiplex families
title_full The contributions of rare inherited and polygenic risk to ASD in multiplex families
title_fullStr The contributions of rare inherited and polygenic risk to ASD in multiplex families
title_full_unstemmed The contributions of rare inherited and polygenic risk to ASD in multiplex families
title_short The contributions of rare inherited and polygenic risk to ASD in multiplex families
title_sort contributions of rare inherited and polygenic risk to asd in multiplex families
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10400943/
https://www.ncbi.nlm.nih.gov/pubmed/37506195
http://dx.doi.org/10.1073/pnas.2215632120
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