TY - JOUR
T1 - Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder
AU - Siecinski, Stephen K.
AU - Giamberardino, Stephanie N.
AU - Spanos, Marina
AU - Hauser, Annalise C.
AU - Gibson, Jason R.
AU - Chandrasekhar, Tara
AU - Trelles, Maria del Pilar
AU - Rockhill, Carol M.
AU - Palumbo, Michelle L.
AU - Cundiff, Allyson Witters
AU - Montgomery, Alicia
AU - Siper, Paige
AU - Minjarez, Mendy
AU - Nowinski, Lisa A.
AU - Marler, Sarah
AU - Kwee, Lydia C.
AU - Shuffrey, Lauren C.
AU - Alderman, Cheryl
AU - Weissman, Jordana
AU - Zappone, Brooke
AU - Mullett, Jennifer E.
AU - Crosson, Hope
AU - Hong, Natalie
AU - Luo, Sheng
AU - She, Lilin
AU - Bhapkar, Manjushri
AU - Dean, Russell
AU - Scheer, Abby
AU - Johnson, Jacqueline L.
AU - King, Bryan H.
AU - McDougle, Christopher J.
AU - Sanders, Kevin B.
AU - Kim, Soo Jeong
AU - Kolevzon, Alexander
AU - Veenstra-VanderWeele, Jeremy
AU - Hauser, Elizabeth R.
AU - Sikich, Linmarie
AU - Gregory, Simon G.
N1 - Funding Information:
The authors disclose receipt of the following sources of financial support for the research, analysis, authorship, and publication described in this manuscript: This work was supported by the NIH through two R01 awards to support the SOARS‐B phase 2 clinical trial (RFA‐HD 12‐196) and the subsequent molecular analysis of the samples from SOARS‐B participants (R01‐HD‐088007) and by the Autism Speaks Weatherstone Fellowship (Grant # 10136).
Publisher Copyright:
© 2023 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.
PY - 2023
Y1 - 2023
N2 - Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. Lay Summary: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.
AB - Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. Lay Summary: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.
KW - autism spectrum disorder
KW - genetic association
KW - multiome
KW - plasma oxytocin
UR - http://www.scopus.com/inward/record.url?scp=85146078797&partnerID=8YFLogxK
U2 - 10.1002/aur.2884
DO - 10.1002/aur.2884
M3 - Article
C2 - 36609850
AN - SCOPUS:85146078797
SN - 1939-3792
JO - Autism Research
JF - Autism Research
ER -