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Randomized Controlled Trial
. 2023 Mar;16(3):502-523.
doi: 10.1002/aur.2884. Epub 2023 Jan 7.

Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder

Stephen K Siecinski  1 , Stephanie N Giamberardino  1 , Marina Spanos  2 , Annalise C Hauser  1 , Jason R Gibson  1 , Tara Chandrasekhar  2 , Maria Del Pilar Trelles  3 , Carol M Rockhill  4 , Michelle L Palumbo  5 , Allyson Witters Cundiff  6 , Alicia Montgomery  7 , Paige Siper  3 , Mendy Minjarez  4 , Lisa A Nowinski  5 , Sarah Marler  6 , Lydia C Kwee  1 , Lauren C Shuffrey  7 , Cheryl Alderman  2   8 , Jordana Weissman  3 , Brooke Zappone  4 , Jennifer E Mullett  5 , Hope Crosson  7 , Natalie Hong  7 , Sheng Luo  8   9 , Lilin She  8 , Manjushri Bhapkar  8 , Russell Dean  10 , Abby Scheer  2 , Jacqueline L Johnson  10 , Bryan H King  4 , Christopher J McDougle  5 , Kevin B Sanders  6 , Soo-Jeong Kim  4 , Alexander Kolevzon  3 , Jeremy Veenstra-VanderWeele  7 , Elizabeth R Hauser  1   9 , Linmarie Sikich  2   8 , Simon G Gregory  1   11
Affiliations
Randomized Controlled Trial

Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder

Stephen K Siecinski et al. Autism Res. 2023 Mar.

Abstract

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.

Keywords: autism spectrum disorder; genetic association; multiome; plasma oxytocin.

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Conflict of interest statement

Declarations:

Declaration of Conflicts of Interest

The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
Participant and sample inclusion for each modality tested within the study
Figure 2.
Figure 2.
A workflow schema of the computational tools used in each of the array and omics-based analyses. Grey nodes represent molecular data types and the experimental platforms used to generate the data. Blue nodes represent QC / pre-processing steps; green nodes represent analytical steps.
Figure 3:
Figure 3:
Genome-wide Common variant analysis of the SOARS-B cohort for association with plasma oxytocin. A) Manhattan plot showing 14 SNPs associated with plasma oxytocin (1 × 10−5) and B) Q-Q plot of our data showing appropriate control of population stratification.
Figure 4:
Figure 4:
Locus Zoom plot for RBFOX1, the most significantly associated region with plasma oxytocin levels using a common SNP approach.
See this image and copyright information in PMC

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