Integrative Analysis Prioritised Oxytocin-related Biomarkers Associated with the Aetiology of Autism Spectrum Disorder

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2022 Jun 6

PMID 35665681

Authors

Tao Wang

Tingting Zhao

Liqiu Liu

Huajing Teng

Tianda Fan

Yi Li

Yan Wang

Jinchen Li

Kun Xia

Zhongsheng Sun

Affiliations

Soon will be listed here.

Abstract

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with high phenotypic and genetic heterogeneity. The common variants of specific oxytocin-related genes (OTRGs), particularly OXTR, are associated with the aetiology of ASD. The contribution of rare genetic variations in OTRGs to ASD aetiology remains unclear.

Methods: We catalogued publicly available de novo mutations (DNMs) [from 6,511 patients with ASD and 3,391 controls], rare inherited variants (RIVs) [from 1,786 patients with ASD and 1,786 controls], and both de novo copy number variations (dnCNVs) and inherited CNVs (ihCNVs) [from 15,581 patients with ASD and 6,017 controls] in 963 curated OTRGs to explore their contribution to ASD pathology, respectively. Finally, a combined model was designed to prioritise the contribution of each gene to ASD aetiology by integrating DNMs and CNVs.

Findings: The rare genetic variations of OTRGs were significantly associated with ASD aetiology, in the order of dnCNVs > ihCNVs > DNMs. Furthermore, 172 OTRGs and their connected 286 ASD core genes were prioritised to positively contribute to ASD aetiology, including top-ranked MAPK3. Probands carrying rare disruptive variations in these genes were estimated to account for 10∼11% of all ASD probands.

Interpretation: Our findings suggest that rare disruptive variations in 172 OTRGs and their connected 286 ASD core genes are associated with ASD aetiology and may be potential biomarkers predicting the effects of oxytocin treatment.

Funding: Guangdong Key Project, National Natural Science Foundation of China, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province.

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References

Martins D, Paduraru M, Paloyelis Y . Heterogeneity in response to repeated intranasal oxytocin in schizophrenia and autism spectrum disorders: A meta-analysis of variance. Br J Pharmacol. 2021; 179(8):1525-1543. DOI: 10.1111/bph.15451. View

Morales-Hidalgo P, Roige-Castellvi J, Hernandez-Martinez C, Voltas N, Canals J . Prevalence and Characteristics of Autism Spectrum Disorder Among Spanish School-Age Children. J Autism Dev Disord. 2018; 48(9):3176-3190. DOI: 10.1007/s10803-018-3581-2. View

LoParo D, Waldman I . The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Mol Psychiatry. 2014; 20(5):640-6. DOI: 10.1038/mp.2014.77. View

Guo H, Peng Y, Hu Z, Li Y, Xun G, Ou J . Genome-wide copy number variation analysis in a Chinese autism spectrum disorder cohort. Sci Rep. 2017; 7:44155. PMC: 5345089. DOI: 10.1038/srep44155. View

Parker K, Oztan O, Libove R, Sumiyoshi R, Jackson L, Karhson D . Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proc Natl Acad Sci U S A. 2017; 114(30):8119-8124. PMC: 5544319. DOI: 10.1073/pnas.1705521114. View

Jurek B, Neumann I . The Oxytocin Receptor: From Intracellular Signaling to Behavior. Physiol Rev. 2018; 98(3):1805-1908. DOI: 10.1152/physrev.00031.2017. View

Bacchelli E, Cameli C, Viggiano M, Igliozzi R, Mancini A, Tancredi R . An integrated analysis of rare CNV and exome variation in Autism Spectrum Disorder using the Infinium PsychArray. Sci Rep. 2020; 10(1):3198. PMC: 7035424. DOI: 10.1038/s41598-020-59922-3. View

Al-Ayadhi L . Altered oxytocin and vasopressin levels in autistic children in Central Saudi Arabia. Neurosciences (Riyadh). 2012; 10(1):47-50. View

Wang T, Zhang Y, Liu L, Wang Y, Chen H, Fan T . Targeted sequencing and integrative analysis of 3,195 Chinese patients with neurodevelopmental disorders prioritized 26 novel candidate genes. J Genet Genomics. 2021; 48(4):312-323. DOI: 10.1016/j.jgg.2021.03.002. View

10.

Quintana D, Lischke A, Grace S, Scheele D, Ma Y, Becker B . Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research. Mol Psychiatry. 2020; 26(1):80-91. PMC: 7815514. DOI: 10.1038/s41380-020-00864-7. View

11.

Andari E, Duhamel J, Zalla T, Herbrecht E, Leboyer M, Sirigu A . Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci U S A. 2010; 107(9):4389-94. PMC: 2840168. DOI: 10.1073/pnas.0910249107. View

12.

Yamasue H, Kojima M, Kuwabara H, Kuroda M, Matsumoto K, Kanai C . Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial. Brain. 2022; 145(2):490-499. DOI: 10.1093/brain/awab291. View

13.

Bernaerts S, Boets B, Steyaert J, Wenderoth N, Alaerts K . Oxytocin treatment attenuates amygdala activity in autism: a treatment-mechanism study with long-term follow-up. Transl Psychiatry. 2020; 10(1):383. PMC: 7648620. DOI: 10.1038/s41398-020-01069-w. View

14.

Davis A, Murphy C, Johnson R, Lay J, Lennon-Hopkins K, Saraceni-Richards C . The Comparative Toxicogenomics Database: update 2013. Nucleic Acids Res. 2012; 41(Database issue):D1104-14. PMC: 3531134. DOI: 10.1093/nar/gks994. View

15.

Yatawara C, Einfeld S, Hickie I, Davenport T, Guastella A . The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry. 2015; 21(9):1225-31. PMC: 4995545. DOI: 10.1038/mp.2015.162. View

16.

Richter M, Murtaza N, Scharrenberg R, White S, Johanns O, Walker S . Altered TAOK2 activity causes autism-related neurodevelopmental and cognitive abnormalities through RhoA signaling. Mol Psychiatry. 2018; 24(9):1329-1350. PMC: 6756231. DOI: 10.1038/s41380-018-0025-5. View

17.

Gurbich T, Ilinsky V . ClassifyCNV: a tool for clinical annotation of copy-number variants. Sci Rep. 2020; 10(1):20375. PMC: 7683568. DOI: 10.1038/s41598-020-76425-3. View

18.

Karczewski K, Francioli L, Tiao G, Cummings B, Alfoldi J, Wang Q . Author Correction: The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2021; 590(7846):E53. PMC: 8064911. DOI: 10.1038/s41586-020-03174-8. View

19.

Kou J, Zhang Y, Zhou F, Gao Z, Yao S, Zhao W . Anxiolytic Effects of Chronic Intranasal Oxytocin on Neural Responses to Threat Are Dose-Frequency Dependent. Psychother Psychosom. 2022; 91(4):253-264. DOI: 10.1159/000521348. View

20.

Anagnostou E, Soorya L, Chaplin W, Bartz J, Halpern D, Wasserman S . Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism. 2012; 3(1):16. PMC: 3539865. DOI: 10.1186/2040-2392-3-16. View