GABA Signaling Pathway-associated Gene PLCL1 Rare Variants May be Associated with Autism Spectrum Disorders

Zheng, Fengyun; Liu, Guoyuan; Dang, Ting; Chen, Qiaowen; An, Yu; Wu, Minmin; Kong, Xiangxuan; Qiu, Zilong; Wu, Bai-Lin

doi:10.1007/s12264-021-00707-7

Cited by 10 publications

(7 citation statements)

References 15 publications

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“…For example, rs12636275 on 3p11.1 is located within an intron of EPHA3 , a gene that encodes an ephrin receptor subunit that regulates the formation of axon projection maps ( 48 ), and has also been associated with functional connectivity between language-related regions ( 49 ). As another example, rs7580864 on 2q33.1 is an eQTL of PLCL1 that is implicated in autism ( 50 ), a neurodevelopmental disorder that often affects language and social skills. Other positional candidate genes based on the 31 SNPs include CRHR1 , encoding corticotropin releasing hormone receptor 1, and CENPW (centromere protein W) involved in chromosome maintenance and the cell cycle (Fig.…”

Section: Resultsmentioning

confidence: 99%

Genetic architecture of the white matter connectome of the human brain

et al. 2023

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White matter tracts form the structural basis of large-scale brain networks. We applied brain-wide tractography to diffusion images from 30,810 adults (U.K. Biobank) and found significant heritability for 90 node-level and 851 edge-level network connectivity measures. Multivariate genome-wide association analyses identified 325 genetic loci, of which 80% had not been previously associated with brain metrics. Enrichment analyses implicated neurodevelopmental processes including neurogenesis, neural differentiation, neural migration, neural projection guidance, and axon development, as well as prenatal brain expression especially in stem cells, astrocytes, microglia, and neurons. The multivariate association profiles implicated 31 loci in connectivity between core regions of the left-hemisphere language network. Polygenic scores for psychiatric, neurological, and behavioral traits also showed significant multivariate associations with structural connectivity, each implicating distinct sets of brain regions with trait-relevant functional profiles. This large-scale mapping study revealed common genetic contributions to variation in the structural connectome of the human brain.

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Section: Resultsmentioning

confidence: 99%

Genetic architecture of the white matter connectome of the human brain

et al. 2023

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“…ESR1 was previously shown to regulate OT signaling during gestation and parturition (Fleming et al, 2006; Kim et al, 2017) and variation in ESR1 is associated with social interaction and emotional regulation in individuals with ASD (Doi et al, 2018), but it has not been previously associated with circulating OT levels. Similarly, PLCL1 has been associated with ASD (Zheng et al, 2021) and plays an inhibitory role in uterine contraction through modulation of the OT signaling pathway (Peavey et al, 2021), but has not been reported in modulating plasma OT levels. These findings build upon a growing body of evidence for the roll of these genes in OT signaling and social behavior.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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.

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“…ESR1 was previously shown to regulate OT signaling during gestation and parturition 111, 112 and variation in ESR1 is associated with social interaction and emotional regulation in individuals with ASD 113 , but it has not been previously associated with circulating OT levels. Similarly, PLCL1 has been associated with ASD 114 and plays an inhibitory role in uterine contraction through modulation of the OT signaling pathway 115 , but has not been reported in modulating plasma OT levels. These findings build upon a growing body of evidence for the roll of these genes in OT signaling and social behavior.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, PLCL1 has been associated with ASD 114 and plays an inhibitory role in uterine contraction through modulation of the OT signaling pathway 115 , but has not been reported in modulating plasma OT levels. These findings build upon a growing body of evidence for the roll of these genes in OT signaling and social behavior.…”

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confidence: 99%

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

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Giamberardino

Spanos

et al. 2022

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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 hypothesized that genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To test this hypothesis, 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 shows subtle, but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. We also identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. 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.

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GABA Signaling Pathway-associated Gene PLCL1 Rare Variants May be Associated with Autism Spectrum Disorders

Cited by 10 publications

References 15 publications

Genetic architecture of the white matter connectome of the human brain

Genetic architecture of the white matter connectome of the human brain

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

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

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