Leveraging epigenetics to examine differences in developmental trajectories of social attention: A proof-of-principle study of DNA methylation in infants with older siblings with autism

Gui, Anna; Jones, Emily J. H.; Wong, Chloe; Meaburn, Emma L.; Baocong, X.; Pasco, Greg; Lloyd‐Fox, Sarah; Charman, Tony; Bolton, Patrick; Johnson, Mark H.

doi:10.1016/j.infbeh.2019.101409

Cited by 10 publications

(14 citation statements)

References 113 publications

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“…diagnosis for ASD or atypical development) and dimensional (e.g. adaptive skills and candidate intermediate ASD phenotypes) MWAS comparing infants with older siblings with autism against those with no immediate relatives with ASD (Gui et al, 2020). Although none of the CpGs reached a stringent level of genome-wide significance, several of nominal significance at the discovery level from the dimensional analyses could be associated with previously identified ASD risk genes from the SFARI Gene database.…”

Section: Discussionmentioning

confidence: 99%

Altered DNA methylation in a severe subtype of idiopathic autism: Evidence for sex differences in affected metabolic pathways

Yang

et al. 2020

Autism

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Although differences in DNA methylation have been associated with both syndromic and idiopathic autism, differential methylation has not been examined previously with respect to sex differences. The goals of this study were to (1) identify differences in the DNA methylation profiles of lymphoblastoid cell lines derived from a subgroup of severely affected individuals with idiopathic autism and their respective sex-matched siblings, (2) describe autism spectrum disorder–relevant pathways and functions that may be impacted by differentially methylated genes, and (3) investigate sex-dependent differences in methylation patterns and signaling pathways. Our results revealed significant differences in DNA methylation in cells from individuals with idiopathic autism spectrum disorders and from their unaffected sex-matched siblings. The samples were divided either by sex or by separation into discovery and validation groups. The genes in differentially methylated regions were statistically enriched in autism susceptibility genes and canonical pathways commonly associated with autism spectrum disorders, including synaptogenesis, semaphorin, and mammalian target of rapamycin signaling pathways. Differentially methylated region–associated genes in females were additionally associated with pathways that implicate mitochondrial dysfunction and metabolic disorders that may offer some protection against autism spectrum disorders. Further investigations of sex differences are required to develop a fuller understanding of the pathobiology, gene regulatory mechanisms, and differential susceptibility of males and females toward autism spectrum disorders. Lay abstract This study investigates altered DNA methylation that may contribute to autism spectrum disorders. DNA methylation is an epigenetic mechanism for regulating the level at which genes are expressed, and is thus complementary to genetics and gene expression analyses which look at the variations in gene structure and gene products in cells. Here, we identify DNA methylation differences between autistic and sex-matched non-autistic siblings, focusing on a subgroup of severely affected individuals with language impairment to reduce the clinical heterogeneity among the cases. Our results show significant differentially methylated genes between the sibling groups that are enriched in autism risk genes as well as in signaling and biochemical pathways previously associated with the pathobiology of autism spectrum disorders. Moreover, we show for the first time that these differences are in part sex dependent, with differentially methylated genes in females associated with pathways that implicate mitochondrial dysfunction and metabolic disorders that may offer some protection to females against autism spectrum disorders. Further investigations of sex differences are required to develop a fuller understanding of the pathobiology, gene regulatory mechanisms, and differential susceptibility of males and females toward autism spectrum disorders.

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Section: Discussionmentioning

confidence: 99%

Altered DNA methylation in a severe subtype of idiopathic autism: Evidence for sex differences in affected metabolic pathways

Yang

et al. 2020

Autism

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“…Wang et al, also observed a high level of concordance for gaze following (0.58) and concordance across gaze following and the biological motion measures (0.91) in monozygotic adolescent twins ( 264 ). Finally, the observation of associations between differences in DNA methylation and changes in attention to face stimuli with direct gaze in a sample of infant siblings provided the first evidence of possible epigenetic effects on social attention and eye contact effects in development ( 265 ).…”

Section: The Neurogenetics Of Social Attentionmentioning

confidence: 99%

The Bidirectional Social-Cognitive Mechanisms of the Social-Attention Symptoms of Autism

Mundy

Bullen

2022

Front. Psychiatry

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Differences in social attention development begin to be apparent in the 6th to 12th month of development in children with Autism Spectrum Disorder (ASD) and theoretically reflect important elements of its neurodevelopmental endophenotype. This paper examines alternative conceptual views of these early social attention symptoms and hypotheses about the mechanisms involved in their development. One model emphasizes mechanism involved in the spontaneous allocation of attention to faces, or social orienting. Alternatively, another model emphasizes mechanisms involved in the coordination of attention with other people, or joint attention, and the socially bi-directional nature of its development. This model raises the possibility that atypical responses of children to the attention or the gaze of a social partner directed toward themselves may be as important in the development of social attention symptoms as differences in the development of social orienting. Another model holds that symptoms of social attention may be important to early development, but may not impact older individuals with ASD. The alterative model is that the social attention symptoms in infancy (social orienting and joint attention), and social cognitive symptoms in childhood and adulthood share common neurodevelopmental substrates. Therefore, differences in early social attention and later social cognition constitute a developmentally continuous axis of symptom presentation in ASD. However, symptoms in older individuals may be best measured with in vivo measures of efficiency of social attention and social cognition in social interactions rather than the accuracy of response on analog tests used in measures with younger children. Finally, a third model suggests that the social attention symptoms may not truly be a symptom of ASD. Rather, they may be best conceptualized as stemming from differences domain general attention and motivation mechanisms. The alternative argued for here that infant social attention symptoms meet all the criteria of a unique dimension of the phenotype of ASD and the bi-directional phenomena involved in social attention cannot be fully explained in terms of domain general aspects of attention development.

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“…Reports of significant ASD-associated methylation biomarkers detected early in development from accessible peripheral tissues, including buccal swabs [ 89 ] and placenta [ 51 , 54 ], could be implemented in ASD risk factor calculations, thereby giving clinicians additional levels of evidence when attempting to make an early ASD diagnosis. Furthermore, the development of methods for assessing ASD biomarkers prenatally through the assessment of cell-free fetal DNA (cffDNA) would provide a window of opportunity for in utero interventions.…”

Section: Epigenetic Asd Biomarkersmentioning

confidence: 99%

Future Prospects for Epigenetics in Autism Spectrum Disorder

Williams

LaSalle

2022

Mol Diagn Ther

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Despite decades of investigation into the genetics of autism spectrum disorder (ASD), a current consensus in the field persists that ASD risk is too heterogeneous to be diagnosed by a single set of genetic variants. As such, ASD research has broadened to include assessment of other molecular biomarkers implicated in the condition that may be reflective of environmental exposures or gene by environment interactions. Epigenetic variance, and specifically differential DNA methylation, have emerged as areas of particularly high interest to ASD, as the epigenetic markers from specific chromatin loci collectively can reflect influences of multiple genetic and environmental factors and can also result in differential gene expression patterns. This review examines recent studies of the ASD epigenome, detailing common gene pathways found to be differentially methylated in people with ASD, and considers how these discoveries may inform our understanding of ASD etiology. We also consider future applications of epigenetics in ASD research and clinical practice, focusing on substratification, biomarker development, and experimental preclinical models of ASD that test causality. In combination with other -omics approaches, epigenomics allows an improved conceptualization of the multifactorial nature of ASD, and opens future lines of inquiry for both basic research and clinical practice.

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Leveraging epigenetics to examine differences in developmental trajectories of social attention: A proof-of-principle study of DNA methylation in infants with older siblings with autism

Cited by 10 publications

References 113 publications

Altered DNA methylation in a severe subtype of idiopathic autism: Evidence for sex differences in affected metabolic pathways

Altered DNA methylation in a severe subtype of idiopathic autism: Evidence for sex differences in affected metabolic pathways

The Bidirectional Social-Cognitive Mechanisms of the Social-Attention Symptoms of Autism

Future Prospects for Epigenetics in Autism Spectrum Disorder

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