A Model Incorporating Potential Skewed X‐Inactivation in MZ Girls Suggests that X‐Linked QTLs Exist for Several Social Behaviours Including Autism Spectrum Disorder

Abstract

SummarySex differences in the frequency and patterns of behaviours are frequently observed and largely unexplained. We have investigated the possible role of X-linked genes in the aetiology of social behaviour problems, including those involved in autistic spectrum disorders. A novel approach has been implemented. This is based on predictions following from stochastic patterns of X-inactivation of lower concordance of monozygous female (MZF) twins than MZM twins for behaviours underpinned by X-linked QTLs and the converse that DZF twins are expected to correlate more strongly for X-linked traits than DZM twins because unlike males, females always have at least one X chromosome in common. These expectations were tested in an ongoing longitudinal cohort study in which all twins born in England and Wales between 1994 and 1996 were invited to take part. 1000 each of MZF, MZM, DZF and DZM pairs from TEDS were tested at 7 and 8 years of age. The results suggest the persistent influence of X-linked genes on cognition and social behaviour problems, including those involved in autistic spectrum disorders, from early to middle childhood. This emphasises the potential importance of X-linked genes in the developmental trajectories of behaviour and mental health and the need to stratify genetic analysis of behaviours by gender.

Twins Early Development Study (TEDS): A Genetically Sensitive Investigation of Cognitive and Behavioral Development From Childhood to Young Adulthood

“…7 years: Arden & Plomin (2006); Harlaar et al (2007); Saudino et al (2005); Viding et al (2005); Walker et al (2004). 8 years: Greven et al (2011); Loat et al (2008); Ronald et al (2006). 9 years: Hanscombe et al (2010); Haworth et al (2009a); Oliver et al (2008); Trzaskowski et al (2012); Wardle et al (2008).…”

Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia

“…Here, we focused on X-linked synaptic genes, as several evidences have implicated the X chromosome in ASD and SCZ. 20,21 The proportion of X-linked genes involved in brain development and cognition is high when compared with autosomal genes. 22–24 Numerous X-linked genes have been implicated in non-syndromic mental retardation (NS-MR) and in syndromes associated with autistic features.…”

Autism in association with Triple X syndrome

“…While the combination of both disorders may be a chance association, it is, however, possible that the presence of extra X chromosome material may be the reason this child developed autism. It has been shown that X-linked genes influence cognition and social behaviour including those involved in autistic spectrum disorders in early childhood years [11]. It is possible that the male child with Asperger's syndrome may have inherited a maternal X chromosome with some genetic predisposition to autistic spectrum disorder, and that the half sibling with the Triple X syndrome inherited two copies of the same maternal X chromosome, hence with two versions of the genetic predisposition to autistic spectrum.…”