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The Genetics of Autism Advanced article Varun Warrier, Autism Research Centre, University of Cambridge, Cambridgeshire, Article Contents • Introduction UK • Copy Number Variation in Autism Simon Baron-Cohen, Autism Research Centre, University of Cambridge, Cam- • Insights from Next-generation Sequencing bridgeshire, UK and Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), Studies • Transcriptional Dysregulation in Autism Cambridgeshire, UK • Conclusions • Acknowledgements Online posting date: 31st October 2017 Autism spectrum conditions (henceforth ‘autism’) 4 times as many males are diagnosed with autism compared to refer to a group of neurodevelopmental conditions females, which may be due to innate biological factors (e.g. a involving difficulties in social interaction and com- female protective effect) or due to other social or cultural factors munication and unusually repetitive and restricted (e.g. females with autism may be better at ‘masking’ their pheno- types and hence may not be diagnosed with autism, and females behaviours and interest. Twin and family stud- are often diagnosed later than males) (Lai et al., 2013). In addi- ies have established a significant heritability for tion to the difficulties in the core diagnostic criteria, individuals autism. Autism is polygenic with variations across with autism often have other comorbid phenotypes. For example, the allele frequency spectrum contributing to risk. many individuals have atypical language development, sensory Early linkage and candidate gene association stud- hypo or hypersensitivity and difficulties in motor coordination, ies were statistically underpowered to identify including dyspraxia. Approximately 38% of all individuals with significant loci. Current genome-wide association autism have intellectual disability (ID), as estimated by the CDC. studies have identified significant positive genetic Similarly, there is a reasonably high comorbidity with ADHD, correlation between autism and various measures depression and suicidal ideation (Lai et al., 2013). of cognition. The use of genetic microarrays and Aside from clinical comorbidities, on average, individuals with autism tend to perform better on measures of ‘systemising’ drive next-generation DNA sequencing has identified (Baron-Cohen et al., 2003), that is, the drive to analyse and build tens of genes and copy number variants associ- systems, based on identifying the laws that govern the particular ated with autism. In addition, RNA microarray system, in order to predict how that system will work. Systems and sequencing studies of postmortem brain sam- may be abstract, mechanical, natural, collectible and motoric. ples have identified transcriptionally altered genes They also perform better on tests of attention to detail (Jolliffe and and pathways in autism. Multiple lines of evidence Baron-Cohen, 1997), a prerequisite for systemising. Individuals converge on altered glial, synaptic and chromatin who are in the science-technology-engineering-maths (STEM) pathways as contributing to autism risk. fields, or relatives of these individuals, are more likely to bediag- nosed with autism or have higher levels of autistic traits (Ruzich et al., 2015; Wheelwright and Baron-Cohen, 2001; Baron-Cohen et al., 1997). Autistic individuals also, on average, tend to have Introduction difficulties in eye contact (Jones and Klin, 2013), attention to social stimuli (Dawson et al., 1998) and interpreting emotions Autism spectrum conditions (henceforth autism) refer to a het- (Baron-Cohen et al., 2001), which contribute to persistent dif- erogeneous group of neurodevelopmental disorders characterised ficulties in social interaction and communication. This may be by difficulties in social interaction and communication alongside because the social domain is less amenable to systemising, as it unusually repetitive behaviour and unusually narrow interests does not reduce to a set of rules. (Lai et al., 2013). It has an estimated prevalence of 1 in 100, There is considerable evidence that autism is partly genetic. although recent reports from the Centers for Disease Control and Early twin studies established a prominent role for genetic vari- Prevention (CDC) suggest that it may be higher (1 in 68). The ants by investigating concordance rate of both the clinical phe- median worldwide prevalence is estimated between 0.62 and 0.70 notype and associated behavioural and cognitive phenotypes in (Lai et al., 2013). There is a marked sex difference: between 3 and twins (reviewed in Bourgeron, 2016a; Ronald and Hoekstra, 2011). Recently, with increase in diagnosis rates and the avail- eLS subject area: Genetics & Disease ability of electronic records, it has been possible to establish How to cite: familial recurrence rates in large population-based cohorts, pro- Warrier, Varun and Baron-Cohen, Simon (October 2017) The viding converging evidence for familial recurrence rates (Sandin Genetics of Autism. In: eLS. John Wiley & Sons, Ltd: Chichester. et al., 2014; Sandin et al., 2015). Buoyed by the heritability esti- DOI: 10.1002/9780470015902.a0021455.pub2 mates, early molecular genetic studies focused largely on linkage eLS © 2017, John Wiley & Sons, Ltd. www.els.net 1 The Genetics of Autism and candidate gene sequencing and association studies in autism. coheritability analyses of autism and related traits, suggesting Candidate gene association studies were conducted in relatively a significant shared genetic influence. The genetic correlation small sample sizes, with systematic inflation of effect sizes (War- between autism/autistic traits and ADHD/ADHD traits in partic- rier et al., 2015a). Most of the results from these studies have not ular is high reflecting the phenotypic comorbidity (Ronald and replicated in studies with larger samples. Hoekstra, 2011). See also: Twin Studies However, there were some early successes in candidate gene Family recurrence rates have also provided evidence for her- sequencing studies, particularly in identifying genes for syn- itability for autism. Multiple studies from Scandinavian coun- dromic conditions with comorbid autism such as FMR1, TCS2 tries have identified similar risk ratio for siblings of individu- and NF1 (Bourgeron, 2016a). The considerable genetic and phe- als with autism (∼10%) (Sandin et al., 2014; Grønborg et al., notypic heterogeneity in autism has made it challenging to iden- 2013; Jokiranta-Olkoniemi et al., 2016). Family recurrence rates tify genes associated with the condition, necessitating investi- also offer other clues into the underlying genetic architecture gations in large population cohorts given the small effect sizes of autism. One interesting observation is that siblings of female and/or rarity of the genetic variants. Recent studies have lever- probands have higher risk for autism than siblings of male aged large sample sizes available in population databases for probands – an observation that is called the Carter effect (the autism such as the Simon’s Simplex Collection and the Autism effect was originally described in pyloric stenosis (Carter and Genetic Research Exchange. In this article, we review the differ- Evans, 1996), but subsequently used in other conditions). The ent methods used to investigate the genetic architecture of autism Carter effect suggests that females have a protective effect, sug- and related traits, and recent progress in autism genetics research. gesting that a greater mutation burden is required for a clinical diagnosis of autism (this has been confirmed using gene sequenc- Establishing heritability: twin studies ing studies, see the following discussion). If the genetic risk is and familial recurrence partly familial, that is not de novo, this higher genetic risk can be inherited by siblings, thus increasing the risk for autism. Inves- Since the first description in 1943 by Kanner (1943), autism was tigations of twin and multiplex family samples have identified known to be a condition that manifested in early childhood, lead- a higher relative risk for autism in siblings of female probands ing to the hypothesis that the condition is at least partly genetic. (Werling and Geschwind, 2015; Robinson et al., 2013). In con- Establishing heritability is important, as it provides evidence for a trast, large population studies have failed to find support for the causal role of genes in autism risk, which can then inform molecu- Carter effect (Sandin et al., 2014). lar genetic studies. Early family studies that were conducted in the Another interesting finding is the identification of autistic traits 1960s and 1970s did not find evidence for familiality, which was or the BAP in family members of probands (Wheelwright et al., because autism was perceived as an extremely rare condition (in 2010). This is also supported by the identification of higher the 1960s and 1970s, prevalence estimates for autism were 2–4 in relative risk for other psychiatric conditions in family members 10 000). However, deeper examination of family factors provided of probands compared to the general population (Frazier et al., two clues that autism is likely to be, at least partly, heritable. First, 2015; Constantino et al., 2010; Jokiranta-Olkoniemi et al., 2016). the recurrence rate in siblings was considerably higher than the A third interesting finding is that of parental age. A few studies risk in the general population, and second, there was a family his- have demonstrated that increased paternal age increases the risk tory of delayed speech in about a quarter
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