Le numéro de novembre 2021 du Journal of Child Psychology and Psychiatry est consacré à la génétique et la génomique du trouble du spectre de l’autisme.

1. Franke B, Fombonne E, Ronald A. Editorial: The new genetics of autism. Journal of Child Psychology and Psychiatry;2021 (2021/11/01);62(11):1271-1273.

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2. Ghirardi L, Kuja-Halkola R, Butwicka A, Martin J, Larsson H, D’Onofrio BM, Lichtenstein P, Taylor MJ. Familial and genetic associations between autism spectrum disorder and other neurodevelopmental and psychiatric disorders. Journal of Child Psychology and Psychiatry;2021 (2021/11/01);62(11):1274-1284.

Background Familial and genetic associations between autism spectrum disorder (ASD) and other neurodevelopmental and psychiatric disorders have been reported, sometimes with conflicting results. We estimated familial and genetic associations between ASD and nine disorder groups, and explored differences in these associations for ASD in the context of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. Methods Individuals born between 1985 and 2009 living in Sweden on their seventh birthday were linked to their biological parents in order to identify different types of relatives. We retrieved information on all the disorders considered from the National Patient Register. Logistic regression was used to estimate the familial association between ASD and other neurodevelopmental and psychiatric disorders in the different groups of relatives. Structural equation modeling was used to estimate phenotypic (rp) and genetic associations (rg), as well as the contribution of genetic influences to rp. Results The study included 2,398,608 individuals. Among relatives of individuals diagnosed with ASD, there was an increased risk of the disorders considered, compared to relatives of individuals who were not diagnosed with ASD. Stronger associations were detected for ASD without any additional diagnosis of intellectual disability, epilepsy, chromosomal abnormalities, and congenital malformations. The strongest genetic correlation was estimated between ASD and other neurodevelopmental disorders (rg = 0.73; 95% CI = 0.66?0.79). Moderate genetic correlations were estimated for anxiety disorders (rg = 0.47; 95% CI = 0.33?0.61), depression (rg = 0.52; 95% CI = 0.37?0.66), and intentional self-harm (rg = 0.54; 95% CI = 0.36?0.71). Conclusions ASD shows familial and genetic association not only with other neurodevelopmental disorders, but also with other psychiatric disorders, such as anxiety, depression, and intentional self-harm. Family history of ASD comorbid with intellectual disability, epilepsy, congenital malformations, or chromosomal abnormalities is less related to other psychiatric disorders, potentially suggesting a different etiology for this subgroup of patients.

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3. Peyre H, Schoeler T, Liu C, Williams CM, Hoertel N, Havdahl A, Pingault J-B. Combining multivariate genomic approaches to elucidate the comorbidity between autism spectrum disorder and attention deficit hyperactivity disorder. Journal of Child Psychology and Psychiatry;2021 (2021/11/01);62(11):1285-1296.

Background Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. Methods With the summary data from two GWAS, one on ASD (N = 46,350) and another on ADHD (N = 55,374) individuals, we used genomic structural equation modelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. Results We found that 37.5% of the SNPs associated with ASD (at p < 1e-6) colocalized with ADHD SNPs and that 19.6% of the SNPs associated with ADHD colocalized with ASD SNPs. We identified genes mapped to SNPs that are specific to ASD or ADHD and that are shared by ASD and ADHD, including two novel genes INSM1 and PAX1. Our bidirectional Mendelian randomization analyses indicated that the risk of ASD was associated with an increased risk of ADHD and vice versa. Conclusions Using multivariate genomic analyses, the present study uncovers shared and specific genetic variants associated with ASD and ADHD. Further functional investigation of genes mapped to those shared variants may help identify pathophysiological pathways and new targets for treatment.

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4. Wickstrom J, Farmer C, Green Snyder L, Mitz AR, Sanders SJ, Bishop S, Thurm A. Patterns of delay in early gross motor and expressive language milestone attainment in probands with genetic conditions versus idiopathic ASD from SFARI registries. Journal of Child Psychology and Psychiatry;2021 (2021/11/01);62(11):1297-1307.

Background Recent large-scale initiatives have led to systematically collected phenotypic data for several rare genetic conditions implicated in autism spectrum disorder (ASD). The onset of developmentally expected skills (e.g. walking, talking) serve as readily quantifiable aspects of the behavioral phenotype. This study’s aims were: (a) describe the distribution of ages of attainment of gross motor and expressive language milestones in several rare genetic conditions, and (b) characterize the likelihood of delays in these conditions compared with idiopathic ASD. Methods Participants aged 3 years and older were drawn from two Simons Foundation Autism Research Initiative registries that employed consistent phenotyping protocols. Inclusion criteria were a confirmed genetic diagnosis of one of 16 genetic conditions (Simons Searchlight) or absence of known pathogenic genetic findings in individuals with ASD (SPARK). Parent-reported age of acquisition of three gross motor and two expressive language milestones was described and categorized as on-time or delayed, relative to normative expectations. Results Developmental milestone profiles of probands with genetic conditions were marked by extensive delays (including nonattainment), with highest severity in single gene conditions and more delays than idiopathic ASD in motor skills. Compared with idiopathic ASD, the median odds of delay among the genetic groups were higher by 8.3 times (IQR 5.8?16.3) for sitting, 12.4 times (IQR 5.3?19.5) for crawling, 26.8 times (IQR 7.7?41.1) for walking, 2.7 times (IQR 1.7?5.5) for single words, and 5.7 times (IQR 2.7?18.3) for combined words. Conclusions Delays in developmental milestones, particularly in gross motor skills, are frequent and may be among the earliest indicators of differentially affected developmental processes in specific genetically defined conditions associated with ASD, as compared with those with clinical diagnoses of idiopathic ASD. The possibility of different developmental pathways leading to ASD-associated phenotypes should be considered when deciding how to employ specific genetic conditions as models for ASD.

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5. Fish LA, Nyström P, Gliga T, Gui A, Begum Ali J, Mason L, Garg S, Green J, Johnson MH, Charman T, Harrison R, Meaburn E, Falck-Ytter T, Jones EJH, the BSt. Development of the pupillary light reflex from 9 to 24 months: association with common autism spectrum disorder (ASD) genetic liability and 3-year ASD diagnosis. Journal of Child Psychology and Psychiatry;2021 (2021/11/01);62(11):1308-1319.

Background Although autism spectrum disorder (ASD) is heritable, the mechanisms through which genes contribute to symptom emergence remain unclear. Investigating candidate intermediate phenotypes such as the pupillary light reflex (PLR) prospectively from early in development could bridge genotype and behavioural phenotype. Methods Using eye tracking, we longitudinally measured the PLR at 9, 14 and 24 months in a sample of infants (N = 264) enriched for a family history of ASD; 27 infants received an ASD diagnosis at 3 years. We examined the 9- to 24-month developmental trajectories of PLR constriction latency (onset; ms) and amplitude (%) and explored their relation to categorical 3-year ASD outcome, polygenic liability for ASD and dimensional 3-year social affect (SA) and repetitive/restrictive behaviour (RRB) traits. Polygenic scores for ASD (PGSASD) were calculated for 190 infants. Results While infants showed a decrease in latency between 9 and 14 months, higher PGSASD was associated with a smaller decrease in latency in the first year (? = ?.16, 95% CI = ?0.31, ?0.002); infants with later ASD showed a significantly steeper decrease in latency (a putative ?catch-up?) between 14 and 24 months relative to those with other outcomes (typical: ? = .54, 95% CI = 0.08, 0.99; other: ? = .53, 95% CI = 0.02, 1.04). Latency development did not associate with later dimensional variation in ASD-related traits. In contrast, change in amplitude was not related to categorical ASD or genetics, but decreasing 9- to 14-month amplitude was associated with higher SA (? = .08, 95% CI = 0.01, 0.14) and RRB (? = .05, 95% CI = 0.004, 0.11) traits. Conclusions These findings corroborate PLR development as possible intermediate phenotypes being linked to both genetic liability and phenotypic outcomes. Future work should incorporate alternative measures (e.g. functionally informed structural and genetic measures) to test whether distinct neural mechanisms underpin PLR alterations.

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6. Morneau-Vaillancourt G, Andlauer TFM, Ouellet-Morin I, Paquin S, Brendgen MR, Vitaro F, Gouin J-P, Séguin JR, Gagnon É, Cheesman R, Forget-Dubois N, Rouleau GA, Turecki G, Tremblay RE, Côté SM, Dionne G, Boivin M. Polygenic scores differentially predict developmental trajectories of subtypes of social withdrawal in childhood. Journal of Child Psychology and Psychiatry;2021 (2021/11/01);62(11):1320-1329.

Background Children who consistently withdraw from social situations face increased risk for later socioemotional difficulties. Twin studies indicate that genetic factors substantially account for the persistence of social withdrawal over time. However, the molecular genetic etiology of chronic courses of social wariness and preference for solitude, two dimensions of social withdrawal, remains undocumented. The objectives of the present study were (a) to identify high-risk trajectories for social wariness and preference for solitude in childhood and (b) to examine whether falling on these high-risk trajectories can be predicted by specific polygenic scores for mental health traits and disorders and by a general polygenic predisposition to these traits. Methods Teachers evaluated 971 genotyped children at five occasions (age 6 to 12 years) from two prospective longitudinal studies, the Quebec Newborn Twin Study and the Quebec Longitudinal Study of Child Development. Developmental trajectories for social wariness and preference for solitude were identified. We tested whether polygenic scores for attention deficit hyperactivity disorder, autism spectrum disorder, depression, loneliness, and subjective well-being, as well as a general mental health genetic risk score derived across these traits, were associated with the developmental trajectories. Results Polygenic scores differentially predicted social wariness and preference for solitude. Only the loneliness polygenic score significantly predicted the high trajectory for social wariness. By contrast, the general mental health genetic risk score factor was associated with the trajectory depicting high-chronic preference for solitude. Conclusions Distinct associations were uncovered between the polygenic scores, social wariness, and preference for solitude.

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7. Reed ZE, Mahedy L, Jackson A, Davey Smith G, Penton-Voak I, Attwood AS, Munafò MR. Examining the bidirectional association between emotion recognition and social autistic traits using observational and genetic analyses. Journal of Child Psychology and Psychiatry;2021 (2021/11/01);62(11):1330-1338.

Background There is mixed evidence for an association between autism spectrum disorder (ASD) and emotion recognition deficits. We sought to assess the bidirectionality of this association using phenotypic and genetic data in a large community sample. Methods Analyses were conducted in three stages. First, we examined the bidirectional association between social autistic traits at age 8 years and emotion recognition task (ERT) responses at age 24 years (Study 1; N = 3,562); and between Diagnostic Analysis of Non-Verbal Accuracy (DANVA) emotion recognition responses at age 8 years and social autistic traits at age 10 years (Study 2; N = 9,071). Next, we used genetic analyses (Study 3) to examine the association between polygenic risk scores for ASD and outcomes for the ERT and DANVA. The genetic correlation between ASD and ERT responses at age 24 was also estimated. Analyses were conducted in the Avon Longitudinal Study of Parents and Children. Results Social autistic traits at age 8 years were negatively associated with later total correct responses on ERT in Study 1 (b = ?0.18; 95% CI: ?0.27 to ?0.09). We also found evidence of an association in Study 2 (b = ?0.04; 95% CI: ?0.05 to ?0.03). We found the opposite association, that is positive, between the ASD polygenic risk score and ERT (b = 0.40; 95% CI: 0.10 to 0.70); however, this association varied across different p-value thresholds and would not survive multiple testing, so should be interpreted with caution. We did not find evidence of a genetic correlation between ASD and ERT. Conclusion We found an observational association between poorer emotion recognition and increased social autistic traits. Our genetic analyses may suggest a shared genetic aetiology between these or a potential causal pathway; however, future research would benefit from using better powered GWAS to examine this further. Our results may inform interventions targeting emotion recognition.

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8. Frewer V, Gilchrist CP, Collins SE, Williams K, Seal ML, Leventer RJ, Amor DJ. A systematic review of brain MRI findings in monogenic disorders strongly associated with autism spectrum disorder. Journal of Child Psychology and Psychiatry;2021 (2021/11/01);62(11):1339-1352.

Background Research on monogenic forms of autism spectrum disorder (autism) can inform our understanding of genetic contributions to the autism phenotype; yet, there is much to be learned about the pathways from gene to brain structure to behavior. This systematic review summarizes and evaluates research on brain magnetic resonance imaging (MRI) findings in monogenic conditions that have strong association with autism. This will improve understanding of the impact of genetic variability on brain structure and related behavioral traits in autism. Methods The search strategy for this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias (ROB) assessment was completed on included studies using the Newcastle-Ottawa Scales. Results Of 4,287 studies screened, 69 were included pertaining to 13 of the top 20 genes with the strongest association with autism. The greatest number of studies related to individuals with PTEN variants and autism. Brain MRI abnormalities were reported for 12 of the 13 genes studied, and in 51.7% of participants across all 13 genes, including 100% of participants with ARID1B variants. Specific MRI findings were highly variable, with no clear patterns emerging within or between the 13 genes, although white matter abnormalities were the most common. Few studies reported specific details about methods for acquisition and processing of brain MRI, and descriptors for brain abnormalities were variable. ROB assessment indicated high ROB for all studies, largely due to small sample sizes and lack of comparison groups. Conclusions Brain abnormalities are common in this population of individuals, in particular, children; however, a range of different brain abnormalities were reported within and between genes. Directions for future neuroimaging research in monogenic autism are suggested.

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9. Gómez-Vallejo S, Leoni M, Ronald A, Colvert E, Happé F, Bolton P. Autism spectrum disorder and obstetric optimality: a twin study and meta-analysis of sibling studies. Journal of Child Psychology and Psychiatry;2021 (2021/11/01);62(11):1353-1362.

Background Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with a strong genetic basis. Recent studies have suggested that its aetiology is also influenced by environmental factors. Some of the most examined environmental factors are obstetric complications. However, the results are inconsistent. Methods We aimed to explore the association between obstetric complications and autism in a population-based twin sample using the Obstetric Enquiry Scale (OES), a scale that measures the presence or absence of pre-, peri- and neonatal factors. Additionally, we report the meta-analytic results for obstetrical factors reported in previously published sibling studies. Results Our study included 115 cases pairs and 62 controls pairs and showed that children with autism and their unaffected co-twins present significantly more obstetric complications than controls (ASD vs. controls ? 1.26, CI 95% 1.11?1.40 p < .001; unaffected co-twin vs. controls ? 1.20, 95% CI 1.07?1.36 p < .003). However, we did not find statistically significant differences between children with ASD and their unaffected co-twins (? .96, 95% CI 0.85?1.09, p 0.55). Meta-analysis demonstrated that maternal hypertension (RR 1.35, CI 95% 1.23?1.48), uterine bleeding (RR 1.20 CI 95% 1.01?1.42) and exposure to antibiotic during pregnancy (1.11 CI 95% 1.00?1.22) increase risk of ASD. Conclusions This study confirms that children with ASD and their unaffected twins show more obstetric complications than controls. However, these complications do not distinguish between ASD twins and their unaffected co-twins. In addition, the meta-analysis showed little influence of birth factors on ASD which suggests a shared familial liability for both obstetric complications and autism, rather than a causal association.

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10. Manzini A, Jones EJH, Charman T, Elsabbagh M, Johnson MH, Singh I. Ethical dimensions of translational developmental neuroscience research in autism. Journal of Child Psychology and Psychiatry;2021 (2021/11/01);62(11):1363-1373.

Background Since the 1990s, increasing research has been devoted to the identification of biomarkers for autism to help attain more objective diagnosis; enable early prediction of prognosis; and guide individualized intervention options. Early studies focused on the identification of genetic variants associated with autism, but more recently, research has expanded to investigate neurodevelopmental markers. While ethicists have extensively discussed issues around advances in autism genomics, much less ethical scrutiny has focused on research on early neurodevelopment and on the interventions being developed as a result. Objectives We summarize the current state of the science on the identification of early markers for autism and its potential clinical applications, before providing an overview of the ethical issues arising from increasing understanding of children’s neurodevelopment in very early life. Results Advances in the understanding of brain and behavioral trajectories preceding later autism diagnosis raise ethical concerns around three themes: (a) New models for understanding autism; (b) Risks and benefits of early identification and intervention; and (c) Communication of early concerns to families. These ethical issues should be further investigated in research conducted in partnership with autistic people and their families. Conclusions This paper highlights the need for ethical scrutiny of early neurodevelopmental research in autism. Scrutiny requires expertise and methods from the basic sciences and bioethics, as well as constructive collaborations among autistic people, their parents, and autism researchers to anticipate early interventions that serve the community’s interests and accommodate the varied experiences and preferences of people on the spectrum and their families.

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