Autism spectrum disorders and autistic traits share genetics and biology

Bralten, Janita; Hulzen, K.J.E. van; Martens, Marijn B.; Galesloot, Tessel E.; Vásquez, Alejandro Arias; Kiemeney, Lambertus A.; Buitelaar, Jan K.; Muntjewerff, Jan-Willem; Franke, Barbara; Poelmans, Geert

doi:10.1038/mp.2017.98

Cited by 144 publications

(130 citation statements)

References 57 publications

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“…Thus, aggressive and anti-social behaviors seem to have a continuous distribution in the population, with individuals having ADHD+DBDs representing an extreme. This is in line with what has been observed for other complex phenotypes, such as diagnosed ADHD representing the upper tail of impulsive and inattention behaviors 42 , and diagnosed autism spectrum disorder representing the upper tail for social communication difficulties and rigidity 55,56 .…”

Section: Discussionsupporting

confidence: 90%

Identification of risk variants and characterization of the polygenic architecture of disruptive behavior disorders in the context of ADHD

Demontis

Walters

Rajagopal

et al. 2019

Preprint

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Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). ADHD comorbid with DBDs (ADHD+DBDs) is a complex phenotype with a risk component that can be attributed to common genetic variants. Here we report a large GWAS meta-analysis of ADHD+DBDs based on seven cohorts in total including 3,802 cases and 31,305 controls. Three genome-wide significant loci were identified on chromosomes 1, 7, and 11. A GWAS meta-analysis including a Chinese cohort supported the locus on chromosome 11 to be a strong risk locus for ADHD+DBDs across European and Chinese ancestries (rs7118422, P=3.15x10 -10 , OR=1.17). This locus was not associated with ADHD without DBDs in a secondary GWAS of 13,583 ADHD cases and 22,314 controls, suggesting that the locus is a specific risk locus for the comorbid phenotype.We found a higher SNP heritability for ADHD+DBDs (h 2 SNP =0.34) when compared to ADHD without DBDs (h 2 SNP =0.20). Genetic correlations of ADHD+DBDs with aggressive (r g =0.81) and anti-social behaviors (r g =0.82) were high, and polygenic risk score analyses revealed a significant increased burden of variants associated with ADHD and aggression in individuals with ADHD+DBDs compared to ADHD without DBDs. Our results suggests that ADHD+DBDs represent a more severe phenotype with respect to the genetic risk load than ADHD without DBDs, in line with previous studies, and that the risk load to some extent can be explained by variants associated with aggressive behavior.

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Section: Discussionsupporting

confidence: 90%

Identification of risk variants and characterization of the polygenic architecture of disruptive behavior disorders in the context of ADHD

Demontis

Walters

Rajagopal

et al. 2019

Preprint

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“…There is increasing evidence that ASD is heterogeneous, and that individual trait measures may have distinct etiologies (Happé & Ronald, ). However, for ADHD, it has been observed that the genetic correlation of ADHD as a disorder and ADHD traits approaches 1 (Demontis et al, ), and there is also genetic correlation between ASD and its associated traits (in ALSPAC [Robinson et al, ], and the Psychiatric Genetics Consortium [Bralten et al, ]). This suggests that studying ADHD/ASD traits in general populations is likely to be a powerful method that will provide useful insights into these disorders.…”

Section: Discussionmentioning

confidence: 99%

Association of copy number variation across the genome with neuropsychiatric traits in the general population

Guyatt

Stergiakouli²,

Martin³

et al. 2018

American J of Med Genetics Pt B

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Copy number variants (CNVs) are associated with psychiatric conditions in clinical populations. The relationship between rare CNV burden and neuropsychiatric traits in young, general populations is underexplored. A total of 6,807 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) were studied. CNVs were inferred from single nucleotide polymorphism‐array data using PennCNV. After excluding children with known candidate CNVs for schizophrenia (SCZ), rare (<1%) CNV burden (total number of genes affected by CNVs, total length of CNVs, and largest CNV carried) was analyzed in relation to: psychotic experiences (PEs) and anxiety/depression in adolescence; autism spectrum disorder (ASD) and attention‐deficit hyperactivity disorder (ADHD), ASD and ADHD traits, and cognitive measures during childhood. Outcomes were also assessed in relation to known SCZ CNVs. The number of genes affected by rare CNVs was associated with a continuous measure of ASD: the standardized mean difference [SMD] per gene affected was increased by 0.018 [95%CI 0.011,0.025], p = 3e‐07 for duplications and by 0.021 [95%CI 0.010, 0.032], p = 1e‐04 for deletions. In line with our published results on educational attainment in ALSPAC, intelligence quotient (IQ) was associated with CNV burden: the SMD per gene affected was −0.017 [95%CI −0.025, −0.008] p = 1e‐04 for duplications and −0.023 [95%CI −0.037, −0.009], p = .002 for deletions. Associations were also observed for measures of coherence, attention, memory, and social cognition. SCZ‐associated deletions were associated with IQ (SMD: −0.617 [95%CI −0.936, −0.298], p = 2e‐04), but not with PEs or other traits. We found that rare CNV burden and known SCZ candidate CNVs are associated with neuropsychiatric phenotypes in a nonclinically ascertained sample of young people.

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“…In addition, common variants have been shown to be of causal significance in the disorder [14][15][16] . Although there are only few genome-wide significant SNPs identified for ASD, the cumulative polygenic variation summarized by PRS has shown to be predictive of ASD and autistic traits in the general population 17,18 . Studies have also indicated shared genetic liability of polygenic risk in ASD and psychiatric disorders 19,20 .…”

Section: Introductionmentioning

confidence: 99%

The influence of common polygenic risk and gene sets on social skills group training response in autism spectrum disorder

Olsson

Jiao

et al. 2019

Preprint

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Social skills group training (SSGT) is one of the most frequently used behavior interventions in children and adolescents with autism spectrum disorder (ASD). Current evidence suggests that the effects are moderate and heterogeneous. Genetic predisposition could be one of the factors contributing to this heterogeneity. Therefore, we used polygenic risk score (PRS) and gene-set analysis to investigate the association between SSGT response and common variants in autistic individuals. Participants from the largest randomized clinical trial of SSGT in ASD to date were selected for genotyping. Polygenic risk scores (PRSs) for ASD, attention deficit hyperactivity disorder (ADHD), and educational attainment (EA) were calculated, and their associations with the intervention outcome at post-intervention and follow-up were tested using mixed linear model. In addition, thirty-two gene sets within five categories (synaptic, glial, FMRP, glutamate, and mitochondrial) were selected to evaluate their role in the intervention outcome. Individuals with higher PRSs for ASD and ADHD had inferior response after SSGT. After multiple test correction, significant results were kept for higher ADHD PRS at follow-up (β = 6.67, p = 0.016). Five gene sets within synaptic category showed modest association with reduced response to SSGT in ASD.Taken together, we provided preliminary evidence that genetic liability calculated using PRS and common variants in synapse gene sets could influence the outcome of SSGT.Our results hold promise for future research into the genetic contribution to individual response to ASD interventions, and should be validated in larger cohorts.

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Autism spectrum disorders and autistic traits share genetics and biology

Cited by 144 publications

References 57 publications

Identification of risk variants and characterization of the polygenic architecture of disruptive behavior disorders in the context of ADHD

Identification of risk variants and characterization of the polygenic architecture of disruptive behavior disorders in the context of ADHD

Association of copy number variation across the genome with neuropsychiatric traits in the general population

The influence of common polygenic risk and gene sets on social skills group training response in autism spectrum disorder

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