Autism spectrum disorder severity reflects the average contribution of de novo and familial influences

Abstract

Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions-phenotypically and genetically-although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.neuropsychiatric genetics | epidemiology | heterogeneity | phenotype

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

“…Recent reports have described a similar reduction in IQ in the presence of a de novo LoF (dnLoF) mutation (Iossifov et al, 2014; Robinson et al, 2014; Samocha et al, 2014). Using the combined CNV and exome data in the SSC, we considered how sex and type of de novo mutation interact with non-verbal IQ (NVIQ).…”

Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia

“…Mutations associated with intellectual disability and developmental disorders are often also substantial risk factors for syndromic forms of autism and perhaps schizophrenia 38–40,17 . We did observe the dURV elevation to be concentrated in X-linked intellectual disability (XLID) genes 41,42 (OR=1.88; 95% CI=1.34–2.64; P = 9.5 × 10 −4 ) and in developmental disorder (DD) genes 43 (OR=1.67; 95% CI=1.31-2.13; P = 1.6 × 10 −4 ) ( Online Methods ).…”

The serotonin system in autism spectrum disorder: From biomarker to animal models

“…This could be taken as evidence that the serotonin system is less important than previously thought; however, the high heritability of whole blood 5-HT could suggest that individuals with hyperserotonemia are less likely to have a de novo event and more likely to fit the common, inherited variant model still favored by epidemiological data (Gaugler et al, 2014). It is also possible that hyperserotonemia is less well represented in the group of patients with intellectual disability and/or epilepsy that shows an over-representation of de novo , gene-disrupting variants (Robinson et al, 2014, Sanders et al, 2015). These ideas could be tested by assessing the contribution of de novo mutations in individuals with or without hyperserotonemia.…”