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

Proc Natl Acad Sci U S A
Authors
Keywords
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.

Year of Publication
2014
Journal
Proc Natl Acad Sci U S A
Volume
111
Issue
42
Pages
15161-5
Date Published
2014 Oct 21
ISSN
1091-6490
URL
DOI
10.1073/pnas.1409204111
PubMed ID
25288738
PubMed Central ID
PMC4210299
Links
Grant list
102215 / Wellcome Trust / United Kingdom
K01 MH099286 / MH / NIMH NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
1K01MH099286-01A1 / MH / NIMH NIH HHS / United States