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. 2014 Oct 21;111(42):15161-5.
doi: 10.1073/pnas.1409204111. Epub 2014 Oct 6.

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

Elise B Robinson  1 , Kaitlin E Samocha  2 , Jack A Kosmicki  3 , Lauren McGrath  4 , Benjamin M Neale  5 , Roy H Perlis  6 , Mark J Daly  5
Affiliations

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

Elise B Robinson et al. Proc Natl Acad Sci U S A. .

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.

Keywords: epidemiology; heterogeneity; neuropsychiatric genetics; phenotype.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
De novo LOF mutations and IQ in ASDs. Error bars on IQ attempted but not scored estimates indicate ±1 SE.
Fig. 2.
Fig. 2.
Family history of psychiatric disease and IQ in ASDs. P values are adjusted for race/ethnicity; purple circles indicate fraction of participants with a family history of psychiatric hospitalization, for males and females respectively; blue circles indicate fraction of participants with a family history of DD, BPD, or SCZ, for males and females respectively; error bars on all IQ attempted but not scored estimates indicate ±1 SE. For family history of hospitalization, the male-specific line is obscured by that for all individuals.
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References

    1. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 5th Ed American Psychiatric Publishing; Arlington, VA: 2013.
    1. Fein D, et al. Optimal outcome in individuals with a history of autism. J Child Psychol Psychiatry. 2013;54(2):195–205. - PMC - PubMed
    1. Gotham K, Pickles A, Lord C. Trajectories of autism severity in children using standardized ADOS scores. Pediatrics. 2012;130(5):e1278–e1284. - PMC - PubMed
    1. Skuse DH. Is autism really a coherent syndrome in boys, or girls? Br J Psychol. 2009;100(Pt 1):33–37. - PubMed
    1. Stein JL, Parikshak NN, Geschwind DH. Rare inherited variation in autism: Beginning to see the forest and a few trees. Neuron. 2013;77(2):209–211. - PMC - PubMed

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