title: 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.
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142; erobinson@atgu.mgh.harvard.edu.
authors.forename: Elise B
authors.initials: EB
authors.lastname: Robinson
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142; Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02114;
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Samocha
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142; Center for Biomedical Informatics, Harvard Medical School, Boston, MA 02115;
authors.forename: Jack A
authors.initials: JA
authors.lastname: Kosmicki
authors.affiliation: School of Education, Teaching, and Health, American University, Washington, DC 20016; and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Lauren
authors.initials: L
authors.lastname: McGrath
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142;
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.affiliation: Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142; Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Roy H
authors.initials: RH
authors.lastname: Perlis
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142;
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
mesh_terms: D001519:Behavior; D001714:Bipolar Disorder / Q000235:genetics; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D003072:Cognition Disorders; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007361:Intelligence Tests; D008297:Male; D009154:Mutation; D010641:Phenotype; D012044:Regression Analysis; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics; D012640:Seizures
keywords: epidemiology; heterogeneity; neuropsychiatric genetics; phenotype