Family Neurologic and Psychiatric History and the Risk of Autism Spectrum Disorder
Authors:   , Xie Sherlly , Lee Brian K. 
Published: July 2021

Objective: In this dissertation, we aimed to determine: 1). familial recurrence risk of autism spectrum disorder (ASD) with and without intellectual disability (ID), as well as 2). risk of these ASD subtypes associated with family history of mental and neurologic disorders. Study design: We conducted a population-based cohort study for each research aim. Index persons (IPs) through whom families were identified (n = 567,436) were non-adopted singleton births identified from the Stockholm Youth Cohort, who were born between 1984 and 2009 in Stockholm County, Sweden, could be linked to both biological parents, and had resided in Stockholm County for at least 2 years at the end of follow-up. The Multi-Generation Register was used to determine family relations for each IP up to four degrees of relatedness. Diagnoses data were ascertained from regional and national registers using International Classification of Diseases and Diagnosis and Statistical Manual of Mental Disorders codes, as well as health services records. Methods: Logistic regression with robust standard error was used to estimate the odds ratio of ASD with or without ID in IPs with relative affected vs. unaffected by ASD and other neurologic and psychiatric disorders. Heritability analysis was carried out using structural equation modeling. Results: ASD without ID was more heritable than ASD with ID, broad-sense heritability (95% confidence interval): 61.5% (35.4-88.3%) vs. 25.7% (9.0-57.0%), respectively. ASD without ID was more familial than ASD with ID. The more closely related the affected family member was, the greater the observed risk was of ASD in the IPs, especially for ASD without ID. For example, for IPs with mothers affected by ASD, the IPs' odds of ASD with and without ID increased by 10.8 and 19.6 folds, respectively, whereas for IPs with affected aunts, the odds of ASD with and without ID increased by 1.3 and 1.8 folds, respectively. As for family history of neurologic and psychiatric disorders, ASD without ID was associated with more disorders and generally more strongly compared to ASD with ID, especially for mental disorders. Family history of multiple disorders was associated with greater risk, including history of ASD, ID, attention-deficit/hyperactivity disorder, obsessive compulsive disorder, schizophrenia and other non-affective psychotic disorders, depression, bipolar and personality disorders, cerebral palsy, and epilepsy. Conclusions: Familial risk and heritability of ASD without ID is higher than that of ASD with ID. This implies that risk factors between these phenotypes differ as well. Both of ASD with and without ID variance can be explained by substantial genetic and environmental sources. Also, family history of mental and neurologic disorders is associated with ASD, and this familial risk differs by presence or absence of ID. Our findings encourage us to pursue with examining these phenotypes separately in future ASD risk research and prediction endeavors, and to extend the investigation to extended family members and possible genetic and environmental risk factors as well as their interactions.