Kristen Lyall1, John N Constantino2, Marc G Weisskopf3, Andrea L Roberts4, Alberto Ascherio5, Susan L Santangelo6. 1. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts2Department of Public Health Sciences, University of California, Davis. 2. Department of Psychiatry, Washington University, St Louis, Missouri. 3. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts5Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts. 4. Department of Social and Behavioral Sciences, Harvard School of Public Health, Boston, Massachusetts. 5. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts4Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts7Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital. 6. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts8Department of Psychiatry, Maine Medical Center/Maine Medical Center Research Institute, Portland.
Abstract
IMPORTANCE: Although autism spectrum disorder (ASD) is known to be heritable, patterns of inheritance of subclinical autistic traits in nonclinical samples are poorly understood. OBJECTIVE: To examine the familiality of Social Responsiveness Scale (SRS) scores of individuals with and without ASD. DESIGN, SETTING, AND PARTICIPANTS: We performed a nested case-control study (pilot study: July 1, 2007, through June 30, 2009; full-scale study: September 15, 2008, through September 14, 2012) within a population-based longitudinal cohort. Participants were drawn from the Nurses' Health Study II, a cohort of 116,430 female nurses recruited in 1989. Case participants were index children with reported ASD; control participants were frequency matched by year of birth of case participants among those not reporting ASD. Of 3161 eligible participants, 2144 nurses (67.8%) returned SRS forms for a child and at least 1 parent and were included in these analyses. EXPOSURE: The SRS scores, as reported by nurse mothers and their spouses, were examined in association with risk of ASD using crude and adjusted logistic regression analyses. The SRS scores of the children were examined in association with SRS scores of the parents using crude and adjusted linear regression analyses stratified by case status. MAIN OUTCOMES AND MEASURES: Autism spectrum disorder, assessed by maternal report, validated in a subgroup with the Autism Diagnostic Interview-Revised. RESULTS: A total of 1649 individuals were included in these analyses, including 256 ASD case participants, 1393 control participants, 1233 mothers, and 1614 fathers. Risk of ASD was increased by 85.0% among children whose parents had concordantly elevated SRS scores (odds ratio [OR], 1.85; 95% CI, 1.08-3.16) and by 52.0% when the score of either parent was elevated (OR, 1.52; 95% CI, 1.11-2.06). Elevated scores of the father significantly increased the risk of ASD in the child (OR, 1.94; 95% CI, 1.38-2.71), but no association was seen with elevated scores of the mother. Elevated parent scores significantly increased child scores in controls, corresponding to an increase in 23 points (P < .001). CONCLUSIONS AND RELEVANCE: These findings support the role of additive genetic influences in concentrating inherited ASD susceptibility in successive generations and the potential role of preferential mating, and suggest that typical variation in parental social functioning can produce clinically significant differences in offspring social traits.
IMPORTANCE: Although autism spectrum disorder (ASD) is known to be heritable, patterns of inheritance of subclinical autistic traits in nonclinical samples are poorly understood. OBJECTIVE: To examine the familiality of Social Responsiveness Scale (SRS) scores of individuals with and without ASD. DESIGN, SETTING, AND PARTICIPANTS: We performed a nested case-control study (pilot study: July 1, 2007, through June 30, 2009; full-scale study: September 15, 2008, through September 14, 2012) within a population-based longitudinal cohort. Participants were drawn from the Nurses' Health Study II, a cohort of 116,430 female nurses recruited in 1989. Case participants were index children with reported ASD; control participants were frequency matched by year of birth of case participants among those not reporting ASD. Of 3161 eligible participants, 2144 nurses (67.8%) returned SRS forms for a child and at least 1 parent and were included in these analyses. EXPOSURE: The SRS scores, as reported by nurse mothers and their spouses, were examined in association with risk of ASD using crude and adjusted logistic regression analyses. The SRS scores of the children were examined in association with SRS scores of the parents using crude and adjusted linear regression analyses stratified by case status. MAIN OUTCOMES AND MEASURES: Autism spectrum disorder, assessed by maternal report, validated in a subgroup with the Autism Diagnostic Interview-Revised. RESULTS: A total of 1649 individuals were included in these analyses, including 256 ASD case participants, 1393 control participants, 1233 mothers, and 1614 fathers. Risk of ASD was increased by 85.0% among children whose parents had concordantly elevated SRS scores (odds ratio [OR], 1.85; 95% CI, 1.08-3.16) and by 52.0% when the score of either parent was elevated (OR, 1.52; 95% CI, 1.11-2.06). Elevated scores of the father significantly increased the risk of ASD in the child (OR, 1.94; 95% CI, 1.38-2.71), but no association was seen with elevated scores of the mother. Elevated parent scores significantly increased child scores in controls, corresponding to an increase in 23 points (P < .001). CONCLUSIONS AND RELEVANCE: These findings support the role of additive genetic influences in concentrating inherited ASD susceptibility in successive generations and the potential role of preferential mating, and suggest that typical variation in parental social functioning can produce clinically significant differences in offspring social traits.
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