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    Original Investigation
    February 7, 2020

    Association of Genetic Risks With Autism Spectrum Disorder and Early Neurodevelopmental Delays Among Children Without Intellectual Disability

    Author Affiliations
    • 1Research Center for Child Mental Development, Hamamatsu University School of Medicine, Hamamatsu, Japan
    • 2Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan
    • 3Queens College and Graduate Center, City University of New York, New York
    JAMA Netw Open. 2020;3(2):e1921644. doi:10.1001/jamanetworkopen.2019.21644
    Key Points español 中文 (chinese)

    Question  Are genetic risks for autism spectrum disorder (ASD) also associated with neurodevelopment in infancy and ASD traits among children in the general population?

    Findings  In this cohort study of 734 infants from the Hamamatsu Birth Cohort for Mothers and Children, genetic risks for ASD were associated with ASD traits at age 6 years. The polygenic risk score for ASD was associated with delays in gross motor and receptive language skills at age 18 months.

    Meaning  Genetic risks for ASD are associated with ASD traits in the general population and neurodevelopmental progress among infants as young as 18 months.


    Importance  Autism spectrum disorder (ASD) is highly heritable, and modest contributions of common genetic variants to ASD have been reported. However, the association of genetic risks derived from common risk variants with ASD traits in children from the general population is not clear, and the association of these genetic risks with neurodevelopment in infants has not been well understood.

    Objective  To test whether a polygenic risk score (PRS) for ASD is associated with neurodevelopmental progress at age 18 months and ASD traits at age 6 years among children from the general population.

    Design, Setting, and Participants  In this cohort study, 876 children in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan, underwent testing for the association of an ASD PRS with neurodevelopmental progress and ASD traits. Data collection began in December 2007 and is ongoing. Data analysis was conducted from April to December 2019.

    Main Outcomes and Measures  Summary data from the largest genome-wide association study were used to generate ASD PRSs, and significance of thresholds was calculated for each outcome. The Autism Diagnostic Observation Schedule 2 was used to measure ASD traits at age 6 years, and the Mullen Scales of Early Learning was used to measure neurodevelopmental progress at age 18 months.

    Results  Of 876 participants (mean [SD] gestational age at birth, 38.9 [1.6] weeks; 438 [50.0%] boys; 868 [99.1%] Japanese), 734 were analyzed. The ASD PRS was associated with ASD traits (R2 = 0.024; β, 0.71; SE, 0.24; P = .03). The association of ASD PRS with infant neurodevelopment was most pronounced in gross motor (R2 = 0.015; β, −1.25; SE, 0.39; P = .01) and receptive language (R2 = 0.014; β, −1.19; SE, 0.39; P = .02) scores on the Mullen Scales of Early Learning. Gene set enrichment analyses found that several pathways, such as cell maturation (R2 = 0.057; β, −5.28; SE, 1.40; P < .001) and adenylyl cyclase activity and cyclic adenosine monophosphate concentration (R2 = 0.064; β, −5.30; SE 1.30; P < .001), were associated with ASD traits. Gene sets associated with inflammation were commonly enriched with ASD traits and gross motor skills (eg, chemokine motif ligand 2 production: R2 = 0.051; β, −6.04; SE, 1.75; P = .001; regulation of monocyte differentiation: R2 = 0.052; β, −6.63; SE, 1.90; P = .001; and B-cell differentiation: R2 = 0.051; β, 7.37; SE, 2.15; P = .001); glutamatergic signaling–associated gene sets were commonly enriched with ASD traits and receptive language skills (eg, regulation of glutamate secretion: R2 = 0.052; β, −5.82; SE, 1.68; P = .001; ionotropic glutamate receptor signaling pathway: R2 = 0.047; β, 3.54; SE, 1.09; P = .001; and negative regulation of glutamate secretion: R2 = 0.045; β, −5.38; SE, 1.74; P = .002).

    Conclusions and Relevance  In this study, the ASD PRS was associated with ASD traits among children from the general population. Genetic risks for ASD might be associated with delays in some neurodevelopmental domains, such as gross motor and receptive language skills.