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    • W63. INVESTIGATING THE POLYGENIC ARCHITECTURE OF AUTISM WITH AND WITHOUT INTELLECTUAL DISABILITY

    Jing Zhang,Caitlin Carey,Susan Kuo,Ajay Nadig,Swapnil Awasthi,Jakob Grove,Anders Borglum,Elise Robinson

    EUROPEAN NEUROPSYCHOPHARMACOLOGY（2023）

    Broad Inst MIT & Harvard

    Cited 0|Views16
    Abstract
    Autism is a heterogeneous group of diagnoses, including both individuals with co-existing intellectual disability (ID) and individuals with average or above average intellectual quotient (IQ). Autism is highly heritable and has been associated with multiple classes of genetic variation. De novo single nucleotide and structural variation that increase the probability of an autism diagnosis are often associated with ID or decreased IQ. In contrast, inherited genetic associations to autism are on average IQ increasing. Given the potentially different genetic architectures of autism with (w/) and without (w/o) ID, we conducted a stratified genome-wide association study (GWAS) to investigate the genetic signatures of those subgroups. We analyzed 1,685 trios from Simons Simplex Collection (SSC) and 6,971 trios from Simons Powering Autism Research for Knowledge (SPARK). Intellectual disability in SSC was defined as IQ. The GWAS meta-analysis included 4,357 autism w/o ID trios and 3,993 autism w/ ID trios. We observed one genome-wide-significant locus in the autism w/ ID GWAS (lead SNP: rs12994053; odds ratio = 1.23; P = 3.50e-9), close to the gene ST3GAL5. The SNP heritabilities of autism w/o ID (0.17; SE=0.03) and autism w/ ID (0.16; SE=0.03) were similar, with a high degree of genetic correlation between them (0.81; P=2.37e-7). Autism w/o ID was positively genetically correlated with educational attainment (0.26; P=2.10e-8) and intelligence (0.24; P=5.00e-4). Autism w/ ID was positively genetically correlated with educational attainment (0.18; P=2.00e-4) but not with intelligence (0.09; P=0.21). We report a stratified GWAS meta-analysis of autism w/ and w/o ID in SSC and SPARK. Although the two subgroups have similar SNP heritability and a high degree of genetic correlation, we observed suggestive evidence that autism w/ and w/o ID have different genetic correlation profiles with intelligence. As ID alone is negatively genetically correlated with intelligence, the lack of association between autism w/ ID and intelligence strongly suggests that autism and ID together are genetically different from ID alone. This difference has implications for both research and clinical nosology. Studying the shared and distinct genetic signature of autism w/ and w/o ID might provide an opportunity to parse the heterogeneity and uncover new biological insights into neurodevelopmental variability.
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    Autism
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