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Phenotype-Genotype Associations in Concordant and Discordant Monozygotic and Dizygotic Twins Based on Quantitative Trait and Case-Control Association Analyses Open Access

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Autism is a highly heterogeneous and heritable neurodevelopmental disorder that is characterized by impaired communication, stereotyped behaviors, and impaired social interactions. There has been much discussion about the amount of genetic contribution based on concordance rates of diagnosed autism in monozygotic versus dizygotic twins. However, there is little to no information on the genetic contributions to the individual behavioral traits that make up the diagnostic criteria of autism. Here, we compared the phenotypic profiles of both concordant and discordant mono- and dizygotic twins across five behavioral traits (language, nonverbal communication, play skills, social behaviors, and insistence on sameness), using cumulative trait severity scores from the Autism Diagnostic Interview-Revised instrument for each individual. These trait profiles across the respective twin populations were then used for quantitative trait association analyses using publicly available genotype data for the respective individuals. Any SNPs with an unadjusted p-value less than 10-5 were then used for case-control association analyses, where the cases were individuals represented within the first and third quartiles of the quantitative trait distribution curves and the controls a group of 2,438 non-autistic individuals. Open access genotype data for all of these individuals were downloaded from the Autism Genetics Resource Exchange website. Deep phenotypic analyses revealed significant differences in the severity of discordant non-autistic monozygotic and dizygotic twins, with the dizygotic individuals having a much less severe phenotype across all five traits. On the other hand, both concordant and discordant autistic twins shared a similar phenotype across all five traits, no matter the zygosity. Case-control association analyses with a focus on SNPs from the quantitative trait association analyses revealed significant genetic variants that clearly distinguish the third quartile individuals with high severity from those individuals with low severity in the first quartile, even after Benjamini-Hochberg multiple test correction. Pathway analysis revealed that these genetic variants were significantly associated with a number of functions related to autism. When compared to the SFARI gene list, which includes validated autism genes, hypergeometric distribution analysis reveals an overrepresentation of genes associated with the third quartile of monozygotic discordant twins within this list. In summary, the comparison of monozygotic versus dizygotic discordant twins suggests that genotype plays a significant role in determining autistic traits; the phenotypic similarity of diagnostically concordant dizygotic twins also suggests a role for the environment.

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