Quantitative trait locus analysis for endophenotypes reveals genetic substrates of core symptom domains and neurocognitive function in autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders and is largely attributable to genetic risk factors. Phenotypic and genetic heterogeneity of ASD have been well-recognized; however, genetic substrates for endophenotypes that constitute phenotypic heterogeneity are not yet known. In the present study, we compiled data from the Autism Genetic Resource Exchange, which contains the demographic and detailed phenotype information of 11,961 individuals. Notably, the whole-genome sequencing data available from MSSNG and iHART for 3833 individuals in this dataset was used to perform an endophenotype-wide association study. Using a linear mixed model, genome-wide association analyses were performed for 29 endophenotype scores and 0.58 million common variants with variant allele frequency ≥ 5%. We discovered significant associations between 9 genetic variants and 6 endophenotype scores comprising neurocognitive development and severity scores for core symptoms of ASD at a significance threshold of p < 5 × 10–7. Of note, the Stereotyped Behaviors and Restricted Interests total score in Autism Diagnostic Observation Schedule Module 3 was significantly associated with multiple variants in the VPS13B gene, a causal gene for Cohen syndrome and a candidate gene for syndromic ASD. Our findings yielded loci with small effect sizes due to the moderate sample size and, thus, require validation in another cohort. Nonetheless, our endophenotype-wide association analysis extends previous candidate gene discovery in the context of genotype and endophenotype association. As a result, these candidate genes may be responsible for specific traits that constitute core symptoms and neurocognitive function of ASD rather than the disorder itself.

Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorder

“…Significant features associated with genotype were tested for correlation with phonotype scores, using 29 different scores from 9 instruments for core symptoms of ASD or neurocognitive development ( Table S2 ). 25 We used a generalized linear regression model with subjects’ sex and age as covariates ( phenotype score ∼ log 2 ( feature ) + sex + age ). For features that showed significant associations with both phenotype scores and genetic variants, we conducted a mediation analysis to test whether the metabolite mediated the genetic effect on phenotype score using PROCESS macro v4.1 for IBM SPSS version 27.…”

“… 23 , 24 Moreover, our previous study identified a correlation between common variants in the VPS13B gene, a causal gene for Cohen syndrome, and the total score of Stereotyped Behaviours and Restricted Interests, further highlighting the utility of endophenotypes. 25 Thus, endophenotypes present a promising avenue to connect genotypes with the complex ASD phenotype. This offers the potential to define subgroups with shared pathobiological mechanisms, clinical trajectories, and responses to treatment.…”

Five interdisciplinary tensions and opportunities in neurodiversity research

“…The trait approach is also better suited to explain the complex variability in characteristics among people with the same diagnosis ( Lyall, 2023 ). Moreover, the trait approach is more closely linked to the biological processes underlying neurodevelopmental conditions (e.g., certain genes are linked to specific autistic traits, rather than to an autism diagnosis; Lee et al, 2022 ).…”

Could an Eye-Tracking Test Aid Clinicians in Making an Autism Diagnosis?

“…Finally, quantitative, objective, and scalable biomarkers, such as the eye-tracking test, could be used as an endophenotype in genetic studies. Such measures could be incorporated into studies using quantitative trait locus analysis to understand genetic contributions to autism . Quantitative, easy-to-administer biomarkers that are feasible in large-scale genetic studies will be useful for parsing the heterogeneity of autism and increasing the diversity and representation of participants in autism research studies.…”