Abstract
Individuals with autism spectrum disorder (ASD) have heterogeneous comorbid conditions. This study examined whether comorbid conditions in ASD are associated with polygenic risk scores (PRS) of ASD or PRS of comorbid conditions in non-ASD specific populations. Genome-wide single nucleotide polymorphism (SNP) data were obtained from 1386 patients with ASD from the Autism Genetic Resource Exchange (AGRE) study. After excluding individuals with missing clinical information concerning comorbid conditions, a total of 707 patients were included in the study. A total of 18 subgroups of comorbid conditions (‘topics’) were identified using a machine learning algorithm, topic modeling. PRS for ASD were computed using a genome-wide association meta-analysis of 18,381 cases and 27,969 controls. From these 18 topics, Topic 6 (over-represented by allergies) (p = 1.72 × 10−3) and Topic 17 (over-represented by sensory processing issues such as low pain tolerance) (p = 0.037) were associated with PRS of ASD. The associations between these two topics and the multi-locus contributors to their corresponding comorbid conditions based on non-ASD specific populations were further explored. The results suggest that these two topics were not associated with the PRS of allergies and chronic pain disorder, respectively. Note that characteristics of the present AGRE sample and those samples used in the original GWAS for ASD, allergies, and chronic pain disorder, may differ due to significant clinical heterogeneity that exists in the ASD population. Additionally, the AGRE sample may be underpowered and therefore insensitive to weak PRS associations due to a relatively small sample size. Findings imply that susceptibility genes of ASD may contribute more to the occurrence of allergies and sensory processing issues in individuals with ASD, compared with the susceptibility genes for their corresponding phenotypes in non-ASD individuals. Since these comorbid conditions (i.e., allergies and pain sensory issues) may not be attributable to the corresponding comorbidity-specific biological factors in non-ASD individuals, clinical management for these comorbid conditions may still depend on treatments for core symptoms of ASD.
Highlights
Individuals with autism spectrum disorder (ASD) have heterogeneous comorbid conditions
Combining PRSASD and PRSpain improved the prediction of Topic 17 and boosted the strength of associations for each of the two polygenic risk scores (PRS) (PRSASD S4: p = 0.022; PRSpain S5: p = 0.031)
The current study shows that polygenic loading in ASD may play a larger role in certain subgroups of comorbid conditions in ASD, such as allergy-related conditions, and sensory processing issues than other subgroups of comorbid conditions
Summary
Individuals with autism spectrum disorder (ASD) have heterogeneous comorbid conditions. A recent study used polygenic risk scores (PRS) derived from five psychiatric disorders, such as schizophrenia, major depressive disorder, attention deficit hyperactivity disorder, obsessive–compulsive disorders, and anxiety, and found that the polygenic contributions could distinguish Asperger syndrome (a diagnostic category in the Diagnostic and Statistical Manual (DSM) 4th Edition this term is no longer used in the updated DSM-5) from individuals with other non-Asperger subtypes of A SD16,17 Despite these advances in understanding the relationships between the genetic bases for ASD and associated comorbidities, it is clear that these approaches require further development to fully understand the role of comorbid genetic risk within ASD. The present study extends the topic modeling approach applied by McCoy and colleagues by (1) implementing a novel method for constructing document data from epidemiological data; (2) determining the number of topics was determined by a semi-unsupervised process that maximizes the trade-off between topic sensitivity and term specificity, and (3) jointly investigating associations between topics of ASD and three sets of PRSs of ASD and its clinically co-morbid conditions of interest, namely, chronic pain and allergies, respectively
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