Integrative analysis of genetic data sets reveals a shared innate immune component in autism spectrum disorder and its co-morbidities

Abstract

BackgroundAutism spectrum disorder (ASD) is a common neurodevelopmental disorder that tends to co-occur with other diseases, including asthma, inflammatory bowel disease, infections, cerebral palsy, dilated cardiomyopathy, muscular dystrophy, and schizophrenia. However, the molecular basis of this co-occurrence, and whether it is due to a shared component that influences both pathophysiology and environmental triggering of illness, has not been elucidated. To address this, we deploy a three-tiered transcriptomic meta-analysis that functions at the gene, pathway, and disease levels across ASD and its co-morbidities.ResultsOur analysis reveals a novel shared innate immune component between ASD and all but three of its co-morbidities that were examined. In particular, we find that the Toll-like receptor signaling and the chemokine signaling pathways, which are key pathways in the innate immune response, have the highest shared statistical significance. Moreover, the disease genes that overlap these two innate immunity pathways can be used to classify the cases of ASD and its co-morbidities vs. controls with at least 70 % accuracy.ConclusionsThis finding suggests that a neuropsychiatric condition and the majority of its non-brain-related co-morbidities share a dysregulated signal that serves as not only a common genetic basis for the diseases but also as a link to environmental triggers. It also raises the possibility that treatment and/or prophylaxis used for disorders of innate immunity may be successfully used for ASD patients with immune-related phenotypes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1084-z) contains supplementary material, which is available to authorized users.

Autism spectrum disorder in children with Type 1 diabetes

“…Given the high prevalence of ASD and the extra challenges facing individuals with the condition, it is important to identify with which comorbidities ASD is associated. Individuals with ASD have higher rates of comorbidities including a number of autoimmune diseases [11][12][13][14][15][16][17][18][19]. Some of these studies have shown an increased prevalence of ASD in children with Type 1 diabetes compared with the general population, whereas others have shown no difference.…”

Neonatal levels of acute phase proteins and risk of autism spectrum disorders

“…Of the APP studied, CRP had the strongest association with risk of ASD in the case-control comparison, displaying a U-shaped association with odds of ASD. While the shape of the association between CRP and odds of ASD in the sibling comparison was similar, the association was less apparent with considerably wider confidence intervals in the sibling analysis, possibly reflecting shared common genetic variation in innate immune signaling and risk of ASD (8). We also observed a weaker relationship between CRP and risk of ASD among those whose mothers had a previous history of psychiatric illness in the case-control comparison, with a significant interaction detected between maternal psychiatric history and levels of CRP.…”

“…Peripheral concentrations of cytokines and chemokines involved in the innate and adaptive immune responses vary in individuals already diagnosed with ASD compared to controls (3,4), though the prevalence of multiple disorders of the immune system (e.g., asthma, infections, allergy, autoimmune disorders) is also higher in individuals with ASD (5)(6)(7). Integrative analyses of genetic and transcriptomic data suggest that ASD and several of these commonly co-occurring conditions may be related via shared mechanisms involving innate immunity (8).…”

A comparative study on medical comorbidities among children with autism spectrum disorder and controls in a children’s hospital

“…Co-occurrence of ASD with disorders with immunological aetiology is widely reported in the literature. A recent molecular genetic study revealed shared immune components between ASD and multiple co-morbid medical disorders 7 . It has also been proposed that autism is based on immune mediated mechanisms and implicates the possibility of an aetiological association between bronchial asthma and autism 8 .…”