The genetic architecture of schizophrenia, bipolar disorder, obsessive-compulsive disorder and autism spectrum disorder

Highlights

• 10 common genes were identified for the aetiology of ASD, SCZ, BD and OCD.

• The majority of genes investigated were disorder-specific.

• Neural development and neuronal maintenance are key in neuropsychiatric disorders.

• Cross-disorder results provide good candidates to combat mental health disorders.

Abstract

Considerable evidence suggests that autism spectrum disorders (ASD), schizophrenia (SCZ), bipolar disorder (BD) and obsessive-compulsive disorder (OCD) share a common molecular aetiology, despite their unique clinical diagnostic criteria. The aim of this study was therefore to determine and characterise the common and unique molecular architecture of ASD, SCZ, BD and OCD. Gene lists were obtained from previously published studies for ASD, BD, SCZ and for OCD. Genes identified to be common to all disorders, or unique to one specific disorder, were included for enrichment analyses using the web-server tool Enrichr. Ten genes were identified to be commonly associated with the aetiology of ASD, SCZ, BD and OCD. Enrichment analyses determined that these genes are predominantly involved in the dopaminergic and serotonergic pathways, the voltage-gated calcium ion channel gene network, folate metabolism, regulation of the hippo signaling pathway, and the regulation of gene silencing and expression. In addition to well-characterised and previously described pathways, regulation of the hippo signaling pathway was commonly associated with ASD, SCZ, BD and OCD, implicating neural development and neuronal maintenance as key in neuropsychiatric disorders. In contrast, a large number of previously associated genes were shown to be disorder-specific. And unique disorder-specific pathways and biological processes were presented for ASD, BD, SCZ and OCD aetiology. Considering the current global incidence and prevalence rates of mental health disorders, focus should be placed on cross-disorder commonalities in order to realise actionable and translatable results to combat mental health disorders.

Introduction

Clinically autism spectrum disorders (ASD), schizophrenia (SCZ), bipolar disorder (BD) and obsessive-compulsive disorder (OCD) differ substantially in that they not only fall into different categories of the DSM (American Psychiatric Association, 2013), but also differ in age of onset, neurocognitive profiles and neuroimaging (American Psychiatric Association, 2013). Genetically, however, they might be more similar in a broader sense (psychiatric disorders) whereby common symptom overlap might be somewhat attributable to common underlying molecular mechanisms (Carroll and Owen, 2009; Khanzada et al., 2017). Research supports this theory in that a number of independent single disorder genome-wide association studies (GWAS) have identified the same significant loci regardless of disorder (Consortium et al., 2013), and a number of cross-disorder case-control GWAS association studies have yielded significant results (Carroll and Owen, 2009). Similar behavioural, social, cognitive and perceptual disturbances are observed in individuals suffering from ASD, SCZ, BD and OCD (American Psychiatric Association, 2013; Vannucchi et al., 2014), while molecular overlap, at both genetic and transcriptomic levels, has been identified for the aetiology of SCZ, BD and ASD (Carroll and Owen, 2009; Gandal et al., 2016; Khanzada et al., 2017), and suggested for ASD and OCD (Jacob et al., 2009). Considering the latter, the exact molecular mechanisms that OCD may share with ASD have not been described, while unpublished results suggest molecular overlap between OCD, SCZ and BD (Anttila et al., 2017).

In addition to the molecular overlap described above, clinical evidence further suggests common aetiology for neuropsychiatric disorders. Individuals affected by OCD and SCZ show similar age-related reductions in white matter connectivity, with overlapping spatial pattern deficits, suggesting common neurobiology (Hawco et al., 2016). Obsessive-compulsive behaviors are present in some ASD affected individuals (Cath et al., 2008), while individuals suffering from OCD have increased comorbid diagnoses of both SCZ and BD (Cederlöf et al., 2015), as well as ASD traits (Ivarsson and Melin, 2008), further suggesting common aetiology for these neuropsychiatric disorders. Despite evidence to suggest common aetiology for these neuropsychiatric disorders they present with distinct clinical profiles, suggesting that each must have a corresponding unique genetic architecture.

This study aims to characterise the common and unique molecular architecture of ASD, SCZ, BD and OCD by analysing previously identified associations with the aforementioned neuropsychiatric disorders.