Abstract
Mounting evidence shows genetic overlap between multiple psychiatric disorders. However, the biological underpinnings of shared risk for psychiatric disorders are not yet fully uncovered. The identification of underlying biological mechanisms is crucial for the progress in the treatment of these disorders. We applied gene-set analysis including 7372 gene sets, and 53 tissue-type specific gene-expression profiles to identify sets of genes that are involved in the etiology of multiple psychiatric disorders. We included genome-wide meta-association data of the five psychiatric disorders schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder. The total dataset contained 159 219 cases and 262 481 controls. We identified 19 gene sets that were significantly associated with the five psychiatric disorders combined, of which we excluded five sets because their associations were likely driven by schizophrenia only. Conditional analyses showed independent effects of several gene sets that in particular relate to the synapse. In addition, we found independent effects of gene expression levels in the cerebellum and frontal cortex. We obtained novel evidence for shared biological mechanisms that act across psychiatric disorders and we showed that several gene sets that have been related to individual disorders play a role in a broader range of psychiatric disorders.
Highlights
Psychiatric disorders pose an enormous burden on affected individuals, their families, and society as a whole, and insight into causal factors and successful treatment is strikingly limited (Akil et al, 2010)
This study reported a role of gene sets involved in histone methylation, immune and neuronal signaling, and the synapse across SCZ, bipolar disorder (BD), and major depressive disorder (MDD)
Nine gene sets related to the synapse, five gene sets related to components of the neuron, targets of the Fragile X mental retardation protein (FMRP), targets of the micro RNA MIR137, a gene set related to membrane depolarization, and a gene set related to transcription were significantly associated across the five disorders
Summary
Psychiatric disorders pose an enormous burden on affected individuals, their families, and society as a whole, and insight into causal factors and successful treatment is strikingly limited (Akil et al, 2010). Psychiatric disorders contain a strong genetic component (Polderman et al, 2015) and mounting evidence shows genetic overlap of common single nucleotide variants (SNPs) between multiple disorders (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013a, 2013b; Bulik-Sullivan et al, 2015a; Anttila et al, 2018; Schork et al, 2019), primarily schizophrenia (SCZ), bipolar disorder (BD), major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). This genetic overlap of common SNPs might be driven by biological mechanisms that are shared between multiple disorders. We obtained novel evidence for shared biological mechanisms that act across psychiatric disorders and we showed that several gene sets that have been related to individual disorders play a role in a broader range of psychiatric disorders
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