GWAS SNPs Impact Shared Regulatory Pathways Amongst Multimorbid Psychiatric Disorders and Cognitive Functioning

Abstract

Background: Epidemiological research has reported that attention-deficit hyperactivity disorder (ADHD), anxiety, bipolar disorder (BD), schizophrenia (SCZ), and unipolar depression (UD) are multimorbid conditions that are typically accompanied by cognitive advantages or deficits, suggesting that common biological mechanisms may underlie these phenotypes. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with psychiatric disorders and cognitive functioning. However, the mechanisms by which these SNPs contribute to multimorbidities amongst psychiatric and cognitive phenotypes remains largely unknown. Objective: To identify shared regulatory mechanisms amongst multimorbid psychiatric disorders and cognitive functioning. Methods: We integrated data on 3D genome organization, expression quantitative trait loci (eQTLs), and pathway analyses to identify shared and specific regulatory impacts of 2,893 GWAS SNPs (p < 1 × 10^-6) associated with ADHD, anxiety, BD, SCZ, UD, and cognitive functioning on genes and biological pathways. Drug-gene interaction analysis was performed to identify potential pharmacological impacts on these genes and pathways. Results: The analysis revealed 33 genes and 62 pathways that were commonly affected by tissue-specific gene regulatory interactions associated with all six phenotypes despite there being no common SNPs in our original dataset. The analysis of brain-specific regulatory connections revealed similar patterns at eQTL and eGene levels, but no pathways shared by all six phenotypes. Instead, pairwise overlaps and individualized pathways were identified for psychiatric and cognitive phenotypes in brain tissues. Conclusions: This study offers insight into the shared genes and biological pathways that are affected by tissue-specific regulatory impacts resulting from psychiatric- and cognition-associated genetic variants. These results provide limited support for the "p-factor" hypothesis for psychiatric disorders and potential mechanisms that explain drug side-effects. Our results highlight key biological pathways for development of therapies that target single or multiple psychiatric and cognitive phenotypes.

Keywords: anxiety; attention deficit hyperactivity disorder; bipolar disorder; cognitive functioning; multimorbidity; p-factor; schizophrenia; unipolar depression.

Figure 1

Genetic model of multimorbidity and the SNP-phenotype relationship. Phenotype-specific genetic variants alter tissue-specific gene expression by changing regulatory connections within the 3D dimensional organization of the genome. The gene products, whose expression is altered, interact within biological pathways. Multimorbidity results when affected gene products co-occur within pathways. The co-occurrence of affected gene products within shared pathways changes the way pathways respond to environmental signals and thus affects cellular activities at tissue and system levels. Orange—genetic variants, genes, and pathways specific to phenotype A. Green—genetic variants, genes, and pathways specific to phenotype B. Gray—genetic variants, genes, and pathways shared between phenotypes A and B. White—genes that are not specific to either phenotype A or phenotype B.

Figure 2

Pipeline used to study the multimorbidities between psychiatric and cognitive phenotypes. SNPs associated with ADHD, anxiety, BD, SCZ, UD, and cognitive functioning were obtained from the GWAS Catalog and analyzed using CoDeS3D (Supplementary Figure 1) to identify the genes associated with significant spatial eQTLs. Phenotype-specific lists of eQTLs are presented in Supplementary Spreadsheet 2. Pathway analysis was used to identify pathways containing co-occurring eGenes for the different phenotypes (Supplementary Table 5). Drug-eGene interaction analysis was performed to identify druggable genes (Supplementary Spreadsheet 5).

Figure 3

Shared biological pathways link psychiatric disorders and cognition. Psychiatric disorders and cognitive functions have low levels of genetic similarity at the SNPs (A), eQTLs (B), and eGene (C) levels. A FDR-adjusted p < 0.05 was used to identify eQTLs and eGenes. (D) Psychiatric disorders and cognition share a large degree of commonality at the biological pathways level. Biological pathways containing eGenes for each phenotype were identified using iPathwayGuide (Supplementary Spreadsheet 4). Among the most impacted pathways, 61 were shared between psychiatric disorders and cognition, 66—across all five psychiatric disorders. Only one pathway (i.e., Pancreatic secretion) was unique to ADHD, three pathways [i.e., Vasopressin-regulated water reabsorption, Ovarian steroidogenesis, and Dilated cardiomyopathy (DCM)] were specific to anxiety, three were unique to BD (i.e., IL-17 signaling pathway, Antifolate resistance, and Cytosolic DNA-sensing pathway), 2—to SCZ (i.e., p53 signaling pathway and Prion diseases), 2—to UD (i.e., Rheumatoid arthritis and Malaria) and 1—to cognition (i.e., Carbohydrate digestion and absorption). The full list of shared and unique pathways is in Supplementary Spreadsheet 5.

Figure 4

Psychiatric and cognitive SNPs mark eQTLs that are associated with gene expression within the neurotrophin signaling pathway. The co-occurrence of the affected shared or phenotype-specific eGenes and imbalance in gene expression within this pathway may lead to a series of cellular functions and events associated with psychiatric and cognitive phenotypes and the multimorbidities between them.

Figure 5

Psychiatric disorders and cognition show no shared pathways among all phenotypes in brain tissues. Psychiatric disorders and cognitive functions have low levels of genetic similarity at the eQTLs (A) and eGene (B) levels in brain tissues. A FDR-adjusted p < 0.05 was used to identify eQTLs and eGenes. More pairwise brain-specific pathway overlaps (C) and individualized pathways were identified for psychiatric and cognitive phenotypes.