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.
Highlights
Attention-deficit hyperactivity disorder (ADHD), anxiety, bipolar disorder (BD), schizophrenia (SCZ), and unipolar depression (UD) are highly prevalent psychiatric disorders [1]
Epidemiological research has reported that ADHD [2], anxiety [2, 3], BD [2], SCZ [4], and UD [5] are highly heritable [6] and represent multimorbid conditions that can be accompanied by cognitive advantages or deficits [7]
Consistent with this, multiple genetic studies of psychiatric disorders and cognitive functioning have revealed a surprising degree of genetic overlap amongst these phenotypes, with the highest genetic correlations observed between SCZ and BP, ADHD and UD, BP and UD, SCZ and UD [8,9,10]
Summary
Attention-deficit hyperactivity disorder (ADHD), anxiety, bipolar disorder (BD), schizophrenia (SCZ), and unipolar depression (UD) are highly prevalent psychiatric disorders [1]. Consistent with this, multiple genetic studies of psychiatric disorders and cognitive functioning have revealed a surprising degree of genetic overlap amongst these phenotypes, with the highest genetic correlations observed between SCZ and BP (rg = 0.70), ADHD and UD (rg = 0.44), BP and UD (rg = 0.36), SCZ and UD (rg = 0.34) [8,9,10] This suggests the possible existence of common biological mechanisms underlying these phenotypes. 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. The mechanisms by which these SNPs contribute to multimorbidities amongst psychiatric and cognitive phenotypes remains largely unknown
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