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

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

• Multimorbidity of psychiatric disorders (ADHD, anxiety, BD, SCZ, UD) often involves cognitive deficits or advantages.
• Common biological mechanisms are suspected for these psychiatric and cognitive phenotypes.
• Genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) linked to these conditions, but underlying regulatory mechanisms remain unclear.

Purpose of the Study:

• To identify shared regulatory mechanisms connecting multimorbid psychiatric disorders and cognitive functioning.
• Investigate the impact of GWAS SNPs on genes and biological pathways relevant to these phenotypes.

Main Methods:

• Integrated 3D genome organization, expression quantitative trait loci (eQTLs), and pathway analyses.
• Analyzed 2,893 GWAS SNPs (p < 1 × 10^-6) associated with ADHD, anxiety, BD, SCZ, UD, and cognitive functioning.
• Performed drug-gene interaction analysis to explore pharmacological implications.

Main Results:

• Identified 33 genes and 62 pathways commonly affected by tissue-specific regulatory interactions across all six phenotypes, despite no shared SNPs.
• Brain-specific analyses showed shared patterns at eQTL and eGene levels but no pathways common to all six phenotypes.
• Revealed pairwise overlaps and individualized pathways for psychiatric and cognitive phenotypes in brain tissues.

Conclusions:

• The study provides insights into shared genes and pathways influenced by genetic variants in psychiatric and cognitive traits.
• Results offer limited support for the 'p-factor' hypothesis and suggest mechanisms for drug side effects.
• Highlights key biological pathways for developing targeted therapies for single or multiple psychiatric and cognitive phenotypes.