MicroRNA binding site variation is enriched in psychiatric disorders

Area of Science:

• Genetics and Genomics
• Neuroscience
• Molecular Biology

Background:

• Psychiatric disorders exhibit polygenic architecture, with many genomic loci influencing disease risk.
• Heritability of these disorders often stems from regulatory sequences in noncoding DNA.
• Variants affecting cis-acting RNA sequences, such as microRNA binding sites, are understudied regulatory elements.

Purpose of the Study:

• To investigate the association of microRNA binding site variants (MBSVs) with psychiatric disorders.
• To compare the enrichment of MBSVs against non-MBSVs in brain-expressed regulatory regions.
• To identify specific microRNA families and gene pathways implicated in disease pathophysiology.

Main Methods:

• Intersected genome-wide association study (GWAS) summary statistics with the dbMTS database of predicted MBSVs.
• Compared GWAS p-values for MBSVs versus non-MBSVs within 3' untranslated regions (3'UTRs) of brain-expressed genes.
• Aggregated GWAS p-values at gene, pathway, and microRNA family levels for multiple psychiatric and nonpsychiatric traits.

Main Results:

• Significant enrichment of MBSVs observed in schizophrenia, depression, bipolar disorder, and anorexia nervosa.
• Specific microRNA families (e.g., miR-335-5p, miR-21-5p/590-5p) showed strong associations with psychiatric traits.
• MBSVs in synaptic gene sets were associated with schizophrenia and bipolar disorder; type 2 diabetes also showed associations.

Conclusions:

• MicroRNAs play a significant role in the pathophysiology of psychiatric disorders.
• MBSVs represent a critical class of regulatory variants with functional implications across various complex diseases.
• This study underscores the importance of noncoding RNA variants in understanding genetic contributions to human health and disease.