Multiple regulatory variants modulate expression of 5-hydroxytryptamine 2A receptors in human cortex

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• The 5-hydroxytryptamine 2A receptor (HTR2A) is a key serotonin target in the brain, crucial for neuropsychiatric disorders.
• Despite numerous genetic studies, the precise role of HTR2A genetic variability in health and disease remains unclear.

Purpose of the Study:

• To identify and characterize regulatory variants within the HTR2A gene.
• To understand how these variants impact HTR2A expression and its downstream signaling.

Main Methods:

• Whole transcriptome sequencing across 10 human brain regions.
• Massively parallel RNA sequencing to measure allelic expression of HTR2A mRNA variants.
• In vitro characterization of functional variants' impact on gene expression.

Main Results:

• Identified three polymorphisms affecting HTR2A alternative exons and untranslated regions (UTRs), altering RNA and protein levels.
• A common promoter variant (rs6311) reduces translation efficiency of a longer 5'UTR.
• A variant (rs7665058) unique to individuals of African descent modulates allelic HTR2A mRNA expression.
• Functional HTR2A variants associated with depression severity and citalopram response in the STAR*D study.

Conclusions:

• Regulatory HTR2A polymorphisms modulate gene expression in an isoform-specific manner.
• These variants influence novel untranslated regions and alternative exon usage.
• Findings provide a basis for understanding HTR2A's role in central nervous system disorders and serotonin signaling.