Characterization of the chromosome 7 locus associated with suicidal behavior

Area of Science:

• Neurogenetics
• Psychiatric Genetics
• Molecular Psychiatry

Background:

• Suicidal behaviors have high heritability, yet genetic underpinnings remain largely unknown.
• Genome-wide association studies identified a significant single nucleotide polymorphism (SNP), rs62474683, associated with suicidal behavior.
• The intergenic nature of rs62474683 necessitates functional investigation into its mechanism of action.

Purpose of the Study:

• To investigate the functional effects of the rs62474683 genotype on gene expression in relevant brain regions.
• To explore the relationship between genetic variation at rs62474683 and gene expression in individuals with depression who died by suicide.
• To examine cell-type-specific effects of the variant on gene expression and chromatin accessibility.

Main Methods:

• Gene expression analysis in two brain regions from individuals with depression and a history of suicide.
• Investigation of the association between rs62474683 genotype and gene expression.
• Single-cell RNA sequencing and chromatin accessibility assays to explore cellular effects.

Main Results:

• Several genes showed differential expression, with Forkhead box P2 (FOXP2) being most consistently altered.
• FOXP2 expression levels were significantly related to the rs62474683 genotype.
• The association between FOXP2 expression and suicide was specific to brain region and cell type.
• Evidence suggests Homeobox family transcription factors may mediate the relationship between rs62474683 and FOXP2.

Conclusions:

• The study provides functional evidence linking the most significant suicide attempt-associated genetic locus (rs62474683) to altered gene expression.
• FOXP2 emerges as a key gene potentially involved in the biological pathways of suicidal behavior in depression.
• Findings highlight the importance of cell-type and brain-region specificity in understanding the genetic architecture of suicidal behavior.