Genetic Links Between Subcortical Brain Morphometry and Suicide Attempt Risk in Children and Adults

Genome-wide association studies (GWAS) have uncovered genetic variants associated with suicide attempt (SA) risk and regional brain volumes (RBVs). However, the extent of their genetic overlap remains unclear. To address this, we investigated whether the genetic architecture of SA and various RBVs (i.e., caudate nucleus, hippocampus, brainstem, ventral diencephalon, thalamus, globus pallidus, putamen, nucleus accumbens, amygdala and intracranial volume (ICV)) was shared. We leveraged GWAS summary statistics from the largest available datasets on SA (N = 958,896) and intracranial and subcortical RBVs (N = 74,898). Using linkage disequilibrium score regression, we estimated genome-wide genetic correlations between SA and individual RBVs. GWAS-pairwise analyses identified genomic segments associated with both SA and RBVs, followed by functional annotation. Additionally, we examined whether polygenic scores (PGS) for SA were associated with ICV and subcortical brain structure phenotypes in youth of European ancestry (N = 5276) in the Adolescent Brain Cognitive Development (ABCD) study. Linkage disequilibrium score regression results indicated a significant genetic correlation between SA and ICV (rG = -0.10, p-value = 1.9 × 10-3). GWAS-pairwise analyses and functional annotation revealed 10 genomic segments associated with SA and at least one RBV (thalamus, putamen and caudate nucleus). After adjusting for multiple tests, PGS association analysis indicated that a higher PGS for SA was significantly associated with a smaller volume of the right nucleus accumbens (b = -7.05, p = 0.018). Our findings highlight a negative genetic correlation between SA and ICV amongst adults and suggest different neural correlates associated with genetic risk for SA across developmental periods. This study advances our understanding of the shared genetic underpinnings of SA and brain structure, potentially informing future research and clinical interventions.