Genetic prioritization of HSDL2 in suicide and intentional self-harm: multi-omics evidence linking lipid metabolism and neuronal vulnerability.

Abstract

Background: Suicide or other intentional self-harm (SSH) represents a critical global public health burden, yet biologically informed targets remain poorly defined due to its complex and incompletely understood etiology. This study aimed to prioritize genetically supported candidate targets for SSH and characterize their biological and translational relevance.

Methods: We developed a multi-omics evidence framework integrating transcriptomic and proteomic Mendelian randomization, colocalization, and sensitivity diagnostics. The primary SSH outcome was from FinnGen R12 (11,538 cases; 488,810 controls). eQTLGen and GTEx were used for transcriptomic analyses, and UKB-PPP and ARIC for proteomic validation. Downstream analyses included functional enrichment, tissue expression profiling, exploratory metabolomic pathway analysis, brain cell-type-specific eQTL analyses, phenome-wide liability scanning, structural modeling with docking, virtual screening and molecular dynamics simulations, and baseline SSH classification in UKB-PPP individual-level proteomic data.

Results: Transcriptome-wide MR identified 1,164 FDR-significant genes, of which 55 were retained as Tier 1-4 prioritized candidates after proteomic validation, colocalization, and sensitivity assessment. HSDL2 was the sole Tier 1 candidate, supported by consistent eQTL and pQTL evidence, adequate instrument strength, and colocalization at the HSDL2 locus (PP.H4 = 0.797). Genetically predicted HSDL2 expression was associated with higher SSH risk in eQTLGen (OR = 1.133, 95% CI: 1.076-1.192) and showed directionally consistent protein-level evidence in UKB-PPP (OR = 1.050, 95% CI: 1.005-1.098). Enrichment and metabolomic analyses implicated lipid-, bile acid-, and organelle-related pathways. Brain cell-type-specific analyses suggested neuronal involvement, with consistent excitatory-neuron associations across discovery and validation datasets and additional support for inhibitory neurons in SingleBrain, while oligodendrocyte signals required cautious interpretation. Structural analyses supported a putative HSDL2 ligand-binding pocket, providing hypothesis-generating structural context for the metabolic findings. Phenome-wide MR analyses identified additional disease associations, providing phenotypic context for future target evaluation. UKB-PPP baseline classification analyses provided complementary individual-level support for the prioritized protein signal.

Conclusions: HSDL2 was prioritized as a genetically supported and biologically plausible candidate target for SSH, implicating a potential lipid-metabolic and neuronal vulnerability axis. These findings provide a foundation for future mechanistic validation and translational investigation.