Suicide attempts are prevalent among patients with bipolar disorder (BD). Impaired serotonin (5-HT) system in the pathogenesis of suicide attempt is partially heritable. To quantify the combined effects of multiple genetic variants, we developed a dynamic model of the 5-HT presynapse with functionally integrated individual genetic variants. The model includes five genetic variants in 5-HT system genes (TPH2, SLC6A4, MAOA) and quantitatively assesses their influence on 5-HT synthesis, reuptake, and degradation. The model was validated on 140 unaffected individuals and tested on 101 BD patients. Predicted mean concentrations of 5-HT, 5-HT precursor, and degradation product were compared between BD patients with and without a history of attempted suicide, and unaffected individuals. The model consists of eight differential equations that describe the temporal concentration change of model outputs. Calculated concentrations in unaffected control individuals aligned with published experimentally measured values, validating our model. BD patients with a history of suicide attempt showed lower calculated concentrations of 5-HT degradation product 5-hydroxy-3-indolacetic acid (5-HIAA) compared to unaffected individuals (p = 0.044). Additionally, higher calculated concentrations of free cellular 5-HT (p = 0.048) and stored 5-HT (p = 0.047), with the effect size d = 0.35, were observed when comparing suicide attempters to non-attempters.. Our approach illuminated a complex interplay of genetic variants in 5-HT system genes that contributes to the risk of suicide attempt, with quantitative and personalized outputs unattainable through genetic association studies.

Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease caused by a CTG repeat expansion in the DMPK gene. The toxic mutant mRNA sequesters MBNL proteins, disrupting global RNA metabolism. Although alternative splicing in DM1 skeletal muscle pathology has been extensively studied, early-stage transcriptomic changes remained uncharacterized. To gain deeper and contextual insight into DM1 transcriptome, we performed the first Weighted Gene Co-expression Network Analysis (WGCNA) on skeletal muscle RNA sequencing data from the widely used DM1 mouse model HSA^LR (~250 CTG repeats). We identified 532 core genes using data from 16-week-old mice, an age before the onset of muscle weakness. Additional differential expression analysis across multiple HSA^LR datasets revealed 42 common up-regulated coding and non-coding genes. Within identified core genes, the pathway gene-pair signature analysis enabled contextual selection of functionally related genes involved in maintaining proteostasis, including endoplasmic reticulum (ER) protein processing, the ubiquitin-proteasome system (UPS), macroautophagy and mitophagy, and muscle contraction. The enrichment of ER protein processing with prevailing core genes related to ER-associated degradation suggests adaptive chaperone and UPS activation, while core genes such as Ambra1, Mfn2, and Usp30 indicate adaptations in mitochondrial quality control. Coordinated early alterations in processes maintaining protein homeostasis, critical for muscle mass and function, possibly reflect a response to cellular stress due to repeat expansion and appears before muscle weakness development. Although the study relies exclusively on transcriptomic analyses, it offers a comprehensive, hypothesis-generating perspective that pinpoints candidate pathways, preceding muscle weakness, for future mechanistic validation.