Background: Clinical course variability in Duchenne muscular dystrophy (DMD) is partially explained by the mutation location in the DMD gene and variants in modifier genes. We assessed the effect of the SPP1, CD40, and LTBP4 genes and DMD mutation location on loss of ambulation (LoA). Methods: SNPs in SPP1-rs28357094, LTBP4-rs2303729, rs1131620, rs1051303, rs10880, and CD40-rs1883832 were genotyped, and their effect was assessed by survival and hierarchical cluster analysis. Results: Patients on glucocorticoid corticosteroid (GC) therapy experienced LoA one year later (p = 0.04). The modifying effect of SPP1 and CD40 variants, as well as LTBP4 haplotypes, was not observed using a log-rank test and multivariant Cox regression analysis. Cluster analysis revealed two subgroups with statistical trends in differences in age at LoA. Almost all patients in the cluster with later LoA had the protective IAAM LTBP4 haplotype and statistically significantly fewer CD40 genotypes with harmful T allele and “distal” DMD mutations. Conclusions: The modifying effect of SPP1, CD40, and LTBP4 was not replicated in Serbian patients, although our cohort was comparable in terms of its DMD mutation type distribution, SNP allele frequencies, and GC-positive effect with other European cohorts. Cluster analysis may be able to identify patient subgroups carrying a combination of the genetic variants that modify LoA.

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.

Background: Suicide attempts often co-occur with bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCH). Although impairments of the serotonin (5-HT) system have been associated with suicide attempts, it remains unclear whether these alterations reflect suicidal behavior or are confounded by underlying psychiatric diagnosis. This study used a genotype-informed dynamic model of the 5-HT presynapse to disentangle the effects of suicide attempts and psychiatric diagnosis. Methods: We applied a personalized dynamic model of the 5-HT presynapse to 392 psychiatric patients (with BD, MDD, or SCH), categorized by suicide attempt status, and 140 unaffected individuals. The model incorporated five variants across TPH2, SLC6A4, and MAOA genes simulating individual-specific concentration changes of five 5-HT-related molecular species. Model outputs were summarized by six statistical measures (mean, median, maximum, standard deviation, skewness, and kurtosis) and compared across groups. Results: No significant differences were found across groups defined by suicide attempt status and unaffected individuals. However, diagnosis significantly influenced 5-hydroxyindoleacetic acid (5-HIAA) mean, median, maximum, and standard deviation (all p < 0.05). BD patients had lower 5-HIAA levels than SCH patients (mean: p = 0.013; median: p = 0.013; maximum: p = 0.014; standard deviation: p = 0.014). MDD patients also showed lower 5-HIAA levels than SCH patients for the same measures, with differences approaching significance. No significant difference was observed between BD and MDD patients. A diagnosis-by-suicide attempt status interaction was observed for 5-HIAA skewness (p = 0.013). Conclusions: Model-derived 5-HT profiles were shaped primarily by diagnosis, while temporal dynamics of 5-HIAA, rather than its absolute levels, was associated with suicide attempt status. Thus, personalized dynamic modeling incorporating genetic variants may aid in detecting subtle molecular signatures across diagnoses and suicidal behavior.