NEK4: prediction of available drug targets and common genetic linkages in bipolar disorder and major depressive disorder.

Background: Bipolar disorder (BD) is a mental illness characterized by alternating episodes of elevated mood and depression, while major depressive disorder (MDD) is a debilitating condition that ranks second globally in terms of disease burden. Pharmacotherapy plays a crucial role in managing both BD and MDD. We investigated the genetic differences in populations of individuals with MDD and BD, and from a genetic perspective, we offered new insights into potential drug targets. This will provide clues to potential drug targets.

Methods: This study employed genome-wide association studies (GWAS) and summary-data-based Mendelian randomization (SMR) methods to investigate the genetic underpinnings of patients with bipolar disorder (BD) and major depressive disorder (MDD) and to predict potential drug target genes. Genetic variants associated with BD and MDD were identified through large-scale GWAS datasets. For BD, the study utilized a comprehensive meta-analysis comprising 57 BD cohorts from Europe, North America, and Australia, including 41,917 BD cases and 371,549 controls of European ancestry. This dataset included both type 1 and type 2 BD cases diagnosed based on DSM-IV, ICD-9, or ICD-10 criteria through standardized assessments. For MDD, we used data from a meta-analysis by Howard DM et al., which integrated the largest GWAS studies of MDD, totaling 246,363 cases and 561,190 controls. The SMR approach, combined with expression quantitative trait loci (eQTL) data, was then applied to assess causal associations between these genetic variants and gene expression, aiming to identify genetic markers and potential drug targets associated with BD and MDD. Furthermore, two-sample Mendelian randomization (TSMR) analyses were performed to explore causal links between protein quantitative trait loci (pQTL) and these disorders.

Results: The SMR analysis revealed 41 druggable genes associated with BD, of which five genes appeared in both brain tissue and blood eQTL datasets and were significantly associated with BD risk. Furthermore, 45 druggable genes were found to be associated with MDD by SMR analysis, of which three genes appeared simultaneously in both datasets and were significantly associated with MDD risk. NEK4, a common drug candidate gene for BD and MDD, was also significantly associated with a high risk of both diseases and may help differentiate between type 1 and type 2 BD. Specifically, NEK4 showed a strong association with BD (β brain=0.126, P FDR=0.001; βblood=1.158, P FDR=0.003) and MDD (β brain=0.0316, P FDR=0.022; βblood=0.254, P FDR=0.045). Additionally, NEK4 was notably linked to BD type 1 (βbrain=0.123, P FDR=2.97E-05; βblood=1.018, P FDR=0.002), but showed no significant association with BD type 2.Moreover, TSMR analysis identified four proteins (BMP1, F9, ITIH3, and SIGIRR) affecting the risk of BD, and PSMB4 affecting the risk of MDD.

Conclusion: Our study identified NEK4 as a key gene linked to both bipolar disorder (BD) and major depressive disorder (MDD), suggesting its potential as a drug target and a biomarker for differentiating BD subtypes. Using GWAS, SMR, and TSMR approaches, we revealed multiple druggable genes and protein associations with BD and MDD risk, providing new insights into the genetic basis of these disorders. These findings offer promising directions for precision medicine and novel therapeutic strategies in mental health treatment.