Abstract Background Major depressive disorder (MDD) is the most common mental disorder and is associated with substantial functional impairment, socioeconomic costs and reduced quality of life. One third of patients presents treatment-resistant depression (TRD), a major clinical challenge that highly contributes to the socioeconomic burden. Molecular underpinnings of TRD are only partially known. While TRD has distinct heritability, only few underlying genetic determinants have been identified by genome-wide association studies (GWAS). Pleiotropy, that is the association of genetic variants with more than one phenotype, and in-silico post-GWAS functional analyses, can be leveraged to increase our knowledge on the molecular underpinnings of TRD. Aims & Objectives We used a suite of cutting-edge methods on large genome-wide association datasets to identify novel genetic determinants associated with TRD. Method Preliminary analyses included genome-wide summary statistics from the Vanderbilt University Medical Center (VUMC) Synthetic Derivative and the Mass General Brigham (MGB) Research Patient Data Registry GWAS meta-analysis (PMID: 38745458), in which TRD was defined based on treatment with electroconvulsive therapy (VUMC: 225 TRD cases and 106,564 MDD controls; MGB: 242 cases and 78,378 MDD controls, all of European ancestry). Cross-trait analyses with the conditional false discovery rate (condFDR) method to identify novel genetic variants associated with TRD conditioning on inflammatory marker levels (serum C-reactive protein, CRP), metabolic traits (body mass index and type 2 diabetes) as well as aging biomarkers (leukocyte telomere length [LTL] and a multivariate GWAS of aging [mvAge]) are ongoing. Summary-data-based Mendelian randomization (SMR) was used to identify genes associated with TRD via changes in brain gene expression based on data from the PsychENCODE project (RNA-seq data from 1.387 prefrontal cortex samples). Results Using condFDR, we identified eight, four and ten independent genetic variants significantly associated with TRD conditioning on CRP levels, LTL and mvAge, respectively. Two loci located in genes previously associated with TRD, i.e. FTO and MCHR1, and an intergenic locus with AC093326.3 as the nearest gene, were associated with TRD conditioning on all three phenotypes. Two novel loci (located in the JAZF1 and HSD17B12 genes) were identified conditioning either on CRP or mvAge. In addition, novel loci were identified conditioning on CRP levels (CRTAM, CDKL1, WWP2), LTL (RP11-774G5.1) or mvAge (KCNK3, TCF7L2, RNU2-23P, WWP2, ZBTB46). Using SMR, increased expression of XPNPEP3 on chromosome 22 was associated with TRD (top single nucleotide polymorphism: rs2143610, beta SMR = 0.04, p = 4.5E-06, adjusted p = 0.04). Analyses on metabolic phenotypes as well as additional analyses including summary statistics from a larger GWAS that evaluated TRD risk and treatment resistance in MDD across three Nordic countries (PMID: 40571737) are currently ongoing, to further explore and extend the present findings. Discussion & Conclusions Analytical approaches based on pleiotropy and quantitative trait loci can be leveraged to identify novel loci potentially associated with TRD.
C. Pisanu, Y. Xiong, D. Congiu et al.· International Journal of Neu...· 0 citations
Abstract Background Bipolar disorder (BD) is a chronic and debilitating psychiatric illness characterized by recurrent episodes of mania and depression. Despite its high heritability, the underlying molecular mechanisms remain incompletely understood. Gene expression studies, particularly those focusing on total messenger RNA (mRNA), offer a promising avenue for identifying biomarkers and understanding disease pathophysiology. Among available treatments, lithium remains a first-line mood stabilizer with proven efficacy in reducing recurrence and suicide risk in BD patients. However, response to lithium is highly variable, and predictive biomarkers for treatment outcomes are lacking. Investigating total mRNA expression profiles in blood samples from BD patients characterized for lithium response may provide valuable insights into disease mechanisms and treatment response. Aims & Objectives To identify gene expression markers of disease risk and of response to lithium treatment in bipolar disorder. Method RNA sequencing was performed in a sample of 90 Caucasian patients with a diagnosis of BD type I or BD type II according to DSM-5 and 59 non-psychiatric controls with no personal or familial history of psychiatric disorders. Participants were recruited at the Unit of Clinical Pharmacology and the Unit of Clinical Psychiatry of the University of Cagliari and University Hospital Agency of Cagliari, and at the Psychiatric Hospital “Villa Santa Chiara”, Verona (Italy). For a subgroup of patients (n = 58) response to long-term lithium treatment was characterized with the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder scale (Alda scale). Total RNA was extracted from fasting peripheral venous blood samples. Library preparation and bulk RNA sequencing was performed using the Illumina Stranded Total RNA Prep, and paired-end sequencing was performed on a NextSeq 2000 platform (Illumina). After quality control, raw data were processed with the rnaseq nf-core pipeline, alignment with the reference genome (GRCh38) was performed with STAR, while gene expression levels were estimated with RSEM. Identification of differentially expressed genes (DEG) between patients and controls and responders and non-responders to lithium, adjusting for age and sex, was conducted with DESeq2. Results were adjusted for multiple testing based on false discovery rate (FDR) and an adjusted p-value < 0.05 was considered significant. Results We identified 37 DEGs between patients with BD and controls with an adjusted p-value < 0.05, of which 19 were upregulated and 18 downregulated in patients. DEG significant after multiple testing correction are reported in Table 1. DEG were enriched for the protein folding chaperone molecular function GO term (enrichment ratio: 28.79, p = 0.0002, FDR = 0.041, DNAJB1, HSP90AA1 and HSPH1). No DEG was significantly associated with lithium response after multiple testing correction. However, GO analyses on the nominally significant genes showed a significant enrichment for toll-like receptor binding molecular function GO term. Discussion & Conclusions Our study suggests that BD patients present significant differences in gene expression patterns compared to healthy controls. Pathway analyses suggest that protein misfolding and endoplasmic reticulum alterations could be implicated in the pathophysiology of BD, while response to lithium might be related to modulation of inflammatory response through toll-like receptor biding.
A. Squassina, M. Manchia, C. Chillotti et al.· International Journal of Neu...· 0 citations
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