Genetic epidemiology of treatment-resistant depression

Major depressive disorder (MDD) is one of the leading causes of global disability and disease burden. Although many patients improve with antidepressants, a substantial proportion do not remit after multiple adequate trials. This condition, termed treatment-resistant depression (TRD), is linked to higher risks of suicide, hospitalization, and morbidity. Despite its clinical importance, Progress in understanding TRD has been limited by inconsistent definitions and modest sample sizes. This thesis integrates genetic and epidemiological approaches using Swedish registers, clinical cohorts, and biobank data to improve our understanding of the genetic and environmental factors associated with TRD.Study I examined the genetic overlap between treatment resistance in MDD and pharmacological treatment response. By applying polygenic risk scores (PRS) for antidepressant and lithium response to approximately 4,500 MDD cases from three Swedish cohorts, we found that individuals with TRD had significantly higher PRS of lithium response than non-TRD cases. In contrast, PRS for antidepressant response showed no clear association. These findings suggest a genetically conferred sensitivity to lithium in TRD and support the heritable component of treatment-related phenotypes.Study II combined a genome-wide association meta-analysis with copy number variant (CNV) analyses in more than 2,000 TRD cases, compared to around 38,500 non-TRD cases and 441,000 controls across Nordic cohorts. We reported the SNP-based heritability of 26% for TRD risk (compared to healthy controls), identified one genome-wide significant locus mapped with SPATA16, and observed suggestive loci relevant to treatment resistance in MDD. TRD shared genetics with schizophrenia and bipolar disorder. TRD carried a higher burden of rare CNV deletions and was enriched for known neuropsychiatric CNVs. These findings indicate that both common and rare structural variants contribute to TRD.Study III used Swedish national registers to evaluate psychiatric and cardiometabolic comorbidities and familial risk. Individuals with TRD had substantially elevated risks for both co-morbid psychiatric disorders (e.g., anxiety, obsessive-compulsive disorder) and cardiometabolic diseases (e.g., diabetes, cardiovascular disease). Relatives of TRD cases had increased TRD risk, with attenuation by genetic distance, and there was evidence for shared familial liability with both psychiatric and cardiometabolic conditions, suggesting shared genetic or environmental influences.Study IV investigated the association between adverse childhood experiences (ACEs) and TRD in a population-based twin register including over 21,000 Swedish twins. ACEs were associated with increased risk of TRD, with a 76% higher odds per additional ACE. The association remained after accounting for shared familial factors, suggesting an independent environmental contribution. Subtype-specific analyses showed particularly strong associations for physical neglect and sexual abuse, each conferring more than a 5-fold higher risk of TRD.In summary, this thesis presents new evidence on the genetic architecture of TRD, including contributions from polygenic and rare structural variants, and it highlights the roles of psychosocial adversity and comorbid health conditions. These findings highlight TRD as a distinct and complex phenotype, supporting the need for personalized treatment strategies and preventative efforts targeting early-life adversity.List of scientific papersI. Xiong Y, Karlsson R, Song J, Kowalec K, Rück C, Sigström R, Jonsson L, Clements CC, Andersson E, Boberg J, Lewis CM, Sullivan PF, Landén M, Lu Y. Polygenic risk scores of lithium response and treatment resistance in major depressive disorder. Translational Psychiatry. 2023 Sep 28;13(1):301. https://doi.org/10.1038/s41398-023-02602-3II. Xiong Y, Krebs K, Jermy B, Karlsson R, Pasman JA, Nguyen TD, Gong T, Kowalec K, Rück C, Sigström R, Jonsson L, Clements CC, Hörbeck E, Andersson E, Bäckman J; FinnGen; Estonian Biobank Research Team; Ganna A, German J, Sullivan PF, Landen M, Lehto K, Lu Y. Genome-wide association meta-analysis and rare copy number variant analysis of treatment-resistant depression. Molecular Psychiatry. 2025 Jun 26. https://doi.org/10.1038/s41380-025-03084-zIII. Ying Xiong, Shengxin Liu, Thuy-Dung Nguyen, Tong Gong, Ralf Kuja- Halkola, Henrik Larsson, Brian D'Onofrio, Zheng Chang, Isabell Brikell, Paul Lichtenstein, Yi Lu. Association and familial liability of treatment-resistant depression with psychiatric and cardiometabolic comorbidities. ManuscriptIV. Ying Xiong, Philip Daniel Javier Lindersten, Tong Gong, Patrik Magnusson, Shengxin Liu, Yi Lu. Association between adverse childhood experiences and treatment-resistant depression - Evidence from Cohort and Co-Twin control Analyses. Submitted