Understanding the biological basis of trait resilience holds the potential to aid in the development of preventive strategies for mental health conditions through the promotion of higher levels of resilience, particularly in at-risk individuals. To uncover the genetic basis of trait resilience, we combined variant- and gene-based GWAS meta-analyses from six German cohorts (N = 15822) using as outcome measure the RS-11 scores, and investigated the biological context using a network approach. Moreover, we explored the relationship between resilience and the genetic determinants of other personality and mental health traits using PGSs. These analyses suggested 56 potential candidate genes for resilience (protein-coding + non-coding genes; Suppl.Table.3), including three at the genome-wide significance threshold, which participate in processes important for brain development, immunity and vascular homeostasis. In addition, we observed a relationship between resilience and the genetic determinants of personality and mental health traits.
Previously, a GWAS of resilience conducted in about 11500 U.S. Army soldiers participating in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS) reported the association of a small intergenic locus in chromosome 4, near DCLK2, and of the gene KLHL36 with resilience [28]. Although we did not find association signals in those genes previously reported by Stein et al. in a sample of European descent, it should be noted that there were core differences between our studies. Perhaps most importantly, Stein et al. used a 5-item self-report questionnaire to measure psychological resilience in a highly specific population, while our study was aimed at a more general adult population, and the comparability of resilience measurements between this 5-item self-report questionnaire and the RS-11, to our knowledge, has not been determined. Nevertheless, because DCLK2 is crucial for proper hippocampal organization and function [29], the study also indicated that brain development may play a central role in the establishment of resilience.
In our study, network analysis suggested the involvement of various pathways related to brain development, including Wnt, Notch, Rac1, thyroid hormone (TH) and neurotrophin signaling, as well as to immune and stress response pathways, such as B cell receptor and glucocorticoid receptor signaling, and vascular homeostatic processes, including fluid shear stress and cadherin signaling, in trait resilience. Such pathways also overlap and form complex interactions that influence mental health. For example, the Wnt pathway has been shown to indirectly regulate TH function and has been tied to thyroid development and homeostasis as well as to the expression of TH receptors and deiodinases (D1-D3) in TH target tissues. At the same time, THs regulate tissue development and homeostasis [30]. In the brain, THs are not only essential for proper development and function through the lifespan, but they also influence mood and behavior. Therefore, thyroid dysfunction is a known risk factor for psychiatric conditions, including depressive, bipolar and anxiety disorders [31]. Importantly, the immune system is crucial for brain development, participating in cell survival, proliferation, migration and differentiation, axonal growth, synaptogenesis, synaptic remodeling and dendritic pruning. Moreover, chemokines and toll-like receptors are known regulators of cognitive function and behavior [32]. In addition, neurovascular function can be influenced by inflammatory signaling, and compromise of the blood-brain-barrier has been previously observed in the context of vulnerability and resilience to stress [33, 34].
The involvement of such processes was, however, not only observed through network pathway analysis, which might have been biased due to the inclusion of linker genes, but was also supported when querying the genes identified through both meta-analysis approaches in the GeneCards Human Gene Database (https://www.genecards.org/; accessed in June 2023). For example, from the variant-based analysis, summaries of the functions of NEPRO and ULK2 place them as participants of cortex development and maintenance of neural progenitors [35], and of neuronal differentiation [36], respectively, while those of CD200R1L and CD200R1 suggest these function as inhibitors of inflammation [37]. The GWAS Catalog (https://www.ebi.ac.uk/gwas/; accessed in June 2023) also offered important insights into previously reported genetic associations with relevant traits. Here, for example, NEPRO and ULK2 are associated with psychotic symptoms in Alzheimer’s disease [38] and with cortical thickness [39], respectively, while CD200R1L and CD200R1 show associations with various immune traits, such as the proportion of eosinophils and neutrophils in blood, levels of cortisol, and inflammatory diseases like Crohn’s disease and rheumatoid arthritis. Moreover, rs1952935, which supports the signal of the top locus (#4), has a reported association with risk-taking behavior [40].
Similar was the case for the suggestive results from the gene-based analysis, where GeneCards queries led to the identification of processes participating in brain development and synaptic function being represented by genes such as RIT1, ARHGEF2, PCDHB1, MICALL2, SEMA3D, KCTD13 and PANX2, while processes related to immune activity were represented by genes such as BATF2, PAXIP1, DNASE1 and CEACAM6. In the GWAS Catalog, some genes appeared to be of particular interest, including ESRRG, with reported associations with cognitive performance and executive function, risk-taking and externalizing behaviors, anhedonia, major depression and other mental health-related traits; TBX20, associated with cardiovascular disease and suicidal behavior; PAXIP1, associated with cognitive performance, intelligence and brain volume; PALM2, which was associated with various traits related to cognition, vascular function and number of immune cells; and SUDS3, associated with loneliness, neuroticism, educational attainment and depression. Because an extensive discussion of each of the suggestive findings from our study is beyond the aim of our report, we would like to refer the reader to the source databases (i.e. GeneCards and GWAS Catalog) for more details and links to the respective publications. For the purposes of this discussion, all of the above seems to convey evidence indicating that the genes and loci identified in our study participate in developmental and immune processes that have previously shown to also impact mental health traits.
The gene-based meta-analysis of resilience found three genome-wide significant signals, corresponding to ROBO1, CIB3 and LYPD4. Although the function of LYPD4 is unknown, this gene appears to be associated with serum levels of protein PCDHGA1 [41], which may be involved in the establishment and maintenance of specific neuronal connections in the brain [42]. ROBO1 functions in axon guidance, neuronal precursor cell migration and interaural interaction in auditory pathways [43–45]. The gene has been associated with various mental health-relevant traits, including cognitive function measurement, information processing speed, unipolar depression, depressive symptoms, facial emotion recognition, schizophrenia, cortical thickness and other brain measurements, educational attainment, mathematical ability and blood pressure (source: GWAS Catalog). Interestingly, CIB3 encodes an auxiliary subunit of the sensory mechanoelectrical transduction (MET) channel in cochlear hair cells [46], which places the second resilience-associated gene also in the auditory system. Sensory processing difficulties in mental disorders other than autism spectrum disorders are largely understudied. However, there is evidence that individuals with depression, bipolar disorder and schizophrenia, among other mental health problems, show patterns of sensory processing that differ from those in healthy individuals [47]. In particular, some studies have also proposed neuroanatomical correlates of (stress) resilience that involve the auditory system, including activity of the amygdala and a thalamic-primary auditory cortex circuit [48, 49]. This opens the possibility for the implementation of interventions, such as music therapy, to promote resilience for the prevention and treatment of mental health problems.
We acknowledge that relying on the RS-11 measure of resilience importantly limited our ability to consider more cohorts for inclusion in our meta-analysis, resulting in a relatively small sample size that prevented the identification of genome-wide associations at the variant-level. In addition, because we included only cohorts from the German population, the applicability of our findings to individuals from other nationalities and ancestries remains to be investigated. Therefore, efforts to collect resilience measurements using unified instruments in large international cohorts to unravel the genetics of trait resilience in the general population should be encouraged. This would also enable the investigation of the genetic correlation between resilience and personality and mental health traits, which was not possible in our study due to the lack of full summary statistics for the personality and mental health traits, and that of independent samples suitable for the generation of a resilience PGS derived from our GWAS meta-analysis. Despite the limitations, our study represents, to our knowledge, the largest investigation of the genetics of trait resilience to date, and provides initial and valuable insights into the biology of resilience and its relationship with the genetics of personality traits and mental health.