All individuals are faced with challenges and traumatic life events at different points throughout their life. However, not all individuals who face difficulties develop mental health problems. Many seem to be able to easily move on and live happy, fulfilled lives. But, what makes them different? The ability of individuals to successfully adapt to difficult conditions is called resilience. Individuals with high levels of resilience will be able to overcome challenging life situations more quickly than those with low levels of resilience who, on the other hand, will become more prone to developing mental health problems such as anxiety and depression. In our modern society, where mental health issues have arisen as major public health concerns of considerable societal impact, the study of the biology of resilience holds the promise to help us understand how resilience is determined, identify the protective and detrimental factors that contribute to build resilience, and use this knowledge to come up with alternative ways to prevent and treat mental illness by promoting resilience.
Together with collaborators at various sites in Germany, we carried out the largest study to date of the genetics of resilience in the general population. That is, we studied the contribution of common genetic variants to the observed levels of resilience in a large number of individuals without a particular medical or psychological condition. This is important because, thus far, most of the genetic studies pertaining to resilience have focused on the outcome, comparing individuals with specific disorders, such as depression, anxiety and post-traumatic stress disorder, to individuals without psychiatric disease. Resilience levels are measured using specific instruments. In our study, all cohorts measured resilience using the 11-item Resilience Scale (RS-11), which provides a quantitative measure of resilience based on 11 questions that assess personal competence and acceptance of self and life. Because heterogeneity of instruments and conceptualizations of resilience are likely to impact the robustness of results, using the same instrument to measure resilience in a large number of samples is an advantage of our study. Genetic associations were tested throughout the genome using both single variants and whole genes. Genes showing certain level of association in either test were used to explore the potential biological meaning of these associations through computational tools such as network analysis, which leverages information from known or predicted interactions between human proteins, and gene set enrichment analysis, which utilizes information about known human gene functions and their participation in specific biological processes to test for overrepresentation of particular functions within the network. In addition, we wished to know whether the levels of resilience are linked to the genetic components of other indicators of mental health, including personality traits, which we measured using polygenic scores (PGSs). PGSs represent the genetic predisposition of an individual to present a certain characteristic. For example, your PGS for blood pressure might tell you if you have a propensity to hypo- or hypertension based on your genetic information. In our study, we used PGS instruments that were previously created and validated in larger samples, and measured the genetic predictions of 12 mental health indicators in each participant of one of the included cohorts.
Genes that showed significant and suggested associations with the levels of resilience
Our study involved 15,822 individuals from six German cohorts, in which we identified three genes associated with the levels of resilience. According to what we found in the literature, the associated genes, ROBO1, CIB3 and LYPD4, might have relevant functions in establishing and maintaining certain connections between neurons, particularly in the auditory system. This raises the questions of whether the levels of resilience could result affected by auditory input, and whether healthier levels of resilience could be promoted using strategies such as music therapy. Answering these questions could have important clinical implications for the management of mental health. Our observations also suggested that the levels of resilience are not highly determined by genetics, but might be influenced by immune activity and stress, among other processes, particularly during periods of brain development. This would imply that environmental factors play a big role in determining resilience at early stages of life and that, even when resilience tends to present as a relatively stable trait throughout the adult life, it might be possible to increase resilience levels by leveraging the effects of environmental factors that promote resilience. In addition, our study found in 3,879 individuals that higher levels of resilience are linked to lower genetic predisposition to neuroticism and higher genetically-predicted general happiness, with further correlations suggested for lower PGSs of intelligence, sensitivity and anxiety-related characteristics. These observations help us better understand the relationship between resilience and other personality characteristics, offering potential non-genetic targets for therapeutic intervention in mental health that promote resilience.
A. Protein-protein interaction network integrating resilience candidate genes. B. Biological pathways overrepresented in the network that include resilience candidate genes.
Despite the exciting hypothesis-generating findings of our paper, much work remains to be done in this area. For example, it is not clear whether our observations will apply to individuals from other ancestries and geographical regions, and whether similar findings would be obtained when using different instruments to measure resilience. Also, sample sizes for confirmatory genetic studies should be increased, while functional and preclinical studies testing our generated hypotheses would need to be conducted. Therefore, we would like to encourage international collaborations to investigate these aspects and work towards resilience-promoting strategies to improve mental health in the general population.