key: cord-0278739-1ydv39g6 authors: Heilbronner, U.; Streit, F.; Vogl, T.; Senner, F.; Sabrina, S.; Reich-Erkelenz, D.; Papiol, S.; Oraki Kohshour, M.; Klohn-Saghatolislam, F.; Kalman, J. L.; Maria, H.; Gade, K.; Comes, A. L.; Budde, M.; Andlauer, T. F.; Anderson-Schmidt, H.; Adorjan, K.; Sturmer, T.; Loerbroks, A.; Amelang, M.; Poisel, E.; Foo, J.; Heilmann-Heimbach, S.; Forstner, A. J.; Degenhardt, F.; Zimmermann, J.; Wiltfang, J.; von Hagen, M.; Spitzer, C.; Schmauss, M.; Reininghaus, E.; Reimer, J.; Konrad, C.; Juckel, G.; Lang, F. U.; Jager, M.; Figge, C.; Fallgatter, A. J.; Dietrich, D. E.; Dannlowski, U.; Baune, B. T.; Ar, title: Interplay between the Genetics of Personality Traits, severe Psychiatric Disorders, and COVID-19 Host Genetics in the Susceptibility to SARS-CoV-2 Infection date: 2021-09-14 journal: nan DOI: 10.1101/2021.09.12.21263447 sha: 990ea22d4c9edf4602d5dcd54acc75da942c4fcd doc_id: 278739 cord_uid: 1ydv39g6 Background The SARS-CoV-2 pandemic, with all its impacts on our way of life, is affecting our experiences and mental health. Notably, individuals with mental disorders have been reported to have a higher risk of contracting SARS-CoV-2. Personality traits could represent an important determinant of preventative health behavior and, therefore, the risk of contracting the virus. Aims We examined overlapping genetic underpinnings between major psychiatric disorders, personality traits, and susceptibility to SARS-CoV-2 infection. Methods Linkage disequilibrium score regression was used to explore the genetic correlations of COVID-19 susceptibility with psychiatric disorders and personality traits based on data from the largest available respective genome-wide association studies (GWAS). In two cohorts (the PsyCourse (n=1346) and the HeiDE (n=3266) study), polygenic risk scores were used to analyze if a genetic association between, psychiatric disorders, personality traits, and COVID-19 susceptibility exists in individual-level data. Results We observed no significant genetic correlations of COVID-19 susceptibility with psychiatric disorders. For personality traits, there was a significant genetic correlation for COVID-19 susceptibility with extraversion (p=1.47x10-5; rg=0.284). Yet, this was not reflected in individual-level data from the PsyCourse and HeiDE studies. Conclusions We identified no significant correlation between genetic risk factors for severe psychiatric disorders and genetic risk for COVID-19 susceptibility. Among the personality traits, extraversion showed evidence for a positive genetic association with COVID-19 susceptibility, in one but not in another setting. Overall, these findings highlight a complex contribution of genetic and non-genetic components in the interaction between COVID-19 susceptibility and personality traits or mental disorders. The global spread of SARS-CoV-2 has revealed differences in susceptibility to and severity of SARS-CoV-2 infection at both the individual and the community level. Studies from different regions of the world suggest a rise in the incidence of psychiatric disorders due to the threat of the virus and the socioeconomic repercussions of preventive measures that have been implemented (1) (2) (3) . Interestingly, a recent study observed that a psychiatric diagnosis prior to SARS-CoV-2 infection was significantly associated with a higher risk of COVID-19 diagnosis (4); this risk was independent of known physical risk factors and living conditions. Personality traits (i.e. relative stable patterns of feelings, thoughts and behavior) might influence disease risk by mediating health-related behaviors such as the adherence to health regulations and recommendations (e.g., social distancing or mask wearing). In line with this, studies support an inverse relationship between extroaersion and likelihood to engage in social distancing behavior at the beginning of the pandemic (5, 6) . The genetic underpinnings of psychiatric traits are known to not only show a large overlap among each other (7) but also with other diseases such as metabolic disorders (8, 9) . An increased load of infections in individuals with psychiatric disorders has also been reported and may, in part, be due to shared genetic liability (10) , although only few large-scale studies have tried to answer this question to date. In addition to very many other factors ranging from sex to pre-existing medical conditions and socioeconomic factors (11, 12) , both common and rare genetic variants have been identified that may predispose individuals to an infection with SARS-CoV-2 or a severe course of . A recent GWAS by the COVID-19 host genetics initiative (COVID-19 HGI(16)), identified 13 loci of genomewide significance for the susceptibility to COVID-19, comparing subjects with self-or All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 14, 2021. ; https://doi.org/10.1101/2021.09.12.21263447 doi: medRxiv preprint physician-reported COVID-19 diagnosis to the general population. Four of these loci seem to be specific to COVID-19 susceptibility rather than disease severity. The identified loci include variants in genes implicated in the innate immune response to viruses but also genomic loci harboring many genes of yet-undetermined function in the context of COVID-19. In light of these findings, we asked whether genetic underpinnings are shared between COVID-19 susceptibility, major psychiatric disorders, and personality traits. We approached this question using both results from the largest GWAS in the respective fields and individual-level data from two observational studies of psychiatric disorders (PsyCourse) and personality traits (PsyCourse and HeiDE). We performed linkage disequilibrium score regression (LDSC) (17) (20) , depression (as a broader phenotype closely related to major depressive disorder (MDD)) (246,363 cases; 561,190 controls) (21) , and Big 5 personality traits (n=70,000 to 120,000) (22) . For the details on phenotype definitions used in the GWAS, please refer to the original publications. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in In a second step, individual-level data were used to calculate polygenic risk scores (PRS). In the PsyCourse Study (n=1786), consisting of individuals with major psychiatric disorders (652 SCZ, 567 BPD, 101 MDD) and controls without major psychiatric disorders (n=466), recruited throughout Germany and Austria and followed longitudinally(23), we assessed whether PRS for susceptibility to COVID-19 were associated with case status or with extraversion scores. PRS were calculated using the PRS-CS method (24) , excluding the HLA region on chromosome 6. All genotyped participants of the PsyCourse Study with a diagnosis from the psychoticto-affective spectrum as well as controls (n=1346, age [mean±SD] 47.75±13.81, 47.39% female) or for whom an extraversion score was available (n= 1190) were included in the analysis. "Case" status was defined as having a lifetime diagnosis of a severe psychiatric disorder from the spectrum of psychotic and affective disorders defined in the DSM-IV and as determined by a trained rater administering the relevant section of the SCID-I interview. The extraversion score (range: 1 to 5, mean: 3.09) was derived from a 10-item questionnaire assessing the Big 5 Personality Traits(25) (Figure) . DNA samples of PsyCourse participants were genotyped on the Illumina Infinium PsychArray, and imputed using the 1000 Genomes project dataset as reference panel (for details, see (23) ). In the HeiDE study (e.g.(26)), we assessed whether extraversion scores (see below) were associated with PRS for COVID-19 susceptibility (generated using PRS-CS; n=3266, age [mean±SD] 52.78±7.06, 52.38% female). Briefly, HeiDE ("Heidelberger Langzeitstudie zu Risikofaktoren und Diagnose chronischer Erkrankungen") is a population-based study carried out in the German city of Heidelberg and surroundings, whose initial aim was to characterize associations of personality and somatic disease. Data analyzed in this study were collected during the baseline assessment (personality traits; 1992 to 1994) and the first follow-up (DNA for All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 14, 2021. ; https://doi.org/10.1101/2021.09.12.21263447 doi: medRxiv preprint genotyping; on average 8.5 years after baseline). Extraversion was measured using the Eysenck-Personality-Inventory, from which we analyzed the sum of two items closely matching the items of the Big 5 personality questionnaire used in the PsyCourse study (range: 0 to 2, mean: 1.48). DNA samples of HeiDE participants were genotyped using the Illumina Infinium PsychArray and the Infinium OmniExpress Exome Array. The combined HeiDE datasets were imputed using the 1000 Genomes phase 3 reference panel (for details, see (27) boards of the primary studies that the utilized summary statistics were taken from (16, (19) (20) (21) (22) 28) . Written informed consent was obtained from all study subjects. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in No genetic correlation was found between COVID-19 susceptibility and MDD, BPD, or SCZ risk (Table 1) . When analyzing the genetic correlation between personality traits (22) and COVID-19 susceptibility, a significant positive correlation (p=1.47x10 -5 ; rg=0.284) was identified for the personality trait of extraversion. No statistically significant correlation was present with any other Big-5 personality trait ( Table 2) . To corroborate these findings by a second, independent line of evidence using individual-level data from two independent cohorts, we turned to an assessment of PRS. In the PsyCourse Study, PRS for COVID-19 susceptibility were not significantly associated with psychiatric case status when compared to controls (p=0.474, beta=-1.132). Further, in the PsyCourse Study, no significant association between COVID-19 susceptibility PRS and extraversion as measured by the 10-item questionnaire assessing the Big-5 Personality Traits (p=0.210, beta=2.369) was found. To validate the finding for extraversion in another study setting and to mitigate any potential influence of an interaction between psychiatric disorders and personality traits in the context of COVID-19 susceptibility possibly present in the PsyCourse study, we recapitulated the extraversion analysis in the larger HeiDE study which was specifically designed to evaluate the interaction between personality traits and somatic disorders. Here, however, we also did not detect a significant association of It is likely that many interdependencies exist between COVID-19 susceptibility and major psychiatric disorders or personality traits. Among these, we shed light on a potential role for shared common genetic risk factors. For major psychiatric All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 14, 2021. ; https://doi.org/10.1101/2021.09.12.21263447 doi: medRxiv preprint disorders, we did not identify a significant genetic overlap that can be ascribed to common genetic variation both when assessing summary statistics of large GWAS by LDSC and when looking at PRS in individual level data, in line with emerging data in the field (16, 29, 30) . With regard to personality traits, the picture is more heterogeneous with a significant signal for a positive genetic correlation between extraversion and COVID-19 susceptibility by LDSC, which needs to be explored further once larger data sets become available. However, it has to be assumed, that the genetic make-up is only one contributor in a very complex network of factors connecting extraversion to COVID-19 susceptibility. The positive correlation identified between COVID-19 susceptibility and extraversion highlighted by the LDSC approach appears to be in line with the literature. Numerous studies performed both before and during the SARS-CoV-2 pandemic have demonstrated the effect of personality determinants on health behavior and outcomes (e.g. (5, 31, 32) ). For example, it was shown that narcissistic tendencies coincide with decreased perceived susceptibility to infection with SARS-CoV-2 (33) while, at least for neuroticism, not genetic overlap was found (29) . Intuitively, less extroverted individuals may find social distancing during the pandemic easier than extroverted individuals and may, therefore, be more compliant with social distancing rules and at an overall decreased risk for COVID-19(5, 6). There is even evidence of a bidirectionality of this phenomenon-the general risk for infectious diseases in a given region may, in part, influence personality traits at population level such that lower mean levels of extraversion are reported in regions with higher prevalence of infectious diseases(34). One possible reason for this could be that in regions where ever-present infectious diseases present a comparatively large thread to health and well-being, less extraversion is present at population level either because people have adapted their behavior or because of potential selective pressure. Yet, it is All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 14, 2021. ; https://doi.org/10.1101/2021.09.12.21263447 doi: medRxiv preprint likely that many interdependencies exist between COVID-19 susceptibility and personality traits or major psychiatric disorders and we investigated only shared common genetic risk factors. Although all included GWAS are the currently largest in the respective fields, sample sizes may still not be large enough to confidently detect genetic correlations in settings with many natural confounders such as levels of exposure to the virus or socioeconomic differences, to name only a few. Also, different instruments where used to evaluate personality traits in PsyCourse and HeiDE and the study populations (individuals with severe psychiatric disorders and controls vs. the general population) were different, possibly contributing to the observed heterogeneity. While LDSC represents a powerful tool to assess genetic correlations, other methods to quantify polygenic overlap irrespective of genetic correlations also exist (e.g., (35) ) and could be used to explore potential shared genetic underpinnings in even greater depth but are beyond the scope of this study. An additional limitation lies in the fact that no direct risk assessment was possible for the individuals with individual-level data on major psychiatric disorders and personality traits since no COVID-19 phenotypes were available. Lastly, we are unable to fully exclude sample overlap especially on the side of the controls used in the included GWAS. However, LDSC results should be robust to both of these overlaps(18). Hypothetically, it is possible that-for example-only a small subset of common genetic risk factors in a given pathway relevant to major psychiatric disorders or personality traits is associated with COVID-19 susceptibility. Although we cannot fully exclude all such effects, our data suggest that non-genetic factors play important roles in the interplay between personality traits and COVID-19. A direct genetic overlap is unlikely to contribute to the increased, but yet-unexplained COVID-19 risk seen in individuals with a psychiatric diagnosis prior to SARS-CoV-2 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 14, 2021. ; https://doi.org/10.1101/2021.09.12.21263447 doi: medRxiv preprint infection(4) but a shared genetic risk could still be mediated by intermediate phenotypes such as, for example, lower socio-economic status or educational attainment in those with severe psychotic disorders. As a consequence, an even greater focus should be placed on psychosocial interventions, ensuring the best treatment for individuals with severe psychiatric disorders as well as targeted measures of prevention and psychoeducation for individuals with personality determinants that place them at an increased pandemic-related risk for health and well-being. We thank Stefan Herms for his support in the technical provision of genotype data. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The data that support the findings in this study are available from the corresponding author, ECS, upon reasonable request. The relevant summary statistics from the GWAS used in the analyses are available from the authors of the primary studies (16, (19) (20) (21) (22) 28) . Interested researchers can also apply for the used as well as additional data for the PsyCourse Study via http://www.psycourse.de/openscience-en.html. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Traits. 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