key: cord-0818369-417k55sp
authors: Adams, C. D.; Tielbeek, J.; Boutwell, B.
title: Shared Genomic Architectures of Covid-19 and Antisocial Behavior: Implications During Pandemics
date: 2021-10-19
journal: nan
DOI: 10.1101/2021.10.18.21265145
sha: b38961eb7e7a42fb850ea24f75394e75af3d9634
doc_id: 818369
cord_uid: 417k55sp

BACKGROUND. Norm violation, aggression, and antisocial behaviors (ASB) are harmful to society. In times of crisis, such as the current pandemic, individuals with higher antisocial tendencies may subvert efforts to ameliorate social problems. Complicating research on this topic, however, is the fact that variance in both ASB and health traits is partly heritable, suggesting the possibility of genetic correlations between them. METHODS. We characterized the shared polygenic architecture of ASB, Covid-19, and related traits, leveraging summary statistics from genome-wide association studies. RESULTS. After multiple-testing correction, ASB was genetically correlated with average income (rg=-0.54; 95% confidence interval [CI]: -0.65, -0.43); education years (rg=-0.48; CI: -0.59, -0.38; verbal reasoning (rg=-0.44; CI: -0.58, -0.30); healthspan (rg=-0.47; CI: -0.62, -0.31), lifespan (rg=-0.33 (CI: -0.46, -0.21); breastfed as baby (rg=-0.24; 95% CI: -0.38, -0.11); cheese intake (rg=-0.28 (CI: -0.38, -0.18); Covid-19 (rg=0.51, 95% CI: 0.12, 0.90; heavy, manual labor (rg=0.58; CI: 0.45, 0.70); noisy workplace (rg=0.63; CI: 0.48, 0.77); Townsend Deprivation Index (rg=0.70; CI: 0.56, 0.84); gastrointestinal diseases (rg=0.46; 95% CI: 0.23, 0.70); chronic obstructive pulmonary disease (rg=0.51; CI: 0.33, 0.68); genitourinary diseases (rg=0.38; CI: 0.22, 0.55); neuroticism (rg=0.29; CI: 0.20, 0.38); seen doctor for nerves, anxiety, tension, or depression (rg=0.42; CI: 0.31, 0.54); plays computer games (rg=0.15; CI: 0.06, 0.25); violent-crime victim (rg=0.36; CI: 0.16, 0.56); risk tolerance (rg=0.50; CI: 0.39, 0.65); saw sudden violent death (rg=0.42; CI: 0.20, 0.64). CONCLUSIONS. Our results suggest ASB shares genetic architecture with Covid-19 and related health outcomes. We discuss the public-health and bioethical implications of our results.

Antisocial behavior (ASB), including aggression, rule-breaking, and violence, is harmful to society. ASB creates a long wake of monetary, social, and emotional disturbances for countries, communities, and individuals 1, 2 . An oft-overlooked yet troublesome consequence of ASB concerns its effect on efforts to solve widespread social problems, such as during a pandemic. To contain the present pandemic, the World Health Organization (WHO) recommended various protective measures against coronavirus disease 2019 (Covid- 19) . These included masking, avoiding crowds, physical distancing, and Covid-19 vaccination-behaviors that can be seen as prosocial, as they function to keep both individuals and others free from

infection. Yet ASB, as its name implies, reflects the converse of prosocial and cooperative behavior. Mechanisms by which ASB might impact pandemic spread are numerous and in general, they remain largely understudied.

Concerning how ASB may abet pandemic spread, O'Connell et al. (2021) reported that those in an online US cohort who engaged more in ASB also more frequently ignored Covid-19 social-distancing measures 3 . Likewise using an online cohort, Carvalho and Machado (2020) found that those with increased psychopathic traits and low levels of empathy tended to adhere less to Covid-19 containment measures 4 . As a final example, Nivette et al. (2020) observed that adolescents and young adults (in a prospective-longitudinal cohort in Switzerland), who had previously scored high on indicators of antisociality (i.e., low acceptance of moral rules, "prepandemic legal cynicism, low shame/guilt, low self-control, engagement in delinquent behaviors, and association with delinquent peers"), were more likely to flout Covid-19 public-health measures 5 . These findings imply that a lack of understanding about ASB and health outcomes could imperil public-health efforts during pandemics.

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The copyright holder for this preprint this version posted October 19, 2021. ;  https://doi.org/10.1101/2021. 10.18.21265145 doi: medRxiv preprint Complicating efforts at causal inference on this topic, however, is the fact that about half of the variance in ASB and health outcomes (to varying degrees depending on the trait) is heritable [6] [7] [8] . The extent to which these traits share a genetic architecture could influence the likelihood of genetic confounding in observational data. A nascent area of research has used the summary statistics from genome-wide association (GWA) studies of ASB and various health and behavioral traits to calculate genetic correlations 9 . These studies revealed links between ASB and most psychiatric and psychological, reproductive, cognitive, and addictive traits 10, 11 . Individuals prone to antisocial, violent, and criminal behaviors are also disproportionately and profoundly unhealthy 12, 13 , and a recent study reported strong negative (r=-0.55) genetic correlations between ASB and self-reported health 10 . In contrast, a comprehensive study reported no significant genetic correlations between ASB and 669 health, physiological, and well-being measures after accounting for multiple testing 14 . Thus, much remains to be discovered regarding any shared genetic etiology of ASB and various aspects of health, including Covid-19.

We characterized the shared polygenic nature of ASB, Covid-19, and related health and behavioral traits using summary statistics from GWA studies and linkage disequilibrium score regression (LDSC; software available at http://www.github.com/bulik/ldsc) 15 . We calculated a matrix of the genetic correlations. Nineteen traits were chosen for novelty (having not been previously reported as either null or significantly correlated with ASB), and four traits were chosen as replicates of previously reported findings (education years; seen doctor for nerves, anxiety, tension, or depression; neuroticism; Parkinson's disease). The novel traits include: average income (before taxes): healthspan (defined as living free from congestive heart failure; myocardial infarction, chronic obstructive pulmonary disease, stroke, dementia, diabetes, cancer, and death; coded as a protective ratio); parental lifespan (coded as a protective ratio); verbal reasoning; having been breastfed as baby; cheese intake; self-reported happiness; Covid-19 (data from two GWA studies; see Table 1 ); heavy, manual labor; noisy workplace; Townsend Deprivation Index (an area-and census-based measure of deprivation, where a higher score indicates more deprivation); gastrointestinal diseases; chronic obstructive pulmonary disease; genitourinary diseases; plays computer games, violent-crime victim, risk tolerance, and saw sudden, violent death. Table 1 contains details about the GWA studies-all performed in those of European ancestry. P=9.60E-04); cheese intake (r g =-0.28 (95% CI: -0.38, -0.18; P=6.97E-08); happiness (r g =-0.10; All rights reserved. No reuse allowed without permission.

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Due to the positive genetic signal between Covid-19 and ASB, we highlight the correlations between Covid-19 and the non-ASB traits. These are displayed in a forest plot in (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 19, 2021. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

To contrast them in the Discussion with the findings for ASB and Covid-19, we report the FDR-significant findings for Parkinson's disease. We observed positive genetic correlations between Parkinson's disease and two traits: average income (r g =0.17; 95% CI: 0.07, 0.28; Covid-19 suggests that individuals who engage in ASB appear more susceptible to Covid-19 than those who do not engage in ASB. This implies they may put themselves and others at higher All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. risk and/or that the health conditions associated with ASB, such as chronic obstructive pulmonary disease, make those prone to ASB an at-risk group for Covid-19.

Controversially though rationally, this information could be used to back Covid-19 vaccine mandates. While the traits jointly inversely associated with Covid-19 and ASB-most saliently, education years, reasoning ability, and average income-are environmentally modifiable, this worked against the poor and undereducated during the Covid-19 pandemic (e.g., low-wage workers disproportionately lost their jobs 16 , and learning was hampered by school shutdowns, especially among the most disadvantaged 17 ). This implies that policies to increase income and education would need to be ramped up and accelerated in times of pandemics, precisely when resources are strained, if increasing income and education are to be used to encourage compliance with prosocial pandemic guidelines.

Observationally, income inequality correlates with types of ASB, most notably crime 18 , but whether economic interventions, such as the federally issued stimulus checks given to a bulk of US citizenry during the Covid-19 pandemic, reduced vaccine hesitancy and social-distancing non-compliance among those prone to ASB is unknown. While addressing that counterfactual is beyond the scope of this paper, what is known is that vaccine mandates for other diseases seem to have been effective at increasing the number of those vaccinated and reducing the populationburden of infectious diseases 19, 20 .

That the genetic correlation between Covid-19 and risk tolerance (a characteristic of ASB) was null suggests that a lack of education and not a propensity for risk-taking behavior may link ASB and spread of Covid-19. This is somewhat hopeful: the aspect of antisociality positively associated with getting Covid-19 does not appear to arise from overt risk-seeking, but from a lack of understanding about a complex issue. Perhaps over the coming years, as All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. introducing vaccine mandates earlier during future pandemics supports both global health and health equity: it would protect many of the least advantaged, including and especially those prone to ASB. Further to this, traits that are positively genetically correlated with both ASB and Covid-19-having a noisy workplace, doing heavy, manual labor, and having chronic obstructive pulmonary disease-are also strongly inversely genetically correlated with education years, verbal reasoning, and average income. Thus, the shared genetic architecture paints a grave picture of inequalities predisposing some to both ASB and Covid-19.

On a less dire but surprising note, our results for Parkinson's disease reveal that education years and average income are not always protective-the genetic correlations with Parkinson's disease were positive. Also counterintuitively, Townsend Deprivation Index, doing heavy, manual labor, and having chronic obstructive pulmonary disease were inversely genetically correlated with Parkinson's disease (implying a possible protective effect). While Parkinson's disease was null for both ASB and Covid-19, it shares genetic architecture with traits strongly associated with them. To help explain this, Frigeror et al. (2005) found that those with higher education had an increased risk and those with jobs involving more physical activity had a decreased risk for Parkinson's disease 21 . This matches our genetic findings. Similarly, a Mendelian randomization (MR) study revealed that those with higher intelligence were less likely to engage in moderate and rigorous physical activity 22 . Thus, it is plausible that the protective architecture against Covid-19 and ASB that is related to more education years and higher intelligence (proxied by both education years and verbal reasoning) is likely not from greater physical activity. This lends more credence to the hypothesis proposed above that the All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. While we observed positive genetic correlations between ASB and the psychiatric and violence-related traits we measured, none of these traits were genetically correlated with Covid- 19 . This comports with a meta-analytic review of mood disorders and risk for Covid-19 in 91 million individuals; Ceban et al. (2021) found no association between pre-existing mood disorders and susceptibility to Covid-19 23 .

Our study has limitations, which must be considered. The SNP heritability estimates for both measures of Covid-19, while >0, were small. Second is that genetic correlations, while being robust against environmental confounders, can still suffer from genetic sources of confounding (i.e., even with genetic correlations, correlation is not always causation). To this point, we think it is highly unlikely that not being breastfed as a baby and eating less cheese cause ASB. In fact, we chose these dietary traits to illustrate this very point. Rather, the shared genetic architecture that these have with education years, verbal reasoning, and average income are the more plausibly causal phenomena. Third, we cannot determine the direction of causality with genetic correlations alone. For much of the discussion above, we tacitly presumed plausible directions of effect (e.g., ASB causing Covid-19 versus Covid-19 causing ASB). But with all the traits in our matrix, the prevailing direction of effect could be the opposite and/or some level of bi-directional causation may exist 15, 24 . These uncertainties are avenues for future research.

Specifically, at present MR cannot be leveraged to test whether ASB causes any of the traits investigated, since few genome-wide significant signals have been found for ASB. But once they are found, bi-directional MR can be used to decipher the prevailing directions. A fourth limitation is that our findings are limited to those of European ancestry. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The limitations notwithstanding, genetic correlations obtained from LDSC are not affected by sample overlap (i.e., participants being in both GWA studies for which the genetic correlations were calculated) 15 . This is a strength of study, which enabled us to capitalize on the power of large, population-based cohorts and publicly available GWA data to probe timely questions. Another strength of our study is that it weaves together its empirical findings with a considerable discussion, albeit a nascent one, about ethical implications.

To conclude, ASB may reflect evolved strategies for procuring resources, perhaps in settings where it is more advantageous to provision most often for oneself while remaining wary of others, where threat-sensitivity and aggression may provide an edge 25, 26 . We hope our study, which is by no means comprehensive, raises interest in this issue further, along with the general importance of studying the etiology of ASB; that it contributes to existing bioethical, medical, and public-health discussions about pandemic control; and that it gets us closer to providing some measure of both protection and relief to a large part of the global population-both those engaged in ASB and those devastated by it. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (rounds 4 and 6) and health and behavioral traits. Closed circles indicate genetic correlations with significant P-values after false-discovery rate (FDR) correction.

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