https://orcid.org/0000-0003-0242-853X
Despite some progress to date, minority and low-income communities still suffer from disproportionally high incidence and mortality rates from many of the most prevalent diseases in the USA [Citation1,Citation2], which has most recently been illustrated in devastating detail through the COVID-19 pandemic [Citation3]. An important question therefore arises: what are the biological processes through which inequality becomes embodied as poor health and disease? This special issue of Epigenomics focuses on a key area that has begun to receive attention from many disciplines – the contribution of epigenomic research to the understanding of how health disparities are produced, potentially shedding new light on how they might be eliminated. Many researchers from biomedical science, social sciences and genetics have been drawn to the field of environmental epigenomics as a way to better understand how the social and physical environments in which we live affect our very biology – how they get ‘under the skin’ to increase our risk of developing a myriad of diseases.
Recent research has demonstrated that, at least for chronic disease, our external environments, lifestyles and behaviors play perhaps the greatest role in shaping the contours of human health and the burden of disease. The genetic heritability of most major noncommunicable chronic diseases is known to be low. Single-nucleotide variants (SNVs) identified in genome-wide association studies (GWASs) as associated with chronic illness explain only a small fraction of the heritability of such complex diseases [Citation4,Citation5]. A recent meta-analysis of 2748 twin studies demonstrated that the contribution of the environment was nearly equal to that of genetics across 17,804 human traits [Citation6], whereas a separate study aggregating data across over 12 monozygotic twin studies has demonstrated that the population attributable fractions of genetic variation for 28 chronic diseases were, on average, just 19% [Citation7]. Now more than ever, we need greater precision in not only understanding how our environments influence disease but, importantly, how certain environments and adversities may be experienced disproportionately by certain populations to produce disease inequality. Epigenomic research methods offer a unique opportunity to study how these important environmental influences on disease become embodied among different communities through revealing a number of biological mechanisms that are sensitive to and modified by environmental conditions outside of the human body. Consequently, many researchers have described the great potential of epigenomics research as a methodological, conceptual and analytical bridge that can finally help us understand how adverse human environments influence our very physiology and biology [Citation8–10].
Although epigenomic researchers have been investigating the influences of physical environmental exposures (e.g., air pollution, contaminants and heavy metal exposures and lifestyle factors such as smoking, alcohol and nutrition) on epigenetic mechanisms for years under the banner of ‘environmental epigenomics’, the field is at a crossroads where a fundamental rethinking of what constitutes a human environment is necessary, especially in the pursuit of understanding disparities in health and disease. It will be crucial for the field of environmental epigenomics to expand its inquiry to the entire exposome [Citation11] (i.e., all nongenetic influences on health, including social, economic, cultural, built environment and housing and psychosocial dimensions of life) in order to truly come to terms with the determinants of health inequality from an epigenomic perspective. The article by Lock et al. in this special issue makes a compelling case for this new conceptualization of the environment in epigenomics research. Such an approach will require methodological innovations and true transdisciplinary research designs, particularly when the aim is to better understand disparities that affect communities that are under-represented in scientific research. The articles in this special issue were written specifically to acknowledge and address these challenges through original research, methodological summaries, systematic reviews and forward-looking commentaries.
Non et al. have contributed to this special issue the first published study that investigates epigenome-wide DNA methylation and epigenetic age measures among children of Latinx immigrants in the USA. Specifically, they investigated associations between several measures of psychosocial stress before and after the 2016 presidential election with these epigenetic measures. While their results need to be replicated in larger studies, the overall trends they report may indicate age-dependent associations between stress and social exposures and epigenetic clocks among children of Latinx immigrants in the USA. Dereix et al. provide further research that corroborates a growing body of evidence that maternal anxiety and depression during pregnancy are associated with infant cord blood DNA methylation in the glucocorticoid receptor gene (NR3C1), which is a central gene in the hypothalamic–pituitary–adrenal (HPA) axis i.e. (stress pathway). Studies such as these provide crucial evidence that the production of disparities, via potential epigenetic programming, can start as early as the perinatal period.
Shields et al. contribute original research studying the associations between a diverse panel of childhood and adulthood adversity measures among 1000 Black women in the USA in relation to DNA methylation of four stress-related, HPA axis genes. They also investigate the potential influence of several dimensions of religiosity and spirituality on these DNA methylation dynamics. Interestingly, associations reported between childhood adversity and DNA methylation of NR3C1 and FKBP5 in previously published studies could not be replicated. The authors also show that some associations between stress and DNA methylation only persist among those who do not endorse having strong resiliency (measured in this case in terms of religious/spiritual coping and resilience). The authors point to the need for future research to not only study the direct effects of adversity on DNA methylation but also to investigate the potential impact of resilience in modifying the relationship between psychosocial stressors and DNA methylation. Results of this study also emphasize the need for future attention to be paid to differences in results from high-risk versus general population samples when studying adversity and DNA methylation, as well as potential differences between studies of children versus retrospective studies of childhood adversity among adults.
Two reviews in this special issue also address crucial topics in relation to epigenomics and health disparities: inclusion of minority participants in epigenomics research and advancing work in social epigenomics to better understand environment–methylation dynamics that influence disparities in health. Fundamentally, using epigenomic methods to better understand health disparities requires the inclusion of racial/ethnic and socioeconomic minority participants in data sets used for epigenomics analyses. To address this, Collier et al. conducted a systematic review evaluating race/ethnicity representation in DNA methylomic studies of preterm birth. They found that Black and non-Hispanic Black deliveries were well represented (28%) in the literature in which race/ethnicity was reported. However, many large analyses based on study populations that were more than 95% white were excluded from their review because they failed to classify the self-identified race or ethnicity for the 5% of their study population that was nonwhite. Where studies including minority populations do exist, they are most often conducted in a homogeneous study population of a particular minority community, which prevents direct comparison of DNA methylomic differences across race/ethnicities within individual studies. This review highlights a lack of awareness and consistency on the part of epigenomics researchers in reporting the race/ethnicity breakdown of their participant samples and the need for future comparative research in mixed population samples.
A second (nonsystematic) review article by Non focuses on the future of social epigenomic research, giving an overview of progress made to date alongside methodological and analytical challenges and suggestions for improvement. Her recommendations include investigating more diverse sample populations and conducting cross-cultural, longitudinal and multigenerational studies. Echoing several other papers in this special issue, Non calls for more collaborative efforts between social scientists and (epi)geneticists in the pursuit of more rigorous social and environmental epigenomics research.
Salas et al. have written a methods-focused piece outlining important methodological recommendations for researchers to employ while trying to understand the relationship between DNA methylation and adversity in under-represented communities. In particular, they discuss the methodological challenges that arise when trying to analyze DNA methylation across diverse participants due to variation in population stratification and cell type proportions. They also discuss methods that have been developed to resolve confounding from unmeasured variables/factors in DNA methylation studies without the use of a reference genome, which is important if a study includes participants from a particularly under-represented genetic ancestry that is not represented by currently published reference genomes. The authors end by discussing epigenomics and cancer disparities in more detail, outlining both advances made in that field but also challenges that remain in elucidating cancer disparities in relation to epigenetic markers.
Finally, Lock, Argentieri and Shields offer a forward-looking commentary from an anthropological perspective outlining how ethnographic methods and qualitative study designs focused on community engagement can be used to broaden and improve environmental epigenomics research among under-represented communities by discovering new forms of adversity and environmental exposure to study. Ethnographic and other qualitative methods are particularly powerful tools for understanding the nature and impact of various adverse experiences from participants’ own personal perspectives. This approach is important to overcome researchers’ a priori assumptions about the most important and salient experiences among participants in their research, especially when the researchers come from social, cultural and economic contexts outside of those experienced by their research participants. Practical tips are given for how some of the ethnographic and qualitative methods proposed can fit within existing epidemiological and environmental epigenomics study designs and participant recruitment procedures. The authors also call for a transdisciplinary approach that requires input from and collaboration between (epi)geneticists, social scientists and epidemiologists.
It will be imperative that research in the field of environmental epigenomics engages meaningfully and substantively with participants from under-represented communities across the world who bear a disproportionate burden of disease in order to contribute to the elimination of health disparities. As a public health priority, it is important to prioritize the inclusion of under-represented communities who experience the greatest burdens of disease in environmental epigenomics research as a potentially expedient way to better understand the upstream determinants of these unequal disease burdens. However, as discussed by Lock et al., it is important that this research is designed and carried out in a community-driven manner such that the most salient experiences and environments experienced by these communities can be uncovered and properly analyzed. Humility is required on the part of researchers to acknowledge that many of the most important influences on health (and potentially epigenetic mechanisms) among under-represented communities may not be known to us a priori. On the analytical side, it is imperative that these efforts are then paired with adequate methodological advances that can address the methodological challenges of conducting research among participants of diverse genetic ancestries and life experiences.
Ultimately, even though epigenomic methods offer a promising avenue to uncover the biological consequences of environmental and psychosocial inequality, we cannot go about this research according to business as usual. Creating teams with expertise in key disciplines, including but not limited to anthropology and the social sciences, biomedicine, molecular biology and computational methods are essential to conducting rigorous, transdisciplinary disparities-focused research. Only then can we fine-tune our methods, analyses and priorities to the task at hand to transform environmental epigenomics into a truly transdisciplinary endeavor that can help illuminate how disparities in the burden of disease are produced and how they can be eliminated.
Financial & competing interests disclosure
This work was supported by the John Templeton Foundation (grant/award number: 48424, 59607). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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References
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