The last decade has seen an explosion in research on genetic contributions to health and well-being. With the emergence of affordable genotyping technologies, researchers from many fields collect and process genomic biomarkers as part of new and ongoing studies of human health and behavior. The information about individual-level differences provided by such biomarkers offers potential for enhancing understanding of patterns of health and well-being. Not all individuals respond in the same way to similar health risks and exposures. Physiological variation, including genomic variation, plausibly contributes to individual response.
Coincidentally, just as health researchers embraced the opportunity to examine genetic differences, they also responded to the call to examine contextual differences, or variation at the societal level, and its contribution to health. Social epidemiology, as described in the influential volume by Berkman and Kawachi,1 brought renewed attention to social context, and the value of locating an individual within this context, for deeper understandings of health risks and exposures. As a consequence of these developments, contemporary health researchers look both deeper within the body itself, and further upstream to environments, thus “situating” the body.
One advantage of an approach that incorporates genomic and contextual variation—individually and in their intersection—is the opportunity to deepen understanding of sex and gender differences in health. Men and women have different susceptibilities to disease, and these differences are not well understood.2,3 Sex-specific biological variation, including genomic variation, may play a role.4 Although sex-specific variation in the human genome is understood to be small, and its functional relevance is the subject of ongoing research investigation, dyadic processes support the production of male and female gametes, which, in turn, are associated with morphological variation.5 In a parallel fashion, gendered social and cultural institutions suggest that individuals experience and create gender-differentiated environments.6,7 They interact on a daily basis within social, economic, and institutional environments, including family, school, and work settings that are highly gendered. These observations lead naturally to the question: How does the interplay of gender-specific variation in environments and sex-specific variation in biology yield differences from birth to death in health trajectories and outcomes for men and women?
We seek to bring attention to the intersection of sex, gender, genetics, and health. Although this intersection yields considerable terrain worthy of investigation, we explore 2 specific questions. First, to what extent are sex and gender incorporated into research on genetics and health? Does this literature examine the interplay between social experiences and biological pathways in an attempt to explain systematic differences in men’s and women’s health? Second, how might social science understandings of sex and gender, and gender differences in health, be more fully integrated into scholarship in this area?
The remainder of this article is divided into 5 sections. The first section reviews the terms sex and gender. The second summarizes typical practices with regard to sex and gender in research on genetics and health based on a review of articles published over the past 5 years in 4 leading peer-reviewed journals. The third section describes persistent and unexplained gender differences in health, and reviews biological and social explanations. The fourth section presents 2 brief examples of the interplay of biological and social factors over the life course in shaping differences in men’s and women’s health. Finally, the article concludes by considering possible future directions for research.
NATURE AND NURTURE, SEX AND GENDER
The terms “sex” and “gender” merit clarification because both are used inconsistently and interchangeably in research on health. Sex refers to the biological distinctions between males and females, most often in connection with reproductive functions.8 Gender, by contrast, emphasizes the socially constructed differences between men and women that give rise to masculinity and femininity.9 The term gender can be applied to individual difference, as well as to cultural, institutional, and structural difference. In the 1970s, feminist scholars promoted use of the term gender to draw attention to the reality that not all differences between men and women could be explained by biology. This distinction allowed scholars to counter academic and popular portrayals of the differences between men and women as natural, and by extension, immutable.
Sex, with its emphasis on sex-specific variation in biology, includes sex-specific variation in chromosomes. In addition to 22 pairs of autosomal chromosomes, humans have an additional pair of what have come to be known as the sex chromosomes. Most females have 2 X chromosomes and most males have an X and Y chromosome. With males and females sharing all 22 autosomal chromosome pairs and an X chromosome, sex-specific variation among the roughly 20 000 protein-coding genes is small. Relatively few genes, estimated around 75, are located on the Y chromosome, including those linked to the development of the testes.10,11 Although a quick reading of such numbers might suggest sex-specific variation in genes of about 0.5%, estimating functionally relevant variation is complex. Recent estimates suggest that protein-coding genes account for only about 3% of the human genome.12 Not all genes code for unique proteins; noncoding DNA is relevant to biological function and phenotypic expression, and methylation patterns, expression levels, and other factors may shape meaningful sex-specific genomic variation.10,12,13
Furthermore, despite the binary that is suggested by human reproduction, both sex and gender are fluid. Variations in chromosomes, hormone levels, and reproductive organs result in more than 2 sexes, reflecting complex processes of sex development across multiple levels, and suggesting that sex itself is culturally constructed.14,15 Likewise, individuals transgress normative gender boundaries in everyday life, recasting gender as more than a simple dichotomy of men and women.16 Gender is created and recreated through social interaction that takes place in dynamic cultural and institutional contexts.7
Much as there is not a neat dichotomy represented within sex or gender, the supposed dichotomy between sex-as-biology (within the body) and gender-as-society (outside the body) masks considerable complexity. More recent scholarship recognizes that gender is not disembodied, and that physiological differences, including sex differences, can contribute to gendered realities. The observation that gender contributes to biological expression is much less prevalent, but is emerging, especially with regard to health and disease.17 In a study of bones, biologist Fausto-Sterling illustrates the myriad pathways through which culture and lived experience can affect biology. For example, Fausto-Sterling explains how culture, which might include gender-specific ideas and opportunities regarding diet or physical activity, can interweave with biology to shape group differences in bone characteristics.18 Others suggest that gender structures in society can constrain individual choices, which can, in turn, have an effect on health, including longevity.19 Moreover, gender contexts in society can shape our very understanding of sex differences, as illustrated by Jordan-Young using the example of brain organization.20
Thus, as our science recognizes that individual attributes reflect the combination of biological and social factors that work in concert over time to shape one another, and that physiological difference can reflect social experience, scholars have called both for greater precision in use of the terms sex and gender, and for abandonment of the false sex and gender dichotomy.18,21,22 Just as the oversimplification represented in a nature–nurture distinction is inadequate, so too is the oversimplification reproduced in the sex–gender distinction. These issues come to the fore in the arena of gender, genetics, and health.
We use the phrase “gender differences in health” to refer to differences between men and women. Because health itself refers to the body, we understand that gender differences in health reflect social and biological factors. We use the terms sex and “sex differences” when referring more narrowly to physiological differences associated with male and female bodies, and reporting on literatures that primarily use the term sex. Although we recognize that these differences also reflect social factors, and the very argument of this article is to more fully represent this integration, we adopt what we understand to be the conventional interpretation of sex in public health and medical research for the purposes of this article, rather than the term “sex/gender” as is sometimes used by gender scholars and social scientists.23