By Brea Perry, Ph.D.

Nearly every biological system, from genetics to neurology, is susceptible to influence and modification by gender. Men and women are stratified into distinct environments and often have qualitatively different experiences and social or physiological responses under similar environmental conditions, producing gender-specific health outcomes. In a study funded by the McManus Foundation and published in the American Journal of Sociology, I extend social science insights regarding gender and health to genomics, asking whether gender moderates gene-environment interactions (GxE) in substance use pathways.

Confronting the Complexity of Social Genomics

The relationship between genotypes and environments is complex, dynamic, and dependent on the particular social locations of the individuals being studied. Consequently, GxE findings have proven difficult to replicate in independent samples, suggesting a need for more sophisticated modeling that reflects this complexity. Specifically, it may be useful to account for moderation of GxE by a second “environmental” variable—here, gender (i.e., GxExGender). Where there are systematic gender differences in the consequences of social environments, a GxE effect might be observable only among men or women, or the magnitude or direction of the GxE could differ across gender groups.

To test the feasibility of a GxExGender model, I examined gender-specific moderation of a GABAergic genetic risk score by social integration in alcohol and nicotine dependence. This is an appropriate empirical case because it satisfies three conditions:

• There is a well-replicated genetic effect.
• There is evidence that the genetic effect is susceptible to moderation by social environmental conditions.
• Based on evidence, these social environmental conditions are moderated by gender.

GABA receptor genes confer risk for substance use disorders through reward pathways that increase maladaptive behavioral responses to stress and other environmental cues. At the same time, there is substantial empirical evidence demonstrating that Gamma-aminobutyric acid (GABA) receptor genes interact with social environmental variables, with the effects of genetic risk being attenuated in the presence of protective relationships and social support. Additionally, while social integration is broadly protective of health, ample empirical evidence suggests greater or even exclusive health benefits of social integration for men relative to women. This may be because women invest disproportionately in family and community, and perform more physical and emotional labor (e.g., care work) in the context of relationships than men. Consequently, I expected the protective effects of social integration on GABAergic genetic risk for substance dependence to operate exclusively or more strongly among men than women.

Genetic Contingencies in the Protective Effects of Social Integration for Men and Women

This research used data from the Collaborative Study on the Genetics of Alcoholism (COGA), a multisite case-control study using a family selection sampling strategy. Genetic risk was indexed using a hypothesis-driven, literature-based polygenic risk scale comprising eight single nucleotide polymorphisms (SNPs) in the GABAergic system, while social integration was operationalized using marital status and a nine-item scale measuring positive subjective responses to social and family relationships.

Findings revealed that having low genetic risk, being married, and feeling socially integrated reduced the odds of nicotine dependence. Two-way interactions (i.e., ExGender, GxGender, and GxE) were non-significant, but three-way interactions reflected strong gender-specific GxE effects. As expected, being currently married and reporting more positive social integration experiences conferred greater protection from nicotine dependence for men with high genetic risk than for women with high-genetic risk or for men with low-genetic risk.

Implications for Research and Policy

An important methodological implication of these findings is that ExE may mask GxE. While gender is the focus here, implications extend to race, socioeconomic status, and other fundamental social causes of disease. This phenomenon could explain the replication problem, which likely reflects a compound genetic architecture that is further obscured by an even more complex environment. Interactions between multiple genes and environments can render even strong general GxE effects nearly impossible to detect in independent samples. Consequently, in cases where social environments are reflective of gender (or other) differences, hypotheses on GxE must be gender-specific.

The social epidemiological approach to GxE employed in this research expands the concept of the environment beyond the individual, incorporating upstream normative and cultural forces that may moderate social and genetic influences on health and behavior. This complexity poses challenges for intervention, implying that responses to policies or treatments may vary as a function of both gender and genotype in a non-additive fashion. It is critical to identify how resources or conditions that are protective for one gender and/or genotype group can be leveraged to the benefit of other groups. In the case of social integration, this might be achieved through social policies that ease the burden of caring for women, such as progressive family leave policies or universal child care.

Brea L. Perry is an associate professor in the Department of Sociology and the Indiana University Network Science Institute at Indiana University, Bloomington. Her research examines relationships between social networks, social inequality, and biological systems in disease etiology and the illness career, focusing largely on mental illness and related conditions. Dr. Perry’s research has been funded by the National Science Foundation, National Institute on Drug Abuse, National Center for Craniofacial and Dental Research, National Center for Research Resources, and several charitable foundations. 

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