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. 2025:30:296-313.
doi: 10.1142/9789819807024_0022.

Social Determinants of Health and Lifestyle Risk Factors Modulate Genetic Susceptibility for Women's Health Outcomes

Lindsay A Guare  1 , Jagyashila Das  2 , Lannawill Caruth  3 , Shefali Setia-Verma  4
Affiliations

Social Determinants of Health and Lifestyle Risk Factors Modulate Genetic Susceptibility for Women's Health Outcomes

Lindsay A Guare et al. Pac Symp Biocomput. 2025.

Abstract

Women's health conditions are influenced by both genetic and environmental factors. Understanding these factors individually and their interactions is crucial for implementing preventative, personalized medicine. However, since genetics and environmental exposures, particularly social determinants of health (SDoH), are correlated with race and ancestry, risk models without careful consideration of these measures can exacerbate health disparities. We focused on seven women's health disorders in the All of Us Research Program: breast cancer, cervical cancer, endometriosis, ovarian cancer, preeclampsia, uterine cancer, and uterine fibroids. We computed polygenic risk scores (PRSs) from publicly available weights and tested the effect of the PRSs on their respective phenotypes as well as any effects of genetic risk on age at diagnosis. We next tested the effects of environmental risk factors (BMI, lifestyle measures, and SDoH) on age at diagnosis. Finally, we examined the impact of environmental exposures in modulating genetic risk by stratified logistic regressions for different tertiles of the environment variables, comparing the effect size of the PRS. Of the twelve sets of weights for the seven conditions, nine were significantly and positively associated with their respective phenotypes. None of the PRSs was associated with different ages at diagnoses in the time-to-event analyses. The highest environmental risk group tended to be diagnosed earlier than the low and medium-risk groups. For example, the cases of breast cancer, ovarian cancer, uterine cancer, and uterine fibroids in highest BMI tertile were diagnosed significantly earlier than the low and medium BMI groups, respectively). PRS regression coefficients were often the largest in the highest environment risk groups, showing increased susceptibility to genetic risk. This study's strengths include the diversity of the All of Us study cohort, the consideration of SDoH themes, and the examination of key risk factors and their interrelationships. These elements collectively underscore the importance of integrating genetic and environmental data to develop more precise risk models, enhance personalized medicine, and ultimately reduce health disparities.

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Figures

Figure 1:
Figure 1:
Testing the effects of the PRSs on the women’s health outcomes. (a) Coefficients (in odds ratio scale) for logistic regressions based on each PRS. The left axis labels indicate phenotype and PGS Catalog Weights. The right axis labels show the p-value. Scores that were not considered in downstream analyses have a red “X”. (b) Time-to event analyses with one curve per PRS risk tertile. Pairwise log rank comparison p values are indicated as text. X-axes above and below each panel are age at diagnosis (Dx). BC: Breast Cancer; UF: Uterine Fibroids; CC: Cervical Cancer; UC: Uterine Cancer; Endo: Endometriosis; OC: Ovarian Cancer; PE: Preeclampsia.
Figure 2:
Figure 2:
(a) heatmap showing correlation between all nine measurements considered. Correlation values significantly different from zero (p < 0.05) are marked with an asterisk. (b) heatmap showing the number of cases for a given phenotype (column) and measurement (row) combination. BC: Breast Cancer; UF: Uterine Fibroids; CC: Cervical Cancer; UC: Uterine Cancer; Endo: Endometriosis; OC: Ovarian Cancer; PE: Preeclampsia. BMI: Body Mass Index; AU: Alcohol Use; SK: Smoking ; SM: Sedentary Minutes; ST: Steps; LL: Loneliness; NSD: Neighborhood Social Deprivation; NPD: Neighborhood Physical Deprivation and SL: Stress Level.
Figure 3:
Figure 3:
Time-to-event analyses for BMI and the SDoH themes (a - BMI, b - loneliness, c - neighborhood physical disorder, and d - stress). Each panel shows three “survival” curves per phenotype, stratified by the value of the environmental measure where 1 is the lowest tertile and 3 is the highest tertile. The x-axes represent age at diagnosis (Dx). Also indicated in each grid cell are the p-values of pairwise log rank comparisons between those three curves. Any p-values less than 0.05 are annotated with an asterisk. BC: Breast Cancer; UF: Uterine Fibroids; UC: Uterine Cancer; Endo: Endometriosis; OC: Ovarian Cancer; PE: Preeclampsia.
Figure 3:
Figure 3:
Time-to-event analyses for BMI and the SDoH themes (a - BMI, b - loneliness, c - neighborhood physical disorder, and d - stress). Each panel shows three “survival” curves per phenotype, stratified by the value of the environmental measure where 1 is the lowest tertile and 3 is the highest tertile. The x-axes represent age at diagnosis (Dx). Also indicated in each grid cell are the p-values of pairwise log rank comparisons between those three curves. Any p-values less than 0.05 are annotated with an asterisk. BC: Breast Cancer; UF: Uterine Fibroids; UC: Uterine Cancer; Endo: Endometriosis; OC: Ovarian Cancer; PE: Preeclampsia.
Figure 4:
Figure 4:
time-to-event analyses for lifestyle measurements (a - alcohol use, b - sedentary minutes, c - smoking, and d - steps). Each panel shows three “survival” curves per phenotype, stratified by the value of the environmental measure where 1 is the lowest tertile and 3 is the highest tertile. The x-axes represent age at diagnosis (Dx). Also indicated in each grid cell are the p-values of pairwise log rank comparisons between those three curves. Any p-values less than 0.05 are annotated with an asterisk. BC: Breast Cancer; UF: Uterine Fibroids; UC: Uterine Cancer; Endo: Endometriosis; OC: Ovarian Cancer; PE: Preeclampsia
Figure 5:
Figure 5:
All odds ratio and logistic regression tests performed for BMI and SDoH. The environmental factors are (a) BMI, (b) loneliness, (c) neighborhood physical disorder, and (d) stress. The upper left 3x3 grid in each pane shows the odds ratios of the phenotypes in each cell. The rightmost column shows regression coefficients stratified by environmental tertile. The bottom row shows regression coefficients stratified by genetic risk. The bottom right cell shows a histogram of the environmental variable, with the cutoffs between the tertiles marked. BC: Breast Cancer; UF: Uterine Fibroids; UC: Uterine Cancer; Endo: Endometriosis; OC: Ovarian Cancer; PE: Preeclampsia
Figure 5:
Figure 5:
All odds ratio and logistic regression tests performed for BMI and SDoH. The environmental factors are (a) BMI, (b) loneliness, (c) neighborhood physical disorder, and (d) stress. The upper left 3x3 grid in each pane shows the odds ratios of the phenotypes in each cell. The rightmost column shows regression coefficients stratified by environmental tertile. The bottom row shows regression coefficients stratified by genetic risk. The bottom right cell shows a histogram of the environmental variable, with the cutoffs between the tertiles marked. BC: Breast Cancer; UF: Uterine Fibroids; UC: Uterine Cancer; Endo: Endometriosis; OC: Ovarian Cancer; PE: Preeclampsia
Figure 6:
Figure 6:
All odds ratio and logistic regression tests performed for the lifestyle variables. The environmental factors are (a) alcohol use, (b) sedentary minutes, (c) smoking, and (d) steps. The upper left 3x3 grid in each pane shows the odds ratios of the phenotypes in each cell. The rightmost column shows regression coefficients stratified by environmental tertile. The bottom row shows regression coefficients stratified by genetic risk. The bottom right cell shows a histogram of the environmental variable, with the cutoffs between the tertiles marked. BC: Breast Cancer; UF: Uterine Fibroids; UC: Uterine Cancer; Endo: Endometriosis; OC: Ovarian Cancer; PE: Preeclampsia
Figure 6:
Figure 6:
All odds ratio and logistic regression tests performed for the lifestyle variables. The environmental factors are (a) alcohol use, (b) sedentary minutes, (c) smoking, and (d) steps. The upper left 3x3 grid in each pane shows the odds ratios of the phenotypes in each cell. The rightmost column shows regression coefficients stratified by environmental tertile. The bottom row shows regression coefficients stratified by genetic risk. The bottom right cell shows a histogram of the environmental variable, with the cutoffs between the tertiles marked. BC: Breast Cancer; UF: Uterine Fibroids; UC: Uterine Cancer; Endo: Endometriosis; OC: Ovarian Cancer; PE: Preeclampsia
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