Polygenic risk scoring to assess genetic overlap and protective factors influencing posttraumatic stress, depression, and chronic pain after motor vehicle collision trauma

Abstract

Posttraumatic stress (PTS), depressive symptoms (DS), and musculoskeletal pain (MSP) are common sequelae of trauma exposure. Although these adverse posttraumatic neuropsychiatric sequelae (APNS) are often studied separately, clinical comorbidity is high. In a cohort of European American motor vehicle collision (MVC) trauma survivors (n = 781), substantial PTS (≥33, IES-R), DS (≥26, CES-D), and MSP (≥4, 0-10 NRS) were identified via a 6-month survey. Genetic risk was estimated using polygenic risk scores (PRSs) calculated from the largest available GWAS datasets of PTSD, MDD, and back pain. We then assessed comorbidity and genetic risk influence for developing chronic PTS, DS, and MSP after MVC. Secondary analyses explored whether common social determinants of health ameliorate genetic vulnerability. We found that 6 months after MVC, nearly half 357/781 (46%) of the participants had substantial PTS, DS, and/or MSP, and overlap was common (PTS + MSP (23%), DS + MSP (18%), PTS + DS (12%)). Genetic risk predicted post-MVC outcomes. PTSD-PRSs predicted PTS and DS (R² = 2.21% and 2.77%, p_adj < 0.01), MDD-PRSs predicted DS and MSP (R² = 1.89%, p_adj < 0.01) and 0.79%, p_adj < 0.05), and back pain-PRS predicted MSP (R² = 1.49%, p_adj < 0.01). Individuals in the highest quintile of PTSD-PRSs had 2.8 and 3.5 times the odds of developing PTS and DS vs. the lowest quintile (95% CI = 1.39-5.75 and 1.58-7.76). Among these high-risk individuals, those living in non-disadvantaged neighborhoods and with college education had 47% (p = 0.048) and 52% (p = 0.04) less risk of developing PTS, and those with high social support had 60% (p = 0.008) less risk of developing DS. Overall, genetic factors influence the risk of APNS after MVC, genetic risk of distinct APNS are overlapping, and specific social determinants greatly augment genetic risk of APNS development after MVC.

Fig. 1. Overlap in posttraumatic stress (PTS), depressive symptoms (DS), and musculoskeletal pain (MSP) outcomes 6 months following motor vehicle collision trauma in White individuals (n = 781).

Clinical overlap between common adverse posttraumatic neuropsychiatric outcomes is represented here via Venn Diagram. In total, 357 (46%) participants experienced at least one outcome and 424 participants reported full recovery (i.e., no PTS, DS, or MSP). Of those individuals experiencing at least one outcome, 32% (n = 114/357) reported two or more outcomes and 11% (n = 39/357) reported all three outcomes. Further details/summaries are presented in the main body of the manuscript.

Fig. 2. Odds ratios for each quintile of the polygenic risk scores for PTS, DS, and MSP as derived using the respective PTSD, depression, and back-pain GWAS summary statistics.

The first quintile is used as a reference. For every other quintile, the odds ratio relative to the first quintile is displayed for A posttraumatic stress (PTS), B depressive symptoms (DS), and C musculoskeletal pain (MSP). For PTS, individuals in the fifth quintile have 2.8 times higher odds of developing PTS than individuals in the first quintile. The error bars indicate 95% confidence intervals around the odds ratios.

Fig. 3. Prevalence of posttraumatic stress (PTS) and depressive symptoms (DS) 6 months following motor vehicle collision (MVC) trauma based on PTSD GWAS polygenic risk scores and the effect that three social factors have on this genetic vulnerability to PTS and DS.

Prevalence of PTS (A–C) and DS (D–F) were graphed for each polygenic risk group (defined by quintiles as presented in Supplementary Fig. S4, with the second, third, and fourth quintiles grouped in the “Mid” risk category). A, D Influence of living in a disadvantaged neighborhood (striped bars) vs. a non-disadvantaged neighborhood (black bars) on genetic risk for PTS and DS. B, E Influence of social support on genetic risk for PTS and DS (striped bars represent low social support and black bars represent high social support). C, F Influence of education level on genetic risk for PTS and DS (striped bars represent some college or less and black bars represent college education or higher). Significance of equality of proportions models within each polygenic risk category are indicated above relevant bars; *p < 0.05, **p < 0.01.