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 (R = 2.21% and 2.77%, p < 0.01), MDD-PRSs predicted DS and MSP (R = 1.89%, p < 0.01) and 0.79%, p < 0.05), and back pain-PRS predicted MSP (R = 1.49%, p < 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.