Background. Native Americans disproportionately experience adverse childhood experiences (ACEs) as well as health disparities, including high rates of posttraumatic stress, depression, and substance abuse. Many ACEs have been linked to methylation changes in genes that regulate the stress response, suggesting that these molecular changes may underlie the risk for psychiatric disorders related to ACEs. Methods. We reviewed published studies to provide evidence that ACE-related methylation changes contribute to health disparities in Native Americans. This framework may be adapted to understand how ACEs may result in health disparities in other racial/ethnic groups. Findings. Here we provide evidence that links ACEs to methylation differences in genes that regulate the stress response. Psychiatric disorders are also associated with methylation differences in endocrine, immune, and neurotransmitter genes that serve to regulate the stress response and are linked to psychiatric symptoms and medical morbidity. We provide evidence linking ACEs to these epigenetic modifications, suggesting that ACEs contribute to the vulnerability for developing psychiatric disorders in Native Americans. Conclusion. Additional studies are needed to better understand how ACEs contribute to health and well-being. These studies may inform future interventions to address these serious risks and promote the health and well-being of Native Americans. 1. Introduction Reservation-based Native Americans live in pervasively adverse social and physical environments that place them at increased risk of exposure to a myriad of stressors during childhood which impact their psychological and physical health over their lifetimes [1]. About 1 of 2.9 million Native Americans that identify as Native American alone resides on reservations [2]. Indian reservations were established by treaty during the Removal and Relocation (1827–1887) period and are lands set aside for tribes in exchange for ceded land and resources. Today there exist 275 Indian land areas in the USA administered as Indian reservations [3]. Of the ten poorest counties in America, five are home to an Indian reservation [4]. Concentrated poverty results in higher crime rates, underperforming public schools, poor housing, and poor health and limits access to many services and job opportunities [5]. Adverse childhood experiences (ACEs) that are substantial contributors to health disparities include childhood physical and sexual abuse, witnessing violence, poverty, and racism. The concept that these experiences become biologically
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