Gene-environment interactions in cortisol reactivity: Sex, genes, and adversity predict responses to psychosocial stress

Extreme variations in cortisol reactivity are associated with multiple psychological and physiological diseases. These variations may be explained by sex, by genetic vulnerabilities, and by exposure to either recent life stressors (severe life events or ongoing difficulties) or early life adversity (e.g., antipathy; neglect; or psychological, physical, or sexual abuse). To explore interactions among these variables, a subset of 20-22 years-old individuals (N = 373) recruited for an ongoing longitudinal cohort-sequential study of substance abuse risk factors were assessed. These individuals were interviewed about early childhood abuse and recent stressful life experiences. They were also genotyped for multiple polymorphisms within genes associated with attenuated or exaggerated cortisol reactivity (5-HTTLPR and rs25532 in SERT, rs4680 in COMT, rs5522 in MR gene NR3C2, rs110402 and rs1876831 in CRHR1, rs1799971 in OPRM1, and rs1800497 in ANKK1), participated in a laboratory social stress task, and provided salivary cortisol samples throughout the task. Results indicate that cortisol reactivity may be shaped by both early and recent life experiences and genetic vulnerabilities; most interactions between these variables differed depending on an individual's sex. Specifically, carriers of two copies of minor alleles of ANKK1, COMT, and CRHR1 displayed dysregulated cortisol that varied according to sex and early life experiences. Male minor allele carriers who experienced more severe physical abuse displayed attenuated reactivity, and males who were not severely abused displayed exaggerated responses. Female minor allele carriers displayed the opposite pattern - abused females displayed exaggerated reactivity. Carriers of major alleles did not show these patterns. Attenuated cortisol reactivity was also observed in all individuals who experienced sexual abuse or neglect, and elevated responses were observed in individuals carrying two copies of minor alleles in both SERT polymorphisms and OPRM1. Together, results inform a developmental model of cortisol dysregulation. Cortisol reactivity may present a useful endophenotype for future studies of physiological and psychological disease processes and treatment outcomes.