R Polimanti1, J Kaufman2,3, H Zhao4,5, H R Kranzler6, R J Ursano7, R C Kessler8, M B Stein9,10, J Gelernter1,5,11. 1. Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, West Haven, CT, USA. 2. Center for Child and Family Traumatic Stress, Kennedy Krieger Institute, Baltimore, MD, USA. 3. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA. 4. Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA. 5. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. 6. Department of Psychiatry, University of Pennsylvania School of Medicine and VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, USA. 7. Center for the Study of Traumatic Stress, Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 8. Department of Health Care Policy, Harvard Medical School, Boston, MA, USA. 9. Departments of Psychiatry and of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA. 10. VA San Diego Healthcare System, San Diego, CA, USA. 11. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
Abstract
OBJECTIVE: To investigate whether trauma exposure moderates the genetic correlation between substance use disorders and psychiatric disorders, we tested whether trauma exposure modifies the association of genetic risks for mental disorders with alcohol misuse and nicotine dependence (ND) symptoms. METHODS: High-resolution polygenic risk scores (PRSs) were calculated for 10 732 US Army soldiers (8346 trauma-exposed and 2386 trauma-unexposed) based on genome-wide association studies of bipolar disorder (BD), major depressive disorder, and schizophrenia. RESULTS: The main finding was a significant BD PRS-by-trauma interaction with respect to alcohol misuse (P = 6.07 × 10-3 ). We observed a positive correlation between BD PRS and alcohol misuse in trauma-exposed soldiers (r = 0.029, P = 7.5 × 10-3 ) and a negative correlation in trauma-unexposed soldiers (r = -0.071, P = 5.61 × 10-4 ). Consistent (nominally significant) result with concordant effect, directions were observed in the schizophrenia PRS-by-trauma interaction analysis. The variants included in the BD PRS-by-trauma interaction showed significant enrichments for gene ontologies related to high voltage-gated calcium channel activity (GO:0008331, P = 1.51 × 10-5 ; GO:1990454, P = 4.49 × 10-6 ; GO:0030315, P = 2.07 × 10-6 ) and for Beta1/Beta2 adrenergic receptor signaling pathways (P = 2.61 × 10-4 ). CONCLUSIONS: These results indicate that the genetic overlap between alcohol misuse and BD is significantly moderated by trauma exposure. This provides molecular insight into the complex mechanisms that link substance abuse, psychiatric disorders, and trauma exposure.
OBJECTIVE: To investigate whether trauma exposure moderates the genetic correlation between substance use disorders and psychiatric disorders, we tested whether trauma exposure modifies the association of genetic risks for mental disorders with alcohol misuse and nicotine dependence (ND) symptoms. METHODS: High-resolution polygenic risk scores (PRSs) were calculated for 10 732 US Army soldiers (8346 trauma-exposed and 2386 trauma-unexposed) based on genome-wide association studies of bipolar disorder (BD), major depressive disorder, and schizophrenia. RESULTS: The main finding was a significant BD PRS-by-trauma interaction with respect to alcohol misuse (P = 6.07 × 10-3 ). We observed a positive correlation between BD PRS and alcohol misuse in trauma-exposed soldiers (r = 0.029, P = 7.5 × 10-3 ) and a negative correlation in trauma-unexposed soldiers (r = -0.071, P = 5.61 × 10-4 ). Consistent (nominally significant) result with concordant effect, directions were observed in the schizophrenia PRS-by-trauma interaction analysis. The variants included in the BD PRS-by-trauma interaction showed significant enrichments for gene ontologies related to high voltage-gated calcium channel activity (GO:0008331, P = 1.51 × 10-5 ; GO:1990454, P = 4.49 × 10-6 ; GO:0030315, P = 2.07 × 10-6 ) and for Beta1/Beta2 adrenergic receptor signaling pathways (P = 2.61 × 10-4 ). CONCLUSIONS: These results indicate that the genetic overlap between alcohol misuse and BD is significantly moderated by trauma exposure. This provides molecular insight into the complex mechanisms that link substance abuse, psychiatric disorders, and trauma exposure.
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