Investigating Causality Between Blood Metabolites and Emotional and Behavioral Responses to Traumatic Stress: a Mendelian Randomization Study

Author(s)

Carvalho, Carolina Muniz ^{[1, 2, 3, 4]} ; Wendt, Frank R. ^{[1, 2]} ; Stein, Dan J. ^[5] ; Stein, Murray B. ^{[6, 7]} ; Gelernter, Joel ^{[8, 1, 2, 9]} ; Belangero, Sintia I. ^{[3, 4]} ; Polimanti, Renato ^{[1, 2]}

Affiliation

^[1] Yale Sch Med, Dept Psychiat, VA CT 116A2, 950 Campbell Ave, West Haven, CT 06516 - USA

^[2] VA CT Healthcare Ctr, VA CT 116A2, 950 Campbell Ave, West Haven, CT 06516 - USA

^[3] Univ Fed Sao Paulo UNIFESP, Dept Psychiat, Sao Paulo, SP - Brazil

^[4] Univ Fed Sao Paulo UNIFESP, Dept Morphol & Genet, Genet Div, Sao Paulo, SP - Brazil

^[5] Univ Cape Town, Dept Psychiat, MRC Unit Risk & Resilience Mental Disorders, Cape Town - South Africa

^[6] Univ Calif San Diego, Sch Med, Dept Psychiat, 9500 Gillman Dr, La Jolla, CA 92093 - USA

^[7] Vet Affairs San Diego Healthcare Syst, Psychiat Serv, San Diego, CA - USA

^[8] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 - USA

^[9] Yale Univ, Sch Med, Dept Neurosci, New Haven, CT 06510 - USA

• Document type: Journal article
• Source: Molecular Neurobiology; v. 57, n. 3 NOV 2019.
• Web of Science Citations: 0

Abstract

To investigate the causal relationship between blood metabolites and traits related to trauma-response, we combined genome-wide and metabolome-wide datasets generated from large-scale cohorts. Five trauma-response traits ascertained in the UK Biobank (52,816 < N < 117,900 individuals) were considered: (i) ``Avoided activities/situations because of previous stressful experience{''} (Avoidance); (ii) ``Felt distant from other people{''} (Distant); (iii) ``Felt irritable/had angry outbursts{''} (Irritable); (iv) ``Felt very upset when reminded of stressful experience{''} (Upset); (v) ``Repeated disturbing thoughts of stressful experience{''}. These were investigated with respect to 52 blood metabolites tested in a previous genome-wide-association study (N = 24,925 European-ancestry individuals). Linkage disequilibrium score regression, polygenic risk scoring (PRS), and Mendelian randomization were applied to the datasets. We observed that 14 metabolites were genetically correlated with trauma-response traits (p < 0.05). High-resolution PRS of 4 metabolites (citrate; glycoprotein acetyls; concentration of large very-low-density lipoproteins (VLDL) particles (LVLDLP); total cholesterol in medium particles of VLDL (MVLDLC)) were associated with trauma-response traits (false discovery rate Q < 10%). These genetic associations were partially due to causal relationships (Citrate -> Upset beta = - 0.058, p = 9.1 x 10(-4); Glycoproteins -> Avoidance beta = 0.008, p = 0.003; LVLDLP -> Distant beta = 0.008, p = 0.022; MVLDLC -> Avoidance beta = 0.019, p = 3 x 10(-4)). No reverse associations were observed. In conclusion, our study supports causal relationships between certain blood metabolites and emotional and behavioral responses to traumatic experiences. (AU)

• FAPESP's process: 18/05995-4 - Dissecting the causal role of anthropometric traits in the risk of posttraumatic stress disorder in women
• Grantee: Carolina Muniz Felix de Carvalho
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate