Metabolome-Wide Mendelian Randomization Analysis of Emotional and Behavioral Responses to Traumatic Stress

Abstract Trauma exposure is an important risk factor for several psychiatric disorders; however, the mechanisms that underlie emotional and behavioral responses to traumatic stress are unclear. To understand these mechanisms, this study investigated the genetic overlap and causal relationship between blood metabolites and traits related to trauma response using genome-wide data. Five traits related to trauma response “in the past month” ascertained in the UK Biobank (52 816<N<117 900 individuals) were considered: i) “Avoided activities or situations because of previous stressful experience” ( Avoidance ); ii) “Felt distant from other people” ( Distant ); iii) “Felt irritable or had angry outbursts” ( Irritable ); iv) “Felt very upset when reminded of stressful experience” ( Upset ); v) “Repeated disturbing thoughts of stressful experience” ( Repeated Thoughts ). These were investigated with respect to 52 metabolites assessed using nuclear magnetic resonance metabolomics in a previous genome-wide association study (up to 24,925 individuals of European descent). Applying linkage disequilibrium score regression (LDSC), polygenic risk scoring (PRS), and Mendelian randomization (MR), we observed that 14 metabolites were significantly correlated with trauma response traits (p<0.05); PRS of 4 metabolites (citrate (CIT); glycoprotein acetyls (GP); concentration of large very-low-density lipoproteins (VLDL) particles (LVLDLP); total cholesterol in medium particles of VLDL (MVLDLC)) were associated with traits related to trauma response (false discovery rate Q<10%). These associations were partially due to causal relationships (CIT→Upset β=-0.058, p=9.1×10 −4 ; GP→Avoidance β=0.008, p=0.003; LVLDLP→Distant β=0.008, p=0.022; MVLDLC→Avoidance β=0.019, p=3×10 −4 ). No reverse associations were observed. In conclusion, the genetics of certain blood-metabolites are potentially implicated in the response to traumatic experience.