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

  • Carolina Muniz Carvalho
  • Frank R. Wendt
  • Dan J. Stein
  • Murray B. Stein
  • Joel Gelernter
  • Sintia I. Belangero
  • Renato PolimantiEmail author


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 β = − 0.058, p = 9.1 × 10-4; Glycoproteins→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, our study supports causal relationships between certain blood metabolites and emotional and behavioral responses to traumatic experiences.


Mendelian randomization Blood metabolites Trauma response Traumatic stress 



We thank the study participants, research groups, and the members of the cited studies for making their data available.

Funding Information

This research was supported by the Simons Foundation Autism Research Initiative (SFARI Explorer Award: 534858) and the American Foundation for Suicide Prevention (YIG-1-109-16). C.M.C. and S.I.B were supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2018/05995-4) international fellowship.

Compliance with Ethical Standards

Conflict of Interest

Dr. Murray Stein is paid for his editorial work on the journals Biological Psychiatry and Depression and Anxiety, and the health professional reference Up-To-Date. Dr. Dan Stein received personal fees from Lundbeck and Sun Pharmaceutical Industries. The other authors declare no competing interests.

Research Involving Human Participants

Owing to the use of previously collected, deidentified, aggregated data, this study did not require institutional review board approval. Ethical approval had been obtained in the original studies cited.

Supplementary material

12035_2019_1823_MOESM1_ESM.xlsx (102 kb)
ESM 1 (XLSX 102 kb)
12035_2019_1823_MOESM2_ESM.docx (411 kb)
ESM 2 (DOCX 411 kb)


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Authors and Affiliations

  1. 1.Department of PsychiatryYale School of Medicine and VA CT Healthcare CenterWest HavenUSA
  2. 2.Department of PsychiatryUniversidade Federal de São Paulo (UNIFESP)São PauloBrazil
  3. 3.Genetics Division, Department of Morphology and GeneticsUniversidade Federal de São Paulo (UNIFESP)São PauloBrazil
  4. 4.MRC Unit on Risk & Resilience in Mental Disorders, Department of PsychiatryUniversity of Cape TownCape TownSouth Africa
  5. 5.Department of Psychiatry, School of MedicineUniversity of California San DiegoLa JollaUSA
  6. 6.Psychiatry ServiceVeterans Affairs San Diego Healthcare SystemSan DiegoUSA
  7. 7.Departments of Genetics and NeuroscienceYale University School of MedicineNew HavenUSA

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