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Mol Neurobiol. 2019 Nov 30. doi: 10.1007/s12035-019-01823-2. [Epub ahead of print]

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

Author information

1
Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, VA CT 116A2, 950 Campbell Avenue, West Haven, CT, 06516, USA.
2
Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
3
Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.
4
MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town, South Africa.
5
Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA.
6
Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
7
Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, CT, 06510, USA.
8
Department of Psychiatry, Yale School of Medicine and VA CT Healthcare Center, VA CT 116A2, 950 Campbell Avenue, West Haven, CT, 06516, USA. renato.polimanti@yale.edu.

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 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.

KEYWORDS:

Blood metabolites; Mendelian randomization; Trauma response; Traumatic stress

PMID:
31786776
DOI:
10.1007/s12035-019-01823-2

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