Elsevier

Biological Psychiatry

Volume 93, Issue 1, 1 January 2023, Pages 82-91
Biological Psychiatry

Archival Report
Circulating Proteins Influencing Psychiatric Disease: A Mendelian Randomization Study

https://doi.org/10.1016/j.biopsych.2022.08.015Get rights and content

Abstract

Background

There is a pressing need for novel drug targets for psychiatric disorders. Circulating proteins are potential candidates because they are relatively easy to measure and modulate and play important roles in signaling.

Methods

We performed two-sample Mendelian randomization analyses to estimate the associations between circulating protein abundances and risk of 10 psychiatric disorders. Genetic variants associated with 1611 circulating protein abundances identified in 6 large-scale proteomic studies were used as genetic instruments. Effects of the circulating proteins on psychiatric disorders were estimated by Wald ratio or inverse variance–weighted ratio tests. Horizontal pleiotropy, colocalization, and protein-altering effects were examined to validate the assumptions of Mendelian randomization.

Results

Nine circulating protein-to-disease associations withstood multiple sensitivity analyses. Among them, 2 circulating proteins had associations replicated in 3 proteomic studies. A 1 standard deviation increase in the genetically predicted circulating TIMP4 level was associated with a reduced risk of anorexia nervosa (minimum odds ratio [OR] = 0.83; 95% CI, 0.76–0.91) and bipolar disorder (minimum OR = 0.88; 95% CI, 0.82–0.94). A 1 standard deviation increase in the genetically predicted circulating ESAM level was associated with an increased risk of schizophrenia (maximum OR = 1.32; 95% CI, 1.22–1.43). In addition, 58 suggestive protein-to-disease associations warrant validation with observational or experimental evidence. For instance, a 1 standard deviation increase in the ERLEC1-201-to-ERLEC1-202 splice variant ratio was associated with a reduced risk of schizophrenia (OR = 0.94; 95% CI, 0.90–0.97).

Conclusions

Prioritized circulating proteins appear to influence the risk of psychiatric disease and may be explored as intervention targets.

Section snippets

Proteomic Studies

The association between circulating protein levels and genetic variants was assessed in 6 large-scale genome-wide proteomic studies: the Fenland Study (10), the Framingham Heart Study (FHS) (12), the IMPROVE study (11), the INTERVAL study (13), the AGES-Reykjavik study (15), and the KORA F4 study (14). These studies were based on populations predominantly of European ancestries. The Fenland, INTERVAL, AGES, and KORA F4 studies used slow off-rate modified aptamer (SOMAmer)-based SomaLogic

Estimated Potential Causal Effects of Circulating Protein Levels on Psychiatric Disorders

An overview of this two-sample MR is presented in Figure 1. Cis-pQTLs or their LD proxies for circulating proteins profiled in 6 large-scale proteomic studies (10, 11, 12, 13, 14, 15) were selected as genetic instruments. After data harmonization, 1611 proteins or complexes had valid genetic instruments that could be tested in at least 1 of the 10 psychiatric disorder GWASs (Figure S1 in Supplement 1; Table S3 in Supplement 2) (19, 20, 21, 22, 23, 24, 25, 26, 27, 28). Full summary statistics of

Discussion

Psychiatric disorders affect a significant proportion of the population and incur an extremely heavy disease burden worldwide (1, 2, 3). Novel approaches for preventing and treating psychiatric disorders are urgently needed (1,4,5). In this study, we conducted MR studies to systematically screen for circulating proteins that are likely to play a role in the etiology of such disorders, thereby providing a shortlist of potentially modifiable targets for therapeutic development.

We identified 9

Acknowledgments and Disclosures

The JBR research group is supported by the Canadian Institutes of Health Research (CIHR: 365825; Grant No. 409511), the Lady Davis Institute of the Jewish General Hospital, the Canadian Foundation for Innovation, the National Institutes of Health Foundation, Cancer Research UK, Genome Québec, the Public Health Agency of Canada, and the Fonds de Recherche Québec Santé. TwinsUK is funded by the Wellcome Trust, the Medical Research Council, and the European Union; the National Institute for Health

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