Circulating Proteins Influencing Psychiatric Disease: A Mendelian Randomization Study.
Blood-brain barrier
Circulating proteins
Genome-wide association studies
Mendelian randomization
Psychiatric diseases
Quantitative trait loci
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 01 2023
01 01 2023
Historique:
received:
05
02
2022
revised:
11
08
2022
accepted:
17
08
2022
pubmed:
25
10
2022
medline:
6
12
2022
entrez:
24
10
2022
Statut:
ppublish
Résumé
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. 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. 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). Prioritized circulating proteins appear to influence the risk of psychiatric disease and may be explored as intervention targets.
Sections du résumé
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.
Identifiants
pubmed: 36280454
pii: S0006-3223(22)01524-4
doi: 10.1016/j.biopsych.2022.08.015
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
82-91Subventions
Organisme : CIHR
ID : 365825
Pays : Canada
Organisme : CIHR
ID : 409511
Pays : Canada
Informations de copyright
Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.