Proteome-wide Association Study Provides Insights Into the Genetic Component of Protein Abundance in Psychiatric Disorders

doi:10.1016/j.biopsych.2021.06.022

Biological Psychiatry

Volume 90, Issue 11, 1 December 2021, Pages 781-789

https://doi.org/10.1016/j.biopsych.2021.06.022 Get rights and content

Abstract

Background

Genome-wide association studies have identified multiple risk variants for psychiatric disorders. Nevertheless, how the risk variants confer risk of psychiatric disorders remains largely unknown.

Methods

We performed proteome-wide association studies to identify genes whose cis-regulated protein abundance change in the human brain were associated with psychiatric disorders.

Results

By integrating genome-wide associations of four common psychiatric disorders and two independent brain proteomes (n = 376 and n = 152, respectively) from the dorsolateral prefrontal cortex, we identified 61 genes (including 48 genes for schizophrenia, 12 genes for bipolar disorder, 5 genes for depression, and 2 genes for attention-deficit/hyperactivity disorder) whose genetically regulated protein abundance levels were associated with risk of psychiatric disorders. Comparison with transcriptome-wide association studies identified 18 overlapping genes that showed significant associations with psychiatric disorders at both proteome-wide and transcriptome-wide levels, suggesting that genetic risk variants likely confer risk of psychiatric disorders by regulating messenger RNA expression and protein abundance of these genes.

Conclusions

Our study not only provides new insights into the genetic component of protein abundance in psychiatric disorders but also highlights several high-confidence risk proteins (including CNNM2 and CTNND1) for schizophrenia and depression. These high-confidence risk proteins represent promising therapeutic targets for future drug development.

Section snippets

GWASs Used in This Study

Genome-wide associations from four large-scale GWASs of psychiatric disorders were used in this study. The genome-wide associations of schizophrenia were from a recent study by Lam et al. (7). By combining samples from East Asian ancestry and European ancestry, Lam et al. conducted a large-scale GWAS of schizophrenia (56,418 cases and 78,818 controls) and identified 176 independent risk loci (7). The genome-wide summary statistics of bipolar disorder (20,352 cases and 31,358 controls) were from

PWASs Identified 61 Genes Whose Genetically Regulated Protein Abundance Levels in the Brain Were Associated With Risk of Psychiatric Disorders

We first performed PWASs (discovery stage) by integrating the Banner human brain pQTL data (n = 152) and GWASs of four psychiatric disorders (schizophrenia, bipolar disorder, depression, and ADHD). We identified 29 PWS (corrected by Bonferroni adjustment) genes for schizophrenia (Table 1 and Figure 1A) and 3 PWS genes each for bipolar disorder and depression (Tables S1 and S2; Figures 2A and 3A). No PWS genes were identified for ADHD in the Banner dataset (Figure 4A). To validate these results,

Discussion

In this study, we performed PWASs for four common psychiatric disorders by integrating human brain pQTL data and genome-wide associations. We identified 61 genes whose genetically regulated protein abundance levels in the human brain were associated with risk of four common psychiatric disorders. Of note, among these PWS genes, 30 genes (including 20 genes for schizophrenia, 7 genes for bipolar disorder, 1 gene for depression, and 2 genes for ADHD) were not nominated by the original GWASs,

Acknowledgments and Disclosures

This study was equally supported by the Distinguished Young Scientists grant of the Yunnan Province (Grant No. 202001AV070006 [to X-JL]) and the Innovative Research Team of Science and Technology Department of Yunnan Province (Grant No. 2019HC004 [to X-JL]). This work was also supported by the Western Light Innovative Research Team of Chinese Academy of Sciences and the National Nature Science Foundation of China (Grant Nos. 31970561 [to X-JL] and 81901361 [to JL]).

X-JL conceived, designed, and

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Archival ReportProteome-wide Association Study Provides Insights Into the Genetic Component of Protein Abundance in Psychiatric Disorders

Abstract

Background

Methods

Results

Conclusions

Section snippets

GWASs Used in This Study

PWASs Identified 61 Genes Whose Genetically Regulated Protein Abundance Levels in the Brain Were Associated With Risk of Psychiatric Disorders

Discussion

Acknowledgments and Disclosures

Lancet Psychiatry

Lancet

Am J Hum Genet

Biol Psychiatry

Schizophr Res

Cell

Cell

Cell

Eur J Med Genet

J Biol Chem

Am J Hum Genet

The economic costs of mental disorders: Do our societies react appropriately to the burden of mental disorders?

EMBO Rep

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017

Lancet

Genetic architectures of psychiatric disorders: The emerging picture and its implications

Nat Rev Genet

Biological insights from 108 schizophrenia-associated genetic loci

Nature

Comparative genetic architectures of schizophrenia in East Asian and European populations

Nat Genet

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Nat Genet

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

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Genome-wide association study identifies 30 loci associated with bipolar disorder

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Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets

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Archival Report
Proteome-wide Association Study Provides Insights Into the Genetic Component of Protein Abundance in Psychiatric Disorders