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Investigating the shared genetic architecture and causal relationship between pain and neuropsychiatric disorders

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Abstract

Pain often occurs in parallel with neuropsychiatric disorders. However, the underlying mechanisms and potential causality have not been well studied. We collected the genome-wide association study (GWAS) summary statistics of 26 common pain and neuropsychiatric disorders with sample size ranging from 17,310 to 482,730 in European population. The genetic correlation between pair of pain and neuropsychiatric disorders, as well as the relevant cell types were investigated by linkage disequilibrium (LD) score regression analyses. Then, transcriptome-wide association study (TWAS) was applied to identify the potential shared genes by integrating the gene expression information and GWAS. In addition, Mendelian randomization (MR) analyses were conducted to infer the potential causality between pain and neuropsychiatric disorders. Among the 169 pairwise pain and neuropsychiatric disorders, 55 pairs showed positive correlations (median rg = 0.43) and 9 pairs showed negative correlations (median rg =  −0.31). Using MR analyses, 26 likely causal associations were identified, including that neuroticism and insomnia were risk factors for most of short-term pain, and multisite chronic pain was risk factor for neuroticism, insomnia, major depressive disorder and attention deficit/hyperactivity disorder, and vice versa. The signals of pain and neuropsychiatric disorders tended to be enriched in the functional regions of cell types from central nervous system (CNS). A total of 19 genes shared in at least one pain and neuropsychiatric disorder pair were identified by TWAS, including AMT, NCOA6, and UNC45A, which involved in glycine degradation, insulin secretion, and cell proliferation, respectively. Our findings provided the evidence of shared genetic structure, causality and potential shared pathogenic mechanisms between pain and neuropsychiatric disorders, and enhanced our understanding of the comorbidities of pain and neuropsychiatric disorders.

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The original contributions presented in the study are included in the article/Supplementary information, and further inquiries can be directed to the corresponding author.

Abbreviations

GWAS:

Genome-wide association study

LD:

Linkage disequilibrium

LDSC:

Linkage disequilibrium score regression

TWAS:

Transcriptome-wide association study

CNS:

Central nervous system

SNP:

Single-nucleotide polymorphism

1KGP3:

The 1,000 Genomes project phase 3

MR:

Mendelian randomization

GSMR:

Generalized summary-data-based Mendelian randomization

HEIDI:

Heterogeneity in dependent instruments

IV:

Instrumental variable

IVW:

Inverse variance weighted

RAPS:

Robust adjusted profile score

eQTL:

Expression quantitative trail loci

GTEx:

Genotype-tissue expression project

PPI:

Protein–protein interaction

LT:

Long term

ST:

Short term

OR:

Odds ratio

CI:

Confidence interval

SWB:

Subjective well-being

PD:

Parkinson’s disease

AD:

Alzheimer’s disease

BIP:

Bipolar disorder

SCZ:

Schizophrenia

AN:

Anorexia nervosa

ASD:

Autism spectrum disorder

MDD:

Major depressive disorder

PTSD:

Posttraumatic stress disorder

ADHD:

Attention deficit/hyperactivity disorder

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Acknowledgements

We thank participants and investigators who contributed to the GWASs included in our analyses.

Funding

The research of Xingjie Hao was supported by the National Natural Science Foundation of China (Award Number: 82003561).

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Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Mengya Chen, Si Li, Ziwei Zhu, Chengguqiu Dai & Xingjie Hao

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  1. Mengya Chen
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  2. Si Li
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  3. Ziwei Zhu
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  4. Chengguqiu Dai
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  5. Xingjie Hao
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Contributions

Study design: MC and XH; data collection, analysis, and interpretation: MC, SL, ZZ, CD, and XH; manuscript writing: MC and XH; final approval of manuscript: all authors; accountable for aspects of the work: all authors.

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Correspondence to Xingjie Hao.

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Chen, M., Li, S., Zhu, Z. et al. Investigating the shared genetic architecture and causal relationship between pain and neuropsychiatric disorders. Hum Genet 142, 431–443 (2023). https://doi.org/10.1007/s00439-022-02507-z

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