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Identifying novel proteins underlying loneliness by integrating GWAS summary data with human brain proteomes

Neuropsychopharmacology volume 48, pages 1087–1097 (2023)Cite this article

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Abstract

Enduring loneliness is associated with mental disorders and physical diseases. Although genome-wide association studies (GWAS) have identified risk loci associated with loneliness, how these loci confer the risk remains largely unknown. In the current study, we aimed to investigate key proteins underlying loneliness in the brain by integrating human brain proteomes and transcriptomes with loneliness GWAS to perform a discovery proteome-wide association study (PWAS), followed by a confirmatory PWAS, transcriptome-wide association analysis (TWAS), Mendelian randomization (MR), Steigering filtering analysis and Bayesian colocalization analysis. Moreover, given the fact that loneliness is associated with mental disorders, we explored the shared genetic architecture between loneliness and mental disorders. Totally, we identified 18 genes to be associated with loneliness via their cis-regulated brain protein abundance. Eleven of the 18 genes (61.1%) were replicated in the confirmatory PWAS, and mRNA levels of 4 genes were further validated to be associated with loneliness.MR and genetic colocalization analysis further confirmed that the increased protein abundance of ALDH2 and ICA1L was protective against loneliness, while the increased protein abundance of GPX1 was a risk for developing loneliness. Furthermore, we found genetic correlations, bidirectional causal associations and overlapping phenotype-associated protein profiles between loneliness and mental disorders including major depression and schizophrenia. In summary, our findings provided clues about the brain-related molecular basis underlying loneliness, which warrants further investigation.

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Fig. 1: The flowchart of the study.
Fig. 2: Results of PWAS and MR.

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Data availability

The data were obtained from the publicly available database (listed in Supplementary Table 1). The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank all the researchers who provided the original data publicly.

Funding

This study was supported by 1.3.5 projects for disciplines of excellence, West China Hospital, Sichuan University (Grant No. ZYJC21004), the National Natural Science Foundation of China (Grant No. 81871061), and the Postdoctoral Foundation of West China Hospital (Grant No. 2020HXBH041).

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Authors and Affiliations

  1. Mental Health Center and Psychiatric Laboratory, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China

    Xiaojing Gu, Minlan Yuan & Wei Zhang

  2. Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, China

    Xiaojing Gu, Minlan Yuan & Wei Zhang

  3. West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China

    Xiaojing Gu & Wei Zhang

  4. Medical Big Data Center, Sichuan University, Chengdu, China

    Xiaojing Gu & Wei Zhang

  5. Chengdu institute of computer application, Chinese Academy of Sciences, Chengdu, Sichuan, China

    Meng Dou

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  1. Xiaojing Gu
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Contributions

XJG: conceptualization, formal analysis, methodology, writing—original draft; MD: data curation and methodology; MLY: writing—review & editing; WZ: conceptualization; writing—review & editing; supervision.

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Correspondence to Wei Zhang.

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Gu, X., Dou, M., Yuan, M. et al. Identifying novel proteins underlying loneliness by integrating GWAS summary data with human brain proteomes. Neuropsychopharmacol. 48, 1087–1097 (2023). https://doi.org/10.1038/s41386-023-01536-0

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