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Exome-wide screening identifies novel rare risk variants for major depression disorder

Molecular Psychiatry volume 27, pages 3069–3074 (2022)Cite this article

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Abstract

Despite thousands of common genetic loci of major depression disorders (MDD) have been identified by GWAS to date, a large proportion of genetic variation predisposing to MDD remains unaccounted for. By utilizing the newly released UK Biobank 200,643 exome dataset, we conducted an exome-wide association study to identify rare risk variants contributing to MDD. After quality control, 120,033 participants with MDD polygenic risk scores (PRS) values were included. The individuals with lower 30% quantile of the PRS value were filtered for case and control selecting. Then the cases were set as the individuals with upper 10% quantile of the PHQ depression score and lower 10% quantile were set as controls. Finally, 1612 cases and 1612 controls were included in this study. The variants were annotated by ANNOVRA software. After exclusions, 34,761 qualifying variants, including 148 frameshift variant, 335 non-frameshift variant, 33,758 nonsynonymous, 91 start-loss, 393 stop-gain, 36 stop-loss variants were imported into the SKAT R-package to perform single variants, gene-based burden and robust burden tests with minor allele frequency (MAF) < 0.01. Single variant association testing identified one variant, rs4057749 (P = 5.39 × 10−9), within OR8B4 gene at an exome-wide significance level. The gene-based burden test of the exonic variants identified genome-wide significant associations in OR8B4 (PSKAT = 6.23 × 10−5, PSKAT Robust = 4.49 × 10−5), TRAPPC11 (PSKAT = 0.014, PSKAT Robust = 0.015), SBK3 (PSKAT = 0.020, PSKAT Robust = 0.025) and TNRC6B (PSKAT = 0.026, PSKAT Robust = 0.036). We identified multiple novel rare risk variants contributing to MDD in the individuals with lower PRS of MDD. The findings can help to broaden the genetic insights of the MDD pathogenesis.

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Fig. 1: Manhattan plots of the exome-wide association results for single rare variants test.
Fig. 2: Manhattan plots of the exome-wide association results for gene-based tests of rare variants.

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Data availability

The UK Biobank data are available through the UK Biobank Access Management System https://www.ukbiobank.ac.uk/. We will return the derived data fields following UK Biobank policy; in due course, they will be available through the UK Biobank Access Management System.

Code availability

All scripts used to generate the SKAT analyses are available from the authors upon request.

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Acknowledgements

This study was conducted using the UK Biobank Resource (Application 46478).

Funding

This study was supported by the National Natural Scientific Foundation of China (81922059).

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Authors and Affiliations

  1. Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Xi’an Jiaotong University, Xi’an, China

    Shiqiang Cheng, Bolun Cheng, Li Liu, Xuena Yang, Peilin Meng, Yao Yao, Chuyu Pan, Jingxi Zhang, Chun’e Li, Huijie Zhang, Yujing Chen, Zhen Zhang, Yan Wen, Yumeng Jia & Feng Zhang

  2. Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China

    Shiqiang Cheng, Bolun Cheng, Li Liu, Xuena Yang, Peilin Meng, Yao Yao, Chuyu Pan, Jingxi Zhang, Chun’e Li, Huijie Zhang, Yujing Chen, Zhen Zhang, Yan Wen, Yumeng Jia & Feng Zhang

  3. Key Laboratory for Disease Prevention and Control and Health Promotion of Shaanxi Province, Xi’an Jiaotong University, Xi’an, China

    Shiqiang Cheng, Bolun Cheng, Li Liu, Xuena Yang, Peilin Meng, Yao Yao, Chuyu Pan, Jingxi Zhang, Chun’e Li, Huijie Zhang, Yujing Chen, Zhen Zhang, Yan Wen, Yumeng Jia & Feng Zhang

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Contributions

SC and FZ conceived and designed the study, and wrote the manuscript; SC and FZ collected the data and carried out the statistical analyses; BC, LL, XL, PM, YY, CP, JZ, CL, HZ, YC, ZZ, YW, and YJ made preparations for the manuscript at first.

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Correspondence to Feng Zhang.

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Ethical approval of UK Biobank study was granted by the National Health Service National Research Ethics Service (reference 11/NW/0382).

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Cheng, S., Cheng, B., Liu, L. et al. Exome-wide screening identifies novel rare risk variants for major depression disorder. Mol Psychiatry 27, 3069–3074 (2022). https://doi.org/10.1038/s41380-022-01536-4

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