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Transcriptome-wide association analyses identify an association between ARL14EP and polycystic ovary syndrome

Journal of Human Genetics volume 68, pages 347–353 (2023)Cite this article

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Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, which is accompanied by a variety of comorbidities including metabolic, reproductive, and psychiatric disorders. Genome-wide association studies have identified several genetic variants that are associated with PCOS. However, these variants often occur outside of coding regions and require further investigation to understand their contribution to PCOS. A transcriptome-wide association study (TWAS) was performed to uncover heritable gene expression profiles that are associated with PCOS in two independent cohorts. Causal gene prioritization was subsequently performed and expression of genes prioritized through these analyses was examined in 49 PCOS patients and 30 controls. TWAS analyses revealed that increased expression of ARL14EP was significantly associated with PCOS risk in the discovery (P = 1.6 × 10-6) and replication cohorts (P = 2.0 × 10-13). Gene prioritization pipelines provided further evidence that ARL14EP is the most likely causal gene at this locus. ARL14EP gene expression was shown to be significantly different between PCOS cases and controls, after adjusting for body mass index, age and testosterone levels (P = 1.2 × 10-13). This study has provided evidence for the role of ARL14EP in PCOS. Given that ARL14EP has been reported to play an important role in chromatin remodeling, variants affecting the expression of ARL14EP may also affect the expression of other genes that contribute to PCOS pathogenesis.

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Data availability

Summary statistics utilized in this publication were obtained from https://www.repository.cam.ac.uk/handle/1810/283491.

Code availability

The code used in this manuscript is available at https://github.com/SarahMLyle/Identification-of-Gene-Expression-Patterns-Associated-with-Polycystic-Ovary-Syndrome-

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Acknowledgements

Galen EB Wright provided critical feedback during the writing process.

Funding

BID is supported by a CIHR Tier 2 Canada Research Chair in Pharmacogenomics. SML was supported by BioTalent Canada. SA was supported by Research Manitoba and NSERC VADA.

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Authors and Affiliations

  1. Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    Sarah M. Lyle, Samah Ahmed, Mark W. Nachtigal & Britt I. Drögemöller

  2. Department of Obstetrics, Gynecology and Reproductive Sciences, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

    Jason E. Elliott & Mark W. Nachtigal

  3. Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, Canada

    Jason E. Elliott & Britt I. Drögemöller

  4. Department of Physiology and Pharmacology, Karolinska Institute, Solna, Stockholm, Sweden

    Elisabet Stener-Victorin

  5. CancerCare Manitoba Research Institute, Winnipeg, MB, Canada

    Mark W. Nachtigal & Britt I. Drögemöller

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  1. Sarah M. Lyle
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Contributions

SML: Performed the analysis; Wrote the paper. SA: Performed analyses. JE: Wrote the paper. ES-V: Provided data. MN: Wrote the paper. BID: Conceived and designed the analysis; Wrote the paper.

Corresponding author

Correspondence to Britt I. Drögemöller.

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The authors declare no competing interests.

Ethical approval

Ethical approvals were not required for the TWAS, as theses analyses were performed using publicly available summary statistics. The summary statistics obtained did not include identifiable participant information and thus ensured the privacy of participants. Ethical approval for the targeted gene expression analyses was obtained from the Regional Ethical Review Board of the University of Gothenburg in accordance with the Declaration of Helsinki.

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Lyle, S.M., Ahmed, S., Elliott, J.E. et al. Transcriptome-wide association analyses identify an association between ARL14EP and polycystic ovary syndrome. J Hum Genet 68, 347–353 (2023). https://doi.org/10.1038/s10038-023-01120-w

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