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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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your

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our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS CUSTOM EXOME PANEL REVEALED NEW MUTATIONS IN _MAPK14_ AND NOVEL MUTATION IN _RUNX2_ GENE IN PATIENTS WITH PCOS

Article Open access 16 January 2025 RELATIONSHIP BETWEEN THE CHARACTERISTIC TRAITS OF POLYCYSTIC OVARY SYNDROME AND SUSCEPTIBILITY GENES Article Open access 26 June 2020 UNVEILING THE SHARED

GENETIC ARCHITECTURE BETWEEN TESTOSTERONE AND POLYCYSTIC OVARY SYNDROME Article Open access 13 October 2024 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

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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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * Department of Obstetrics, Gynecology and Reproductive

Sciences, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada Jason E. Elliott & Mark W. Nachtigal * Children’s Hospital Research Institute of Manitoba,

Winnipeg, MB, Canada Jason E. Elliott & Britt I. Drögemöller * Department of Physiology and Pharmacology, Karolinska Institute, Solna, Stockholm, Sweden Elisabet Stener-Victorin *

CancerCare Manitoba Research Institute, Winnipeg, MB, Canada Mark W. Nachtigal & Britt I. Drögemöller Authors * Sarah M. Lyle View author publications You can also search for this author

inPubMed Google Scholar * Samah Ahmed View author publications You can also search for this author inPubMed Google Scholar * Jason E. Elliott View author publications You can also search

for this author inPubMed Google Scholar * Elisabet Stener-Victorin View author publications You can also search for this author inPubMed Google Scholar * Mark W. Nachtigal View author

publications You can also search for this author inPubMed Google Scholar * Britt I. Drögemöller View author publications You can also search for this author inPubMed Google Scholar

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. ETHICS DECLARATIONS COMPETING INTERESTS 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. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in

published maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TABLE 1. PREDICTED FUNCTIONAL CONSEQUENCES OF VARIANTS ASSOCIATED (P <1X10-6) WITH PCOS RIGHTS AND

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ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 10 August 2022 * Revised: 05 January 2023 * Accepted: 07 January 2023 * Published: 31

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