Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Summary statistics utilized in this publication were obtained from

Code availability

The code used in this manuscript is available at


  1. Franks S. Polycystic ovary syndrome. N. Engl J Med. 1995;333:853–61.

    Article  CAS  PubMed  Google Scholar 

  2. Azziz R. Introduction: Determinants of polycystic ovary syndrome. Fertil Steril. 2016;106:4–5.

    Article  PubMed  Google Scholar 

  3. Deswal R, Narwal V, Dang A, Pundir CS. The prevalence of polycystic ovary syndrome: A brief systematic review. J Hum Reprod Sci. 2020;13:261–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Liu J, Wu Q, Hao Y, Jiao M, Wang X, Jiang S, et al. Measuring the global disease burden of polycystic ovary syndrome in 194 countries: Global Burden of Disease Study 2017. Hum Reprod. 2021;36:1108–19.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Huddleston HG, Dokras A. Diagnosis and treatment of polycystic ovary syndrome. JAMA - J Am Med Assoc. 2022;327:274–5.

    Article  Google Scholar 

  6. Williams T, Mortada R, Porter S. Diagnosis and treatment of polycystic ovary syndrome. Am Fam Physician. 2016;94:106–13.

    PubMed  Google Scholar 

  7. Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab. 2006;91:2100–4.

    Article  CAS  PubMed  Google Scholar 

  8. Chen ZJ, Zhao H, He L, Shi Y, Qin Y, Shi Y, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet 2011;43:55–9.

    Article  PubMed  Google Scholar 

  9. Shi Y, Zhao H, Shi Y, Cao Y, Yang D, Li Z, et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet. 2012;44:1020–5.

    Article  CAS  PubMed  Google Scholar 

  10. Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nature. Communications 2015;6:14.

    Google Scholar 

  11. Day FR, Hinds DA, Tung JY, Stolk L, Styrkarsdottir U, Saxena R, et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun. 2015;6:1–7.

    Article  Google Scholar 

  12. Day F, Karaderi T, Jones MR, Meun C, He C, Drong A, et al. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet. 2018;14:1–20.

    Article  Google Scholar 

  13. Barbeira AN, Bonazzola R, Gamazon ER, Liang Y, Park YS, Kim-Hellmuth S, et al. Exploiting the GTEx resources to decipher the mechanisms at GWAS loci. Genome Biol. 2021;22:1–24.

    Article  Google Scholar 

  14. Wainberg M, Sinnott-Armstrong N, Mancuso N, Barbeira AN, Knowles DA, Golan D, et al. Opportunities and challenges for transcriptome-wide association studies. Nat Genet. 2019;51:592–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pividori M, Rajagopal PS, Barbeira A, Liang Y, Melia O, Bastarache L, et al. PhenomeXcan: Mapping the genome to the phenome through the transcriptome. Sci Adv. 2020;6:eaba2083.

    Article  CAS  PubMed  Google Scholar 

  16. Doke T, Huang S, Qiu C, Liu H, Guan Y, Hu H, et al. Transcriptome-wide association analysis identifies DACH1 as a kidney disease risk gene that contributes to fibrosis. J Clin Investig. 2021;1:131.

  17. Wu C, Tan S, Liu L, Cheng S, Li P, Li W, et al. Transcriptome-wide association study identifies susceptibility genes for rheumatoid arthritis. Arthr Res Ther. 2021;1:23.

  18. Li X, Su X, Liu J, Li H, Li M, Li W, et al. Transcriptome-wide association study identifies new susceptibility genes and pathways for depression. Transl Psychiatry. 2021;1:11.

  19. Pan C, Ning Y, Jia Y, Cheng S, Wen Y, Yang X, et al. Transcriptome-wide association study identified candidate genes associated with gut microbiota. Gut Pathog. 2021;1:13.

  20. Hormozdiari F, Kichaev G, Yang WY, Pasaniuc B, Eskin E. Identification of causal genes for complex traits. Bioinformatics 2015;31:i206–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mancuso N, Freund MK, Johnson R, Shi H, Kichaev G, Gusev A, et al. Probabilistic fine-mapping of transcriptome-wide association studies. Nat Genet. 2019;51:675–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gazal S, Weissbrod O, Hormozdiari F, Dey KK, Nasser J, Jagadeesh KA, et al. Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity. Nat Genet. 2022;54:827–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Romm A. PCOS Summary Sheet [Internet]. [cited 2022 Jul 7]. Available from:

  24. GWAS. Harmonization And Imputation· hakyimlab/summary-gwas-imputation Wiki [Internet]. GitHub. [cited 2022 Nov 20]. Available from:

  25. Auton A, Abecasis GR, Altshuler DM, Durbin RM, Bentley DR, Chakravarti A, et al. A global reference for human genetic variation. Vol. 526, Nature. Nature Publishing Group; 2015. p. 68–74.

  26. GTEx Project. GTEx portal. GTEx Analysis Release V6p (dbGaP Accession phs000424.v6.p1). 2017.

  27. Barbeira AN, Pividori MD, Zheng J, Wheeler HE, Nicolae DL, Im HK. Integrating predicted transcriptome from multiple tissues improves association detection. PLoS Genet. 2019;15:e1007889.

    Article  PubMed  PubMed Central  Google Scholar 

  28. FinnGen results [Internet]. [cited 2022 Nov 20]. Available from:

  29. Liao C, Laporte AD, Spiegelman D, Akçimen F, Joober R, Dion PA, et al. Transcriptome-wide association study of attention deficit hyperactivity disorder identifies associated genes and phenotypes.

  30. Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLOS Genet. 2014;10:e1004383.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Rentzsch P, Schubach M, Shendure J, Kircher M. CADD-Splice—improving genome-wide variant effect prediction using deep learning-derived splice scores. Genome Med. 2021;1:13.

  32. Cunningham F, Allen JE, Allen J, Alvarez-Jarreta J, Amode MR, Armean IM, et al. Ensembl 2022. Nucleic Acids Res. 2022;50:D988–95.

    Article  CAS  PubMed  Google Scholar 

  33. Watanabe K, Taskesen E, Van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nature. Communications 2017;8:1–11.

    CAS  Google Scholar 

  34. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants - PMC [Internet]. [cited 2022 Dec 9]. Available from:

  35. Kokosar M, Benrick A, Perfilyev A, Fornes R, Nilsson E, Maliqueo M, et al. Epigenetic and transcriptional alterations in human adipose tissue of polycystic ovary syndrome. Sci Rep. 2016;6:22883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stener-Victorin E, Holm G, Labrie F, Nilsson L, Janson PO, Ohlsson C. Are there any sensitive and specific sex steroid markers for polycystic ovary syndrome? J Clin Endocrinol Metab. 2010;95:810–9.

    Article  CAS  PubMed  Google Scholar 

  37. Alkes Group [Internet]. [cited 2022 Nov 20]. Available from:

  38. Misgar RA, Wani AI, Bankura B, Bashir MI, Roy A, Das M. FSH β-subunit mutations in two sisters: the first report from the Indian sub-continent and review of previous cases. Gynecol Endocrinol. 2019;35:290–3.

    Article  CAS  PubMed  Google Scholar 

  39. Li Y, Chen C, Ma Y, Xiao J, Luo G, Li Y, et al. Multi-system reproductive metabolic disorder: significance for the pathogenesis and therapy of polycystic ovary syndrome (PCOS). Vol. 228, Life Sciences. Elsevier Inc.; 2019. p. 167–75.

  40. Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol. 2021;22:96–118.

    Article  CAS  PubMed  Google Scholar 

  41. OMIM Entry - * 612295 - ADP-RIBOSYLATION FACTOR-LIKE GTPase 14 EFFECTOR PROTEIN; ARL14EP [Internet]. [cited 2022 May 12]. Available from:

  42. OMIM Entry - # 194072 - WILMS TUMOR, ANIRIDIA, GENITOURINARY ANOMALIES, AND MENTAL RETARDATION SYNDROME; WAGR [Internet]. [cited 2022 May 12]. Available from:

  43. Duffy KA, Trout KL, Gunckle JM, Krantz SMC, Morris J, Kalish JM. Results From the WAGR Syndrome Patient Registry: Characterization of WAGR Spectrum and Recommendations for Care Management. Front Pediatrics. 2021;9:733018.

    Article  Google Scholar 

  44. Peter CJ, Saito A, Hasegawa Y, Tanaka Y, Nagpal M, Perez G, et al. In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene. Nat Commun. 2019;10:4112.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Sakaue S, Weinand K, Dey KK, Jagadeesh K, Kanai M, Watts GFM, et al. Tissue-specific enhancer-gene maps from multimodal single-cell data identify causal disease alleles [Internet]. Genet Genom Med. 2022 [cited 2023 Jan 3]. Available from:

  46. Zhang Z, Zamojski M, Smith GR, Willis TL, Yianni V, Mendelev N, et al. Single nucleus transcriptome and chromatin accessibility of postmortem human pituitaries reveal diverse stem cell regulatory mechanisms. Cell Rep. 2022;38:110467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Censin JC, Bovijn J, Holmes M, Lindgren C. Colocalization analysis of polycystic ovary syndrome to identify potential disease-mediating genes and proteins. Eur J Human Genet. 2021;29:1446–54.

    Article  CAS  Google Scholar 

  48. Sen A, Prizant H, Light A, Biswas A, Hayes E, Lee HJ, et al. Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Proc Natl Acad Sci USA. 2014;111:3008–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


Galen EB Wright provided critical feedback during the writing process.


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



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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links