Tyrmi, J. S., Arffman, R. K., Pujol-Gualdo, N., Kurra, V., Morin-Papunen, L., Sliz, E., FinnGen Consortium, Estonian Biobank Research Team, Piltonen, T. T., Laisk, T., Kettunen, J., & Laivuori, H. (2022). Leveraging Northern European population history: Novel low-frequency variants for polycystic ovary syndrome. Human Reproduction, 37(2), 352–365. https://doi.org/10.1093/humrep/deab250
Leveraging Northern European population history : novel low-frequency variants for polycystic ovary syndrome
|Author:||Tyrmi, Jaakko S.1,2,3; Arffman, Riikka K.4; Pujol-Gualdo, Natàlia4,5;|
1Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
2Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
3Biocenter Oulu, University of Oulu, Oulu, Finland
4Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital, University of Oulu, Oulu, Finland
5Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
6Department of Clinical Genetics, Faculty of Medicine and Health Technology, Tampere University Hospital and Tampere University, Tampere, Finland
7Finnish Institute for Health and Welfare, Helsinki, Finland
8Department of Obstetrics and Gynecology, Faculty of Medicine and Health Technology, Tampere University Hospital and Tampere University, Tampere, Finland
9Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
10Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
|Online Access:||PDF Full Text (PDF, 1.3 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022111665762
Oxford University Press,
|Publish Date:|| 2022-11-16
Study question: Can we identify novel variants associated with polycystic ovary syndrome (PCOS) by leveraging the unique population history of Northern Europe?
Summary answer: We identified three novel genome-wide significant associations with PCOS, with two putative independent causal variants in the checkpoint kinase 2 (CHEK2) gene and a third in myosin X (MYO10).
What is known already: PCOS is a common, complex disorder with unknown aetiology. While previous genome-wide association studies (GWAS) have mapped several loci associated with PCOS, the analysis of populations with unique population history and genetic makeup has the potential to uncover new low-frequency variants with larger effects.
Study design, size, duration: A population-based case–control GWAS was carried out.
Participants/materials, setting, methods: We identified PCOS cases from national registers by ICD codes (ICD-10 E28.2, ICD-9 256.4, or ICD-8 256.90), and all remaining women were considered controls. We then conducted a three-stage case–control GWAS: in the discovery phase, we had a total of 797 cases and 140 558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2812 cases and 89 230 controls. Finally, we performed a joint meta-analysis of 3609 cases and 229 788 controls from both cohorts. Additionally, we reran the association analyses including BMI as a covariate, with 2169 cases and 160 321 controls from both cohorts.
Main results and the role of chance: Two out of the three novel genome-wide significant variants associating with PCOS, rs145598156 (P = 3.6×10−8, odds ratio (OR) = 3.01 [2.02–4.50] minor allele frequency (MAF) = 0.005) and rs182075939 (P = 1.9×10−16, OR = 1.69 [1.49–1.91], MAF = 0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2 = 0.95) and a missense I157T (r2 = 0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, P = 1.7 × 10−8, OR = 1.16 [1.10–1.23], MAF = 0.44). We also replicated four previous reported associations near the genes Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4), DENN Domain Containing 1A (DENND1A), FSH Subunit Beta (FSHB) and Zinc Finger And BTB Domain Containing 16 (ZBTB16). When adding BMI as a covariate only one of the novel variants remained genome-wide significant in the meta-analysis (the EstBB lead signal in CHEK2 rs182075939, P = 1.9×10−16, OR = 1.74 [1.5–2.01]) possibly owing to reduced sample size.
Large scale data: The age- and BMI-adjusted GWAS meta-analysis summary statistics are available for download from the GWAS Catalog with accession numbers GCST90044902 and GCST90044903.
Limitations, reasons for caution: The main limitation was the low prevalence of PCOS in registers; however, the ones with the diagnosis most likely represent the most severe cases. Also, BMI data were not available for all (63% for FinnGen, 76% for EstBB), and the biobank setting limited the accessibility of PCOS phenotypes and laboratory values.
Wider implications of the findings: This study encourages the use of isolated populations to perform genetic association studies for the identification of rare variants contributing to the genetic landscape of complex diseases such as PCOS.
Study funding/competing interest(s): This work has received funding from the European Union’s Horizon 2020 research and innovation programme under the MATER Marie Skłodowska-Curie grant agreement No. 813707 (N.P.-G., T.L., T.P.), the Estonian Research Council grant (PRG687, T.L.), the Academy of Finland grants 315921 (T.P.), 321763 (T.P.), 297338 (J.K.), 307247 (J.K.), 344695 (H.L.), Novo Nordisk Foundation grant NNF17OC0026062 (J.K.), the Sigrid Juselius Foundation project grants (T.L., J.K., T.P.), Finska Läkaresällskapet (H.L.) and Jane and Aatos Erkko Foundation (H.L.). The funders had no role in study design, data collection and analysis, publishing or preparation of the manuscript. The authors declare no conflicts of interest.
|Pages:||352 - 365|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
3123 Gynaecology and paediatrics
This work has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 813707 (N.P.-G., T.L. and T.P.), the Estonian Research Council grant (PRG687, T.L.), the Academy of Finland grants 315921 (T.P.), 321763 (T.P.), 297338 (J.K.), 307247 (J.K.), 344695 (H.L.), Novo Nordisk Foundation grant NNF17OC0026062 (J.K.), the Sigrid Juselius Foundation project grants (T.L., J.K., T.P.), Finska Läkaresällskapet (H.L.) and Jane and Aatos Erkko Foundation (H.L.). The funders had no role in study design, data collection and analysis, publishing or preparation of the manuscript.
|EU Grant Number:||
(813707) MATER - Innovative Training Network in Female Reproductive Care
|Academy of Finland Grant Number:||
321763 (Academy of Finland Funding decision)
297338 (Academy of Finland Funding decision)
307247 (Academy of Finland Funding decision)
The GWAS meta-analysis summary statistics that support the findings of this study are available for download from the GWAS Catalog at ebi.ac.uk/gwas/ with accession ID numbers GCST90044902 and GCST90044903.
© The Author(s) 2021. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.