Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage.

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
22 Jul 2024
Historique:
received: 24 08 2023
accepted: 21 06 2024
medline: 23 7 2024
pubmed: 23 7 2024
entrez: 22 7 2024
Statut: aheadofprint

Résumé

Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. Functional annotation analysis indicated candidate genes HAND2, TBX3 and RAP2C/FRMD7 at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors. There were strong genetic correlations with birth weight, gestational duration and uterine fibroids. Bleeding in early pregnancy yielded no genome-wide association signals but showed strong genetic correlation with various human traits, suggesting a potentially complex, polygenic etiology. Our results suggest that PPH is related to progesterone signaling dysregulation, whereas early bleeding is a complex trait associated with underlying health and possibly socioeconomic status and may include genetic factors that have not yet been identified.

Identifiants

DOI: 10.1038/s41588-024-01839-y PMID: 39039282
pubmed: 39039282
doi: 10.1038/s41588-024-01839-y
pii: 10.1038/s41588-024-01839-y
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF14CC0001
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF17OC0027594
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF14CC0001
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF17OC0027594

Informations de copyright

© 2024. The Author(s).

Références

Dudukina, E., Horváth-Puhó, E., Sørensen, H. T. & Ehrenstein, V. Risk of diabetes and cardiovascular diseases in women with vaginal bleeding before 20 gestational weeks: Danish population-based cohort study. Int. J. Epidemiol. 52, 1783–1794 (2023).
pubmed: 37758298 doi: 10.1093/ije/dyad130
Lykke, J. A., Dideriksen, K. L., Lidegaard, Ø. & Langhoff-Roos, J. First-trimester vaginal bleeding and complications later in pregnancy. Obstet. Gynecol. 115, 935–944 (2010).
pubmed: 20410766 doi: 10.1097/AOG.0b013e3181da8d38
Bienstock, J. L., Eke, A. C. & Hueppchen, N. A. Postpartum hemorrhage. N. Engl. J. Med. 384, 1635–1645 (2021).
pubmed: 33913640 pmcid: 10181876 doi: 10.1056/NEJMra1513247
Oberg, A. S. et al. Genetic contribution to postpartum haemorrhage in Swedish population: cohort study of 466 686 births. BMJ 349, g4984 (2014).
pubmed: 25121825 pmcid: 4131501 doi: 10.1136/bmj.g4984
Biguzzi, E. et al. Genetic background and risk of postpartum haemorrhage: results from an Italian cohort of 3219 women. Haemophilia 20, e377–e383 (2014).
pubmed: 25333208 doi: 10.1111/hae.12514
Biguzzi, E. et al. Risk factors for postpartum hemorrhage in a cohort of 6011 Italian women. Thromb. Res. 129, e1–e7 (2012).
pubmed: 22018996 doi: 10.1016/j.thromres.2011.09.010
Committee on Practice Bulletins–Obstetrics. Practice Bulletin No. 183: postpartum hemorrhage. Obstet. Gynecol. 130, e168–e186 (2017).
doi: 10.1097/AOG.0000000000002351
World Health Organization. WHO recommendations for the prevention and treatment of postpartum haemorrhage (WHO Press, 2012).
Neary, C., Naheed, S., McLernon, D. & Black, M. Predicting risk of postpartum haemorrhage: a systematic review. BJOG Int. J. Obstet. Gynaecol. 128, 46–53 (2021).
doi: 10.1111/1471-0528.16379
Sollis, E. et al. The NHGRI–EBI GWAS Catalog: knowledgebase and deposition resource. Nucleic Acids Res 51, D977–D985 (2023).
pubmed: 36350656 doi: 10.1093/nar/gkac1010
Moore, J. E. et al. Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature 583, 699–710 (2020).
pubmed: 32728249 pmcid: 7410828 doi: 10.1038/s41586-020-2493-4
Boix, C. A., James, B. T., Park, Y. P., Meuleman, W. & Kellis, M. Regulatory genomic circuitry of human disease loci by integrative epigenomics. Nature 590, 300–307 (2021).
pubmed: 33536621 pmcid: 7875769 doi: 10.1038/s41586-020-03145-z
Marinić, M., Mika, K., Chigurupati, S. & Lynch, V. J. Evolutionary transcriptomics implicates HAND2 in the origins of implantation and regulation of gestation length. eLife 10, e61257 (2021).
pubmed: 33522483 pmcid: 7943190 doi: 10.7554/eLife.61257
Sakabe, N. J. et al. Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth. Sci. Adv. 6, eabc8696 (2020).
pubmed: 33268355 pmcid: 7710387 doi: 10.1126/sciadv.abc8696
Li, Q. et al. The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science 331, 912–916 (2011).
pubmed: 21330545 pmcid: 3320855 doi: 10.1126/science.1197454
Solé-Navais, P. et al. Genetic effects on the timing of parturition and links to fetal birth weight. Nat. Genet. 55, 559–567 (2023).
pubmed: 37012456 pmcid: 10101852 doi: 10.1038/s41588-023-01343-9
Zhang, G. et al. Genetic associations with gestational duration and spontaneous preterm birth. N. Engl. J. Med. 377, 1156–1167 (2017).
pubmed: 28877031 pmcid: 5561422 doi: 10.1056/NEJMoa1612665
Szklarczyk, D. et al. The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51, D638–D646 (2023).
pubmed: 36370105 doi: 10.1093/nar/gkac1000
Hammal, F., de Langen, P., Bergon, A., Lopez, F. & Ballester, B. ReMap 2022: a database of human, mouse, Drosophila and Arabidopsis regulatory regions from an integrative analysis of DNA-binding sequencing experiments. Nucleic Acids Res. 50, D316–D325 (2021).
pmcid: 8728178 doi: 10.1093/nar/gkab996
de Leeuw, C. A., Mooij, J. M., Heskes, T. & Posthuma, D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 11, e1004219 (2015).
pubmed: 25885710 pmcid: 4401657 doi: 10.1371/journal.pcbi.1004219
Karlsson, M. et al. A single-cell type transcriptomics map of human tissues. Sci. Adv. 7, eabh2169 (2021).
pubmed: 34321199 pmcid: 8318366 doi: 10.1126/sciadv.abh2169
Erickson, E. N., Krol, K. M., Perkeybile, A. M., Connelly, J. J. & Myatt, L. Oxytocin receptor single nucleotide polymorphism predicts atony-related postpartum hemorrhage. BMC Pregnancy Childbirth 22, 884 (2022).
pubmed: 36447139 pmcid: 9706912 doi: 10.1186/s12884-022-05205-w
Mesiano, S. Myometrial progesterone responsiveness. Semin. Reprod. Med. 25, 5–13 (2007).
pubmed: 17205419 doi: 10.1055/s-2006-956771
Islam, M. S., Afrin, S., Jones, S. I. & Segars, J. Selective progesterone receptor modulators—mechanisms and therapeutic utility. Endocr. Rev. 41, bnaa012 (2020).
pubmed: 32365199 doi: 10.1210/endrev/bnaa012
Patek, K. & Friedman, P. Postpartum hemorrhage—epidemiology, risk factors, and causes. Clin. Obstet. Gynecol. 66, 344–356 (2023).
pubmed: 37130373 doi: 10.1097/GRF.0000000000000782
Butwick, A. J. et al. Association of gestational age with postpartum hemorrhage: an international cohort study. Anesthesiology 134, 874–886 (2021).
pubmed: 33760074 doi: 10.1097/ALN.0000000000003730
Saraswat, L., Bhattacharya, S., Maheshwari, A. & Bhattacharya, S. Maternal and perinatal outcome in women with threatened miscarriage in the first trimester: a systematic review. BJOG Int. J. Obstet. Gynaecol. 117, 245–257 (2010).
doi: 10.1111/j.1471-0528.2009.02427.x
Sørensen, E. et al. Data resource profile: the Copenhagen Hospital Biobank (CHB). Int. J. Epidemiol. 50, 719–720e (2021).
pubmed: 33169150 doi: 10.1093/ije/dyaa157
Hansen, T. F. et al. DBDS Genomic Cohort, a prospective and comprehensive resource for integrative and temporal analysis of genetic, environmental and lifestyle factors affecting health of blood donors. BMJ Open 9, e028401 (2019).
pubmed: 31182452 pmcid: 6561431 doi: 10.1136/bmjopen-2018-028401
Banasik, K. et al. DanMAC5: a browser of aggregated sequence variants from 8,671 whole genome sequenced Danish individuals. BMC Genom. Data 24, 30 (2023).
pubmed: 37244984 pmcid: 10225079 doi: 10.1186/s12863-023-01132-7
Gudbjartsson, D. F. et al. Large-scale whole-genome sequencing of the Icelandic population. Nat. Genet. 47, 435–444 (2015).
pubmed: 25807286 doi: 10.1038/ng.3247
Koel, M. et al. GWAS meta-analyses clarify the genetics of cervical phenotypes and inform risk stratification for cervical cancer. Hum. Mol. Genet. 32, 2103–2116 (2023).
pubmed: 36929174 pmcid: 10244231 doi: 10.1093/hmg/ddad043
Pujol-Gualdo, N. et al. Advancing our understanding of genetic risk factors and potential personalized strategies for pelvic organ prolapse. Nat. Commun. 13, 3584 (2022).
pubmed: 35739095 pmcid: 9226158 doi: 10.1038/s41467-022-31188-5
Mitt, M. et al. Improved imputation accuracy of rare and low-frequency variants using population-specific high-coverage WGS-based imputation reference panel. Eur. J. Hum. Genet. 25, 869–876 (2017).
pubmed: 28401899 pmcid: 5520064 doi: 10.1038/ejhg.2017.51
Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023).
pubmed: 36653562 pmcid: 9849126 doi: 10.1038/s41586-022-05473-8
Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat. Genet. 40, 1068–1075 (2008).
pubmed: 19165921 pmcid: 4540081 doi: 10.1038/ng.216
Magnus, P. et al. Cohort profile update: the Norwegian Mother and Child Cohort Study (MoBa). Int. J. Epidemiol. 45, 382–388 (2016).
pubmed: 27063603 doi: 10.1093/ije/dyw029
Helgeland, Ø. et al. Characterization of the genetic architecture of infant and early childhood body mass index. Nat. Metab. 4, 344–358 (2022).
pubmed: 35315439 doi: 10.1038/s42255-022-00549-1
Mbatchou, J. et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat. Genet. 53, 1097–1103 (2021).
pubmed: 34017140 doi: 10.1038/s41588-021-00870-7
Halldorsson, B. V. et al. The sequences of 150,119 genomes in the UK Biobank. Nature 607, 732–740 (2022).
pubmed: 35859178 pmcid: 9329122 doi: 10.1038/s41586-022-04965-x
Sveinbjornsson, G. et al. Weighting sequence variants based on their annotation increases power of whole-genome association studies. Nat. Genet. 48, 314–317 (2016).
pubmed: 26854916 doi: 10.1038/ng.3507
Yang, J. et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375 (2012).
pubmed: 22426310 pmcid: 3593158 doi: 10.1038/ng.2213
Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).
pubmed: 21167468 pmcid: 3014363 doi: 10.1016/j.ajhg.2010.11.011
Yang, Z., Paschou, P. & Drineas, P. Reconstructing SNP allele and genotype frequencies from GWAS summary statistics. Sci. Rep. https://doi.org/10.1038/s41598-022-12185-6 (2022).
Myers, T. A., Chanock, S. J. & Machiela, M. J. LDlinkR: an R package for rapidly calculating linkage disequilibrium statistics in diverse populations. Front. Genet. 11, 157 (2020).
pubmed: 32180801 pmcid: 7059597 doi: 10.3389/fgene.2020.00157
Knudsen, L. B. & Olsen, J. The Danish Medical Birth Registry. Dan. Med. Bull. 45, 320–323 (1998).
pubmed: 9675544
Schmidt, M. et al. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin. Epidemiol. 7, 449–490 (2015).
pubmed: 26604824 pmcid: 4655913 doi: 10.2147/CLEP.S91125
Pazokitoroudi, A. et al. Efficient variance components analysis across millions of genomes. Nat. Commun. 11, 4020 (2020).
pubmed: 32782262 pmcid: 7419517 doi: 10.1038/s41467-020-17576-9
Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).
pubmed: 26414676 pmcid: 4797329 doi: 10.1038/ng.3406
Privé, F., Arbel, J. & Vilhjálmsson, B. J. LDpred2: better, faster, stronger. Bioinformatics 36, 5424–5431 (2020).
pmcid: 8016455 doi: 10.1093/bioinformatics/btaa1029
Warrington, N. M. et al. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat. Genet. 51, 804–814 (2019).
pubmed: 31043758 pmcid: 6522365 doi: 10.1038/s41588-019-0403-1
Murphy, A. E., Schilder, B. M. & Skene, N. G. MungeSumstats: a Bioconductor package for the standardization and quality control of many GWAS summary statistics. Bioinformatics 37, 4593–4596 (2021).
pubmed: 34601555 pmcid: 8652100 doi: 10.1093/bioinformatics/btab665
Harrell, F. E. Regression Modeling Strategies: with Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis (Springer International Publishing, 2015). https://doi.org/10.1007/978-3-319-19425-7
Juliusdottir, T. et al. Distinction between the effects of parental and fetal genomes on fetal growth. Nat. Genet. 53, 1135–1142 (2021).
pubmed: 34282336 doi: 10.1038/s41588-021-00896-x

Auteurs

David Westergaard (D)

Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Methods and Analysis, Statistics Denmark, Copenhagen, Denmark.
ORCID: 0000-0003-0128-8432

Valgerdur Steinthorsdottir (V)

deCODE genetics/Amgen, Reykjavik, Iceland.
ORCID: 0000-0003-1846-6274

Lilja Stefansdottir (L)

deCODE genetics/Amgen, Reykjavik, Iceland.

Palle Duun Rohde (PD)

Department of Health Science and Technology, Aalborg University, Gistrup, Denmark.
ORCID: 0000-0003-4347-8656

Xiaoping Wu (X)

Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
ORCID: 0000-0002-7844-1397

Frank Geller (F)

Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
ORCID: 0000-0002-9238-3269

Jaakko Tyrmi (J)

Centre for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Aki S Havulinna (AS)

Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
Finnish Institute for Health and Welfare - THL, Helsinki, Finland.

Pol Solé-Navais (P)

Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
ORCID: 0000-0002-3326-266X

Christopher Flatley (C)

Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
ORCID: 0000-0002-2225-0188

Sisse Rye Ostrowski (SR)

Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Department of Clinical medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
ORCID: 0000-0001-5288-3851

Ole Birger Pedersen (OB)

Department of Clinical medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Clinical immunology, Zealand University Hospital, Køge, Denmark.
ORCID: 0000-0003-2312-5976

Christian Erikstrup (C)

Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
ORCID: 0000-0001-6551-6647

Erik Sørensen (E)

Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Christina Mikkelsen (C)

Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
ORCID: 0000-0002-2945-6197

Mie Topholm Bruun (MT)

Clinical Immunological Research Unit, Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.
Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
ORCID: 0000-0002-8819-5388

Bitten Aagaard Jensen (B)

Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.

Thorsten Brodersen (T)

Department of Clinical immunology, Zealand University Hospital, Køge, Denmark.
ORCID: 0000-0003-4431-9972

Henrik Ullum (H)

Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

Per Magnus (P)

Department of Genetics and Bioinformatics, Health Data and Digitalization, Norwegian Institute of Public Health, Oslo, Norway.
ORCID: 0000-0002-6427-4735

Ole A Andreassen (OA)

NORMENT Centre, University of Oslo, Oslo, Norway.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
ORCID: 0000-0002-4461-3568

Pål R Njolstad (PR)

Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway.
Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway.
ORCID: 0000-0003-0304-6728

Astrid Marie Kolte (AM)

Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Lone Krebs (L)

Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
Department of Clinical medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
ORCID: 0000-0001-5433-4776

Mette Nyegaard (M)

Department of Health Science and Technology, Aalborg University, Gistrup, Denmark.
ORCID: 0000-0003-4973-8543

Thomas Folkmann Hansen (TF)

Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Danish Headache Center, Department of neurology, Copenhagen University Hospital, Glostrup, Denmark.
ORCID: 0000-0001-6703-7762

Bjarke Feenstra (B)

Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
ORCID: 0000-0003-1478-649X

Mark Daly (M)

Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Cecilia M Lindgren (CM)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Big Data Institute Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, UK.

Gudmar Thorleifsson (G)

deCODE genetics/Amgen, Reykjavik, Iceland.
ORCID: 0000-0003-4623-9087

Olafur A Stefansson (OA)

deCODE genetics/Amgen, Reykjavik, Iceland.
ORCID: 0000-0002-9663-3018

Gardar Sveinbjornsson (G)

deCODE genetics/Amgen, Reykjavik, Iceland.
ORCID: 0000-0003-2429-9468

Daniel F Gudbjartsson (DF)

deCODE genetics/Amgen, Reykjavik, Iceland.
School of Science and Engineering, Reykjavik University, Reykjavik, Iceland.
ORCID: 0000-0002-5222-9857

Unnur Thorsteinsdottir (U)

deCODE genetics/Amgen, Reykjavik, Iceland.
Faculty of Medicine, School of Health Sciences, Reykjavik University, Reykjavik, Iceland.

Karina Banasik (K)

Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Bo Jacobsson (B)

Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Genetics and Bioinformatics, Health Data and Digitalization, Norwegian Institute of Public Health, Oslo, Norway.
ORCID: 0000-0001-5079-2374

Triin Laisk (T)

Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
ORCID: 0000-0003-1501-9030

Hannele Laivuori (H)

Centre for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Department of Obstetrics and Gynaecology, Tampere University Hospital, Tampere, Finland.
ORCID: 0000-0003-3212-7826

Kari Stefansson (K)

deCODE genetics/Amgen, Reykjavik, Iceland.
Faculty of Medicine, School of Health Sciences, Reykjavik University, Reykjavik, Iceland.

Søren Brunak (S)

Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Soren.brunak@cpr.ku.dk.
ORCID: 0000-0003-0316-5866

Henriette Svarre Nielsen (HS)

Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark. Henriette.svarre.nielsen@regionh.dk.
Department of Clinical medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Henriette.svarre.nielsen@regionh.dk.
ORCID: 0000-0003-2106-8103

Classifications MeSH