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Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination.
Steinthorsdottir, Valgerdur; Halldorsson, Bjarni V; Jonsson, Hakon; Palsson, Gunnar; Oddsson, Asmundur; Westergaard, David; Arnadottir, Gudny A; Stefansdottir, Lilja; Banasik, Karina; Esplin, M Sean; Hansen, Thomas Folkmann; Brunak, Søren; Nyegaard, Mette; Ostrowski, Sisse Rye; Pedersen, Ole Birger Vesterager; Erikstrup, Christian; Thorleifsson, Gudmar; Nadauld, Lincoln D; Haraldsson, Asgeir; Steingrimsdottir, Thora; Tryggvadottir, Laufey; Jonsdottir, Ingileif; Gudbjartsson, Daniel F; Hoffmann, Eva R; Sulem, Patrick; Holm, Hilma; Nielsen, Henriette Svarre; Stefansson, Kari.
Affiliation
  • Steinthorsdottir V; deCODE genetics/Amgen, Inc., Reykjavik, Iceland. valgerdur.steinthorsdottir@decode.is.
  • Halldorsson BV; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
  • Jonsson H; School of Technology, Reykjavik University, Reykjavik, Iceland.
  • Palsson G; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
  • Oddsson A; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
  • Westergaard D; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
  • Arnadottir GA; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Stefansdottir L; Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.
  • Banasik K; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
  • Esplin MS; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
  • Hansen TF; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Brunak S; Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark.
  • Nyegaard M; Division of Maternal and Fetal Medicine, Intermountain Health, Murray, UT, USA.
  • Ostrowski SR; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Pedersen OBV; Danish Headache Center & Danish Multiple Sclerose Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet-Glostrup, Copenhagen, Denmark.
  • Erikstrup C; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Thorleifsson G; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • Nadauld LD; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Haraldsson A; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Steingrimsdottir T; Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
  • Tryggvadottir L; Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
  • Jonsdottir I; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Hoffmann ER; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
  • Sulem P; Precision Genomics, Intermountain Health, Saint George, UT, USA.
  • Holm H; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
  • Nielsen HS; Children's Hospital Iceland, Landspitali University Hospital, Reykjavik, Iceland.
  • Stefansson K; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Nat Struct Mol Biol ; 31(4): 710-716, 2024 Apr.
Article in En | MEDLINE | ID: mdl-38287193
ABSTRACT
Two-thirds of all human conceptions are lost, in most cases before clinical detection. The lack of detailed understanding of the causes of pregnancy losses constrains focused counseling for future pregnancies. We have previously shown that a missense variant in synaptonemal complex central element protein 2 (SYCE2), in a key residue for the assembly of the synaptonemal complex backbone, associates with recombination traits. Here we show that it also increases risk of pregnancy loss in a genome-wide association analysis on 114,761 women with reported pregnancy loss. We further show that the variant associates with more random placement of crossovers and lower recombination rate in longer chromosomes but higher in the shorter ones. These results support the hypothesis that some pregnancy losses are due to failures in recombination. They further demonstrate that variants with a substantial effect on the quality of recombination can be maintained in the population.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Synaptonemal Complex / Nuclear Proteins Type of study: Risk_factors_studies Limits: Female / Humans / Pregnancy Language: En Journal: Nat Struct Mol Biol Year: 2024 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Synaptonemal Complex / Nuclear Proteins Type of study: Risk_factors_studies Limits: Female / Humans / Pregnancy Language: En Journal: Nat Struct Mol Biol Year: 2024 Document type: Article