Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination

Valgerdur Steinthorsdottir; Bjarni V. Halldorsson; Hakon Jonsson; Gunnar Palsson; Asmundur Oddsson; David Westergaard; Gudny A. Arnadottir; Lilja Stefansdottir; Karina Banasik; M. Sean Esplin; Thomas Folkmann Hansen; Søren Brunak; Mette Nyegaard; Sisse Rye Ostrowski; Ole Birger Vesterager Pedersen; Christian Erikstrup; Gudmar Thorleifsson; Lincoln D. Nadauld; Asgeir Haraldsson; Thora Steingrimsdottir; Laufey Tryggvadottir; Ingileif Jonsdottir; Daniel F. Gudbjartsson; Eva R. Hoffmann; Patrick Sulem; Hilma Holm; Henriette Svarre Nielsen; Kari Stefansson

doi:10.1038/s41594-023-01209-y

Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination

Valgerdur Steinthorsdottir^*, Bjarni V. Halldorsson, Hakon Jonsson, Gunnar Palsson, Asmundur Oddsson, David Westergaard, Gudny A. Arnadottir, Lilja Stefansdottir, Karina Banasik, M. Sean Esplin, Thomas Folkmann Hansen, Søren Brunak, Mette Nyegaard, Sisse Rye Ostrowski, Ole Birger Vesterager Pedersen, Christian Erikstrup, Gudmar Thorleifsson, Lincoln D. Nadauld, Asgeir Haraldsson, Thora SteingrimsdottirLaufey Tryggvadottir, Ingileif Jonsdottir, Daniel F. Gudbjartsson, Eva R. Hoffmann, Patrick Sulem, Hilma Holm, Henriette Svarre Nielsen, Kari Stefansson

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Journal	Nature Structural and Molecular Biology
Volume	31
Issue number	4
Pages (from-to)	710-716
Number of pages	17
ISSN	1545-9993
DOIs	https://doi.org/10.1038/s41594-023-01209-y
Publication status	Published - 2024

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Publisher Copyright:
© 2024, The Author(s).

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Steinthorsdottir, V., Halldorsson, B. V., Jonsson, H., Palsson, G., Oddsson, A., Westergaard, D., Arnadottir, G. A., Stefansdottir, L., Banasik, K., Esplin, M. S., Hansen, T. F., Brunak, S., Nyegaard, M., Ostrowski, S. R., Pedersen, O. B. V., Erikstrup, C., Thorleifsson, G., Nadauld, L. D., Haraldsson, A., ... Stefansson, K. (2024). Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination. Nature Structural and Molecular Biology, 31(4), 710-716. https://doi.org/10.1038/s41594-023-01209-y

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.

In: Nature Structural and Molecular Biology, Vol. 31, No. 4, 2024, p. 710-716.

Research output: Contribution to journal › Journal article › Research › peer-review

Steinthorsdottir, V, Halldorsson, BV, Jonsson, H, Palsson, G, Oddsson, A, Westergaard, D, Arnadottir, GA, Stefansdottir, L, Banasik, K, Esplin, MS, Hansen, TF , Brunak, S, Nyegaard, M, Ostrowski, SR , Pedersen, OBV, Erikstrup, C, Thorleifsson, G, Nadauld, LD, Haraldsson, A, Steingrimsdottir, T, Tryggvadottir, L, Jonsdottir, I, Gudbjartsson, DF, Hoffmann, ER, Sulem, P, Holm, H, Nielsen, HS & Stefansson, K 2024, 'Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination', Nature Structural and Molecular Biology, vol. 31, no. 4, pp. 710-716. https://doi.org/10.1038/s41594-023-01209-y

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. / Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination. In: Nature Structural and Molecular Biology. 2024 ; Vol. 31, No. 4. pp. 710-716.

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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.",

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AU - Steinthorsdottir, Valgerdur

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AU - Jonsson, Hakon

AU - Palsson, Gunnar

AU - Oddsson, Asmundur

AU - Westergaard, David

AU - Arnadottir, Gudny A.

AU - Stefansdottir, Lilja

AU - Banasik, Karina

AU - Esplin, M. Sean

AU - Hansen, Thomas Folkmann

AU - Brunak, Søren

AU - Nyegaard, Mette

AU - Ostrowski, Sisse Rye

AU - Pedersen, Ole Birger Vesterager

AU - Erikstrup, Christian

AU - Thorleifsson, Gudmar

AU - Nadauld, Lincoln D.

AU - Haraldsson, Asgeir

AU - Steingrimsdottir, Thora

AU - Tryggvadottir, Laufey

AU - Jonsdottir, Ingileif

AU - Gudbjartsson, Daniel F.

AU - Hoffmann, Eva R.

AU - Sulem, Patrick

AU - Holm, Hilma

AU - Nielsen, Henriette Svarre

AU - Stefansson, Kari

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AB - 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.

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