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; DBDS genomics consortium; 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, DBDS genomics consortium, Gudmar Thorleifsson, Lincoln D Nadauld, Asgeir HaraldssonThora Steingrimsdottir, Laufey Tryggvadottir, Ingileif Jonsdottir, Daniel F Gudbjartsson, Eva R Hoffmann, Patrick Sulem, Hilma Holm, Henriette Svarre Nielsen, Kari Stefansson^*

^*Corresponding author for this work

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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 & molecular biology
Volume	31
Issue number	4
Pages (from-to)	710-716
Number of pages	7
ISSN	1545-9985
DOIs	https://doi.org/10.1038/s41594-023-01209-y
Publication status	Published - Apr 2024

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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., DBDS genomics consortium, Thorleifsson, G., Nadauld, L. D., ... Stefansson, K. (2024). Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination. Nature structural & molecular biology, 31(4), 710-716. https://doi.org/10.1038/s41594-023-01209-y

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title = "Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination",

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.",

author = "Valgerdur Steinthorsdottir and Halldorsson, {Bjarni V} and Hakon Jonsson and Gunnar Palsson and Asmundur Oddsson and David Westergaard and Arnadottir, {Gudny A} and Lilja Stefansdottir and Karina Banasik and Esplin, {M Sean} and Hansen, {Thomas Folkmann} and S{\o}ren Brunak and Mette Nyegaard and Ostrowski, {Sisse Rye} and Pedersen, {Ole Birger Vesterager} and Christian Erikstrup and {DBDS genomics consortium} and Gudmar Thorleifsson and Nadauld, {Lincoln D} and Asgeir Haraldsson and Thora Steingrimsdottir and Laufey Tryggvadottir and Ingileif Jonsdottir and Gudbjartsson, {Daniel F} and Hoffmann, {Eva R} and Patrick Sulem and Hilma Holm and Nielsen, {Henriette Svarre} and Kari Stefansson",

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year = "2024",

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doi = "10.1038/s41594-023-01209-y",

language = "English",

volume = "31",

pages = "710--716",

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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, DBDS genomics consortium, 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 & molecular biology, vol. 31, no. 4, pp. 710-716. https://doi.org/10.1038/s41594-023-01209-y

TY - JOUR

T1 - Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination

AU - Steinthorsdottir, Valgerdur

AU - Halldorsson, Bjarni V

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 - DBDS genomics consortium

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

PY - 2024/4

Y1 - 2024/4

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=85183620302&partnerID=8YFLogxK

U2 - 10.1038/s41594-023-01209-y

DO - 10.1038/s41594-023-01209-y

M3 - Journal article

C2 - 38287193

SN - 1545-9985

VL - 31

SP - 710

EP - 716

JO - Nature structural & molecular biology

JF - Nature structural & molecular biology

IS - 4

ER -

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

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