The tendency to conceive spontaneous dizygotic (DZ) twins is a complex trait with important contributions from both environmental factors and genetic disposition. In earlier work, we identified the first two genes as maternal susceptibility loci for DZ twinning. The aim of this study was to identify genetic variants influencing multiple births and to genetically correlate the findings across a broad range of traits. We performed a genome-wide association study (GWAS) in 8962 participants with Caucasian ancestry from UK Biobank who reported being part of a multiple birth, and 409,591 singleton controls. We replicated the association between FSHB, SMAD3 and twinning in the gene-based (but not SNP-based) test, which had been established in previous genome-wide association analyses in mothers with dizygotic twin offspring. Additionally, we report a novel genetic variant associated with multiple birth, rs428022 at 15q23 (p = 2.84 × 10−8) close to two genes: PIAS1 and SKOR1. Finally, we identified meaningful genetic correlations between being part of a multiple birth and other phenotypes (anthropometric traits, health-related traits, and fertility-related measures). The outcomes of this study provide important new insights into the genetic aetiology of multiple births and fertility, and open up novel directions for fertility and reproduction research.
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This research has been conducted using the UK Biobank Resource under application number 25472 (PI Bartels). HM and MDvdZ were supported through the VU-Avera Collaborative Agreement between the Vrije Universiteit Amsterdam and the Avera McKennan d/b/a Avera Institute for Human Genetics. MPvdW was supported by a University Research Fellow (URF) of the Vrije Universiteit, Amsterdam to DIB. MGN was supported by a Royal Netherlands Academy of Science Professor Award to DIB (PAH/6635), ZonMw grant: “Genetics as a research tool: A natural experiment to elucidate the causal effects of social mobility on health.” (pnr: 531003014) and ZonMw project: “Can sex- and gender-specific gene expression and epigenetics explain sex-differences in disease prevalence and etiology?” (pnr: 849200011). HFI was supported by the “Aggression in Children: Unraveling gene-environment interplay to inform Treatment and InterventiON strategies” (ACTION) project. ACTION receives funding from the European Union Seventh Framework Program (FP7/2007–2013) under grant agreement no 602768. Computational facilities on Cartesius were supplied by NWO via the grant: “Population scale genetic analysis” 2018/EW/00408559.
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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Mbarek, H., van de Weijer, M.P., van der Zee, M.D. et al. Biological insights into multiple birth: genetic findings from UK Biobank. Eur J Hum Genet 27, 970–979 (2019). https://doi.org/10.1038/s41431-019-0355-z