Biological insights into multiple birth: genetic findings from UK Biobank

• Published in: European journal of human genetics : EJHG 2019-06, Vol.27 (6), p.970-979
• Main Authors: Mbarek, Hamdi, van de Weijer, Margot P, van der Zee, Mathijs D, Ip, Hill F, Beck, Jeffrey J, Abdellaoui, Abdel, Ehli, Erik A, Davies, Gareth E, Baselmans, Bart M L, Nivard, Michel G, Bartels, Meike, de Geus, Eco J, Boomsma, Dorret I
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Biological Specimen Banks; Birth; Co-Repressor Proteins - genetics; Environmental factors; Female; Fertility; Follicle-stimulating hormone; Genetic diversity; Genome-wide association studies; Genome-Wide Association Study; Genomes; Humans; Male; Middle Aged; Multiple Birth Offspring - genetics; Multiple births; Phenotypes; Protein Inhibitors of Activated STAT - genetics; Single-nucleotide polymorphism; Smad3 protein; Small Ubiquitin-Related Modifier Proteins - genetics; Twins, Dizygotic - genetics; Twins, Monozygotic - genetics; United Kingdom
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/s41431-019-0355-z

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 ) 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.