Abstract
Objective: Although dizygotic (DZ) twins occur once every 70 live births and has long been suspected to be familial, the genetic loci driving human twinning have not yet been identified. Based on our recent success in identifying "twin genes" in the marmoset primate (which exclusively gestates twins and triplets), we reasoned that a GWAS approach in a large, multinational cohort comprised of over 315,000 gravidae would confidently identify the responsible human genetic loci. Study Design: We established the Twinning GWAS Consortium (TGC) to characterize the genetic basis of natural DZ twinning in humans using robust discovery and replication datasets built from mothers of DZ twins (MODZT). Cases included only spontaneous MODZT, and controls were screened to exclude subjects from pedigrees containing DZ twins. Genotyping was on multiple overlapping platforms (eg., Affymetrix, Illumina) with robust tailored computational pipelines. The inflation factor (λ) was set at 1.01, eliminating inflation due to population structure. Results: The results of the meta-analysis of MODZT are represented in the Manhattan plot (Figure). In the discovery set, 1,980 mothers of DZ twins and 12,980 singleton controls of European ancestry yielded three predictive loci (rs11031006, rs17293443 and rs12064669, P < 5 × 10 -8). The rs11031006 and rs17293443 loci were validated in an independent Icelandic case-control validation cohort of 3,597 MODZT and 297,348 controls. The occurrence of delivery of a DZ twin pregnancy increased by 18% for each rs11031006-G maternal allele, and 9% for rs17293443-C. The rs11031006 allele, located near FSHB, was significant in its association with maternal serum FSH and surrogate measures for the length of reproductive competence (i.e., maternal age at menarche/ menopause, first and last pregnancy, and total parity; Table). Conversely, rs17293443 (SMAD3) was not associated with FSH levels, but was associated with maternal age at last birth. Conclusion: We have confidently identified, for the first time, the maternal genetic loci driving human DZ twinning, and demonstrate overlap with reproductive competence. Clinical application of these findings will include screening for genetic variants rendering risk of higher order multiples and reproductive competence.
