Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility

Abstract

Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10(-9), and rs17293443 in SMAD3, p = 1.57 × 10(-8)) and replicated (p = 3 × 10(-3) and p = 1.44 × 10(-4), respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.

Figure 1

Manhattan Plot for the Genome-wide Association Meta-analysis of Mothers of Dizygotic Twins SNPs are plotted on the x axis according to their position on each chromosome against the significance of the association on the y axis (shown as –log10 p values). The solid red line denotes p = 5 × 10⁻⁸ statistical significance. The rs numbers point to the chromosomal region that reached genome-wide significance level.

Figure 2

Forest Plots Depicting the Risk Allele Odds Ratio Estimates in the Discovery and the Replication Cohorts Black squares indicate the odds ratio (OR) and horizontal lines represent the 95% CIs. The combined results are indicated by the black diamond. rs11031006 (A), rs17293443 (B), rs12064669 (C). Abbreviations are as follows: NTR, Netherlands Twin Register; QIMR, QIMR Berghofer Medical Research Institute; MCTFR, Minnesota Center for Twin and Family Research; deCODE, Iceland.