Scientists have identified two genes which may make women more likely to give birth to nonidentical twins.
If a woman's female relatives have fraternal twins, she is more likely to give birth to twins herself, but the genes behind this phenomenon have remained a mystery.
Researchers have now shown genetic links between having twins and female production of, and response to, follicle-stimulating hormone, which may help predict how some women respond to infertility treatments.
An international team of researchers including scientists from Vrije Universiteit (VU) in Amsterdam aggregated genetic data from twin databases in the Netherlands, Australia and the US.
The sample totalled 1,980 mothers of fraternal twins conceived without fertility treatments and 12,953 controls.
Researchers were looking for genetic variants, shared by mothers with twins, that showed a different frequency from those in the control groups.
Once researchers had identified a handful of candidates, they sent the results to collaborators in Iceland, who crunched the numbers on their own set of 3,597 mothers with twins and 297,348 controls.
"They looked for whether these variants were also significant in their cohort," said Hamdi Mbarek from VU.
Two of the gene variants were replicated in the Icelandic cohort, appearing more often in the mothers with fraternal twins conceived without fertility treatments, researchers said.
One of the variants, located near a gene called FSHB, is associated with higher levels of follicle-stimulating hormone (FSH), they said.
This hormone triggers follicle growth in a woman's ovaries, eventually leading to an egg being released - and with higher FSH levels, multiple eggs may be released at the same time, leading to twins if two get fertilised, researchers said.
"The second genetic variant, in a gene called SMAD3 involved in cell signalling, probably plays a role in how the ovaries respond to FSH," said Cornelis Lambalk from VU.
If a woman produces an average level of FSH, but her ovaries are more sensitive to the hormone, she may still release multiple eggs at a time, researchers said.
"This genetic variant is totally novel and hadn't been shown before as a candidate gene for twinning," said Mbarek.
FSH is injected to stimulate the ovaries and obtain eggs for in vitro fertilisation, but some women's ovaries hyper-respond to the hormone.
These two genetic variants are only the first piece of the twinning puzzle. The FSHB variant increased the relative odds of having twins by 18 per cent, and SMAD3 by 9 per cent (and if a woman had both variants, her relative risk was increased by 29 per cent), researchers said.
The findings were published in the American Journal of Human Genetic.