Researchers have long known that women whose families include fraternal twins are more likely to give birth to twins themselves, and they’re finally starting to figure out why. After scanning data from nearly 2000 mothers of fraternal twins, scientists from eight countries found two genes that increase a woman’s chance of having twins—one that affects hormone levels and another that may alter how ovaries respond to them. The second of these may also have implications for why some women respond better than others to in vitro fertilization.
Unlike identical twins—who are genetically the same—fraternal twins are no more closely related in terms of DNA than regular siblings. But scientists often like to compare identical and fraternal twins to understand how much variation in a trait is due to environment versus genetics. Because of that, several large databases track twins as they age. In 1987, a young behavioral geneticist at Vrije Universiteit in Amsterdam named Dorret Boomsma started the Netherlands Twin Register, which now contains more than 75,000 twins, triplets, and other children of multiple births. The participants’ parents all had the same question: Why did they have twins? “People want to understand,” Boomsma says.
Researchers like Boomsma have some ideas, especially as fraternal twin births are on the rise in Western countries—for instance, the United States saw a 76% increase from 1980 to 2011. In vitro fertilization, for which demand has surged, is more likely to yield twins. Older women, who are having more children than in the past, are also more likely to release more than one egg, increasing their chances of giving birth to fraternal twins.
To definitively unravel the mystery, a new team led by Hamdi Mbarek, a molecular geneticist at Vrije Universiteit, combined data from almost 2000 mothers of fraternal twins coming from databases in the Netherlands, Australia, and Minnesota, and compared them against women who hadn’t had twins, or women who had had identical twins. The researchers searched for individual DNA bases called single nucleotide polymorphisms, or SNPs, that can vary from person to person—specifically, ones that popped up more often in the mothers of fraternal twins and not in the others. Once they came up with some potential SNPs, they ran the analysis all over again in a separate database from Iceland, narrowing their key findings down to just two SNPS. Having one copy of each SNP increased a mother’s chance of having fraternal twins by 29%, they report today in The American Journal of Human Genetics.
The first SNP is near a gene called FSHB, which is involved in the production of follicle-stimulating hormone (FSH). FSH levels fluctuate as eggs in the ovaries mature—if levels stay too high for too long, the ovaries release multiple eggs, the first in a series of events that could lead to a fraternal twin birth. So it’s no surprise that the FSH gene would be associated with having twins.
The second SNP was more of a surprise. It was in a gene called SMAD3. By altering how molecules signal to one another, SMAD3 changes how ovaries respond to FSH, at least in mice. Although SMAD3’s role is somewhat of a mystery here, Mbarek says that SMAD3 could be a candidate for understanding why some women respond better to in vitro fertilization than others. “That’s a newer area of biology that’s been uncovered in this paper,” says Anna Murray, a geneticist at the University of Exeter in the United Kingdom, who was not involved with the study. She agrees this is an intriguing avenue to explore, but stresses that the study is only a first step.
Mbarek next plans to study whether women who have the SMAD3 variant are more likely to get pregnant from in vitro fertilization. But for now, it’s exciting to know anything about the genetics at all. “This is the first robust demonstration of the genes that are involved with [having fraternal twins],” Murray says. For her part, Boomsma is delighted to have seen the story through its full 30 years—from the first enrollment in the Dutch registry to today’s findings.