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Fraternal Twin Birth Linked to Two Loci in GWAS

NEW YORK (GenomeWeb) – The chance of giving birth to non-identical twins appears to be higher in women with particular common variants near the FSHB and SMAD3 genes, according to a study appearing online today in the American Journal of Human Genetics.

An international team led by investigators in the Netherlands did a genome-wide association study of nearly 2,000 women from twin registries in the Netherlands, Australia, and the US who had given birth to dizygotic twins, also known as fraternal twins, without assisted reproductive technology.

In that group, and in a replication cohort comprised of thousands of individuals from Iceland, the team found that moms to fraternal twins were more likely to carry the rs17293443 variant near the cell signaling gene SMAD3 and/or the rs11031006 SNP near the gene FSHB, which influences levels of the follicle-stimulating hormone that mediates egg release.

The results so far are expected to inform researchers' understanding of fertility and offer clues to responses to hormone treatment within the context of assisted reproduction approaches such as in vitro fertilization, though the study's authors suspect additional loci are yet to be detected.

"There is a very clear suggestion and indication that more loci are contributing to the risk of having dizygotic twins as well," senior author Dorret Boomsma, a biological psychology researcher at VU Amsterdam, said in a statement.

It's long been known that a woman has higher-than-usual chance of having non-identical twins if someone else in her family has given birth to dizygotic twins. To delve into genetic factors that might explain that association, the team did a GWAS on 1,980 women who spontaneously conceived dizygotic twins and 12,953 control individuals.

Individuals in the discovery stage of the analysis had been enrolled through the Netherlands Twin Register, the QIMR Berghofer Medical Research Institute in Australia, or the Minnesota Twin Family study.

Based on genotyping patterns identified in cases and controls using Illumina arrays and imputation, the team narrowed in on SNPs at three sites in the genome that were suspected of coinciding with fraternal twin birth.

After replication testing in nearly 3,600 twin mothers from Iceland and more than 297,000 controls, all profiled by Decode Genetics, the researchers were left with two significant loci: the FSHB locus on chromosome 11 and the SMAD3 locus on chromosome 15.

The apparent SMAD3 connection is particularly novel, co-author Cornelis Lambalk, a gynecologist at VU University Medical Center, noted in a statement, and suggests that the signaling pathway it participates in might mediate ovarian response to the follicle-stimulating hormone.

"This genetic variant is totally novel and hadn't been shown before as a candidate gene for twinning," Lambalk said.

The team's blood testing on almost 18,000 genotyped individuals from Iceland and their relatives indicated that the fraternal twin-associated SNP near FSHB influences blood levels of follicle-stimulating hormone, while the hormone's concentration in the blood did not vary depending on the SMAD3 variants present.