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Searching for twinning genes

It is common knowledge that in some families more twins are born than in other families. Our previous research has shown that heritability plays a role in the dizygotic twin pregnancy. The big question is which gene or genes are responsible.

These genes could be involved in the regulation of hormones (sex hormones such as the luteinizing hormone (LH) and the follicle stimulating hormone (FSH)). These hormones ensure the maturation of an ovary follicle and the release of a follicle so it can be fertilized. When there is too much FSH in the blood, this could result in the simultaneous maturation of more than one ovary follicle. At ovulation more than one follicle will be released and when two of these are fertilised, this results in a dizygotic twin pregnancy.

In collaboration with the Queensland Institute of Medical Research, we examined the genes responsible for the occurrence of a dizygotic twin pregnancy. In the Netherlands and in Australia we asked sisters who both were mother of a dizygotic twin to participate in the study, since they may be carriers of the gene or genes that we are searching for. Daughters may inherit this gene from their mother but also from their father. We therefore also studied the genes of the parents of these sister pairs (the grandparents of the twins). Though we found some evidence for the involvement of the FSH gene, that was supported also by further study in a USA sample, it was clear that we needed far larger numbers to draw definite conclusions about the genes involved in the dizygotic twin pregnancy.

To this purpose the TWINNING consortium was recently set up. Combining whole genome association data from twin registers from all over the world, a large-scale effort is ongoing to finally identify the genes involved. Results are expected in the near future.

More on the Twinning GWAS consortium

The Twinning Gwas Consortium (TGC) is a highly collaborative international consortium set up to characterize the genetic basis of twinning in humans. We have collected over 35,000 individuals of European ancestry from six large twin registries collected in the World (Netherlands, Australia, USA, UK, Finland. Sweden). Our approach was aimed at conducting a meta-analyses of genome-wide association studies to identify genetic polymorphisms associated with Twinning, defined as the birth of multiple babies at once. Knowledge of these genes will identify key mechanisms controlling ovarian function and provide a greater understanding of female fertility and infertility, the most common reproductive disorder. Major advances have been made in the treatment of infertility, but it is clear that important issues remain. While assisted reproductive technologies (ART) are successful in generating pregnancies, it has resulted in a major increase in twinning frequencies. On average, 25% of in vitro fertilization (IVF) pregnancies result in twins and the figure can be as high as 40-50% with associated risks to both mother and infants. Recent reports highlight the adverse outcomes for twin pregnancies following ART and the high costs to the health care system. This project will address two forms of twinning: Dizygotic (DZ) twinning and Monozygotic (MZ) twinning.

Dizygotic twinning

Dizygotic are twins which result from the fertilization of 2 different eggs with 2 different sperms. DZ twins are known also as fraternal twins. Early association studies of DZ twinning were with obvious candidate genes, including those for peptide hormones known to be involved in reproduction (FSHB, FSHR, LHB, inhibins, GNRH and FST) as well as less obvious ones including the fragile-X syndrome gene FRAXA, PPARG and MTHFR. As with candidate gene studies in most other complex traits, results have been mixed and only few replicable associations have been found. Many of these studies were also statistically underpowered given current ideas of gene effect sizes. It is now clearly necessary to take a more global approach to this problem, using genome wide association with a very large population to obtain adequate statistical power.

Monozygotic twinning

Monozygotic twins result from the fertilization of one egg and one sperm. The fertilized embryo then splits within days after fertilization resulting in two individuals which usually share the same chromosomes. Monozygotic twins are also known as identical or maternal twins. There is no clear evidence yet for the implication of hereditary factors in a genetic contribution to having monozygotic twins. However, in some rare cases MZ twinning seems to be segregating in families. And although this is likely a rare allele with substantial effect Mendelian trait, given the enrichment that twin studies have in their data for MZ twins as well as DZ twins this might be the right sample to look for these specific mutations.