That there is a link between particular variations in our genetic code and diseases is well established. But because researchers cannot usually identify the parental origin of a sequence variant, until now it was not clear whether or how that origin might affect disease risk. Augustine Kong, a statistical geneticist at deCODE Genetics in Reykjavík, and his colleagues have determined that parental origin can have an important causative role (see page 868). He tells Nature more about the discoveries.
How did you determine whether gene variants were of maternal or paternal origin?
Thanks to national censuses and parish records, Iceland has complete genealogical records going back 10 generations for the entire population, which totals just 317,000. That means that in a population-based genetic study such as ours — so far we've analysed almost 40,000 people — how everyone involved is related is already known. So as we gathered genetic data on each individual, we were often able to use data from relatives to infer the genetic make-up of that individual's parents, in cases in which the parents themselves were not available for genotyping. In this way, we were able to distinguish the paternal contribution of gene variants from the maternal one. There is nowhere else in the world where this kind of study could be done on such a large scale.
How does the parental origin of gene variants affect the risk of disease?
It depends on the variant. We analysed two variants already known to be associated with disease — one with breast cancer and one with basal-cell carcinoma. In both cases, we found that if the variants are of paternal origin, they will confer a greater risk for those diseases. If they're inherited from the mother, nothing changes — there's neither more nor less risk. We also examined three variants known to increase the risk of type 2 diabetes. We found that those variants confer risk only when inherited maternally, having no effect when inherited paternally.
What was your most exciting finding?
During the course of the study, we discovered an entirely new susceptibility variant for type 2 diabetes. It is unlike the other variants we studied in that it increases the risk of developing the disease if it is inherited from the father, but decreases risk — that is, it is protective — when inherited from the mother.
Will this parent-of-origin influence apply to many gene variants?
Right now we can't say. We expect to learn much more about this in the next few years.