Genetics of the menopause

Arguably, one of the key questions about the menopause is when this will happen to an individual - knowing that would take a huge weight off many couples shoulders, because it would help them to plan better when to start a family. A major determinant is down to the genes you carry as a recent, very large study published in the journal Nature has shown. Chris spoke with one of the team behind that work, Cambridge University Obstetrician, Catherine Aiken...

Catherine - We looked at millions of genetic variants across hundreds of thousands of women - there are over 13 million places in the genome where you can have variations in your genetic code. And when we looked at how those were linked to age at menopause, we could identify nearly 300 independent signals within the genes that could explain a large amount of the variation in the age at which women were going through the menopause naturally.

Chris - How did you gain access to so much information about so many people?

Catherine - These are databases available to scientists worldwide to study problems exactly like this, where you need an enormous number of people to be able to sift through so many tiny, tiny, tiny little pieces of the genetic code. The trouble is that there's so much variation naturally in the genes of different people. And so you need an awful lot of women to add together, to be able to predict with any kind of accuracy when somebody would go through the menopause.

Chris - I see. So you've basically got a massive, great group of women. And you're able to ask in this group, are there any parts of the genome that keep cropping up as different in relation to how their age at menopause changes? So you can see there's a sort of link there between that bit of the genome changing in a certain way and the age of menopause changing in the same direction each time.

Catherine - That's right. And we find nearly 300 different places across the genes where that is true. Some of those have a very strong effect, and in other places the effect size is less. But when you add up all those tiny, tiny variations, you find that you actually get quite a powerful effect on your age at menopause. Normally when we think of genetics, we think of a single gene changing and that having a profound effect on whether an individual has a medical condition or not. But in this case, what we find is that there's no single gene. It's a very subtle effect of lots and lots of genes added up. And that's why age at menopause has traditionally been so difficult to predict and why it's been very, very hard to know who's going to go through the menopause at 40 and who might still be premenopausal well into their 50s.

Chris - I suppose what one can do is to ask, well, now you've got those regions of the genome that seem to have this influence, what do those genes in those regions of the genome do? Because if you know what the genes do, that can give you some kind of insight into what the mechanism of an earlier or a later menopause might be.

Catherine - Yes, so that's really interesting. When we look at all those genes, a large, large number of them are connected with what's called the DNA damage response. Basically that's the biological system that makes sure that cells are maintained in their young and healthy state - it's the body's natural repair system. The trouble is that when the body's natural repair system isn't working so well, then that has a profound effect on the ovary. As we already heard, the eggs in the ovary are set before birth, and so it's even more important for eggs than other cells that they are well maintained and that the cells around them that support them are well maintained in terms of constantly repairing any damage, because those cells have been in the ovaries for so long - over 40 years in most cases. And so these genetic variants that we find are mainly to do with how well you can maintain and repair all the cells that support your eggs in your ovaries, which mean that they last longer, if you carry certain variants in those genes compared to others.

Chris - And if you know what those variants are, and you know that some seem to associate with better DNA repair and therefore longer lived eggs, and some seem to associate with a less powerful DNA repair process and therefore eggs that might wear out more quickly, does this mean we are now approaching a stage where we can make some kind of prediction about who might be at risk of an earlier menopause or even roughly when that menopause might happen?

Catherine - We're not quite there yet. We are absolutely approaching that and certainly this recent study gets us a whole big step closer to that. Before we did this study, we thought we knew about 15% of what contributed to somebody's age at menopause. This has taken us up to closer to 40%. It's still not good enough to use in a clinical setting for an individual person.

Chris - If it explains 40%, what's the other 60%?

Catherine - So there are probably genetic variants that we haven't found yet. We also know that there are lifestyle factors: alcohol consumption and tobacco smoking affect age at menopause. Those will all be additive and what we'll find is that there are certain things that interact with certain genetic variants, so smoking may be particularly bad for people who carry particular genetic links.

Chris - One other thing I'd like to pick up with you in this study, because you were finding genes that are linked to DNA damage and repair, and there are other diseases which are really profoundly tied up with DNA damage and repair, but also linked to hormones. I'm thinking, for example, some of the cancers, especially things like breast cancer. Was there any associations that you found in this study in terms of age of menopause and risk of those sorts of conditions?

Catherine - Yeah, absolutely. So the amount of data that we had - the biobanks that we use - are extremely well characterised. What we were able to do was then go back and look at women who had different combinations of genes and what their other health outcomes were. And that's really interesting to us because what we found was very strong associations between genetic patterns that predicted early menopause and genetic patterns that predict other diseases. What we found was that for women whose age at natural menopause was predicted to be later, their risk of several types of cancer increased, and those are the particular types of cancer that we know are linked to hormones. That really was exciting for us because it validates that connection between the genetic pathways that are causing age at menopause and how that interacts with a woman's health globally. So her risk of breast cancer, her risk of ovarian cancer, and then other things like type two diabetes and so on, that are clearly bound up, not only with genetics, but also with the hormonal effects of the menopause and so on.