Hi I’m Perry Wilson and this is Impact Factor – your weekly commentary on the most interesting
or important articles appearing in the medical literature.
This week, how Mendelian randomization works, and what it can tell us about Vitamin D, milk
drinking, and bone fractures as we check out this study, appearing in the BMJ:
So – what is Mendelian randomization?
Broadly, it’s a statistical framework that attempts to figure out if some exposure causes
some outcome.
Causation is the holy grail of medical research, because, for example, if low vitamin D levels
cause bone fractures, then treating low vitamin D levels would prevent fractures.
So let’s say you want to know whether low vitamin D levels cause bone fractures.
You measure vitamin D levels in a bunch of people, follow them over time, and see if
those with lower levels develop more fractures.
But be careful – what you just described was an association between low vitamin D levels
and fracture risk.
You know very well that other factors, like diet, exercise and sun exposure can affect
vitamin D levels and might independently change your fracture risk.
These other factors are known as confounders, variables that are linked with both the exposure
of interest (vitamin D level) and outcome of interest (fracture) and they are the bane
of observational research.
We have a slew of statistical tools to try to account for confounders, but none are perfect.
No if you really want to get at causation, you should do a randomized trial, but these
can be tricky and very expensive.
It’s not always ethical or feasible to randomize people to certain exposures, which is probably
why we have yet to see a definitive trial exploring the efficacy of absinthe use on
painting ability.
Mendelian randomization gets around these issues via an interesting epidemiologic trick.
We know there are a host of things – like lack of exercise - that might be associated
both with low vitamin D levels and fracture risk.
But there are genes that are associated with low Vitamin D levels too.
Some people are born with gene variants that predispose them to lower Vitamin D levels
throughout their lives.
Whether you get one of those genes or not, practically speaking, is random.
It has nothing to do with eating habits or exercise - It’s an accident of birth.
So if low vitamin D levels cause fracture, than a group of people genetically cursed
to be predisposed to low vitamin D levels should have higher fracture rates.
On the other hand, if low Vitamin D levels are merely a marker of other healthful behaviors,
being born predisposed to have low levels will have no effect on fracture risk.
This is the genius of Mendelian randomization.
We use the genes people have had their whole lives, genes that never change, to get around
the mess of the myriad life choices that affect measured Vitamin D levels.
The genius of the BMJ manuscript is that they used genome-wide association data from over
500,000 individuals to perform mendelian randomization analysis not just on vitamin D levels, but
on a host of classic fracture risk factors: including dairy intake, diabetes, age at menopause
and more – all things that are associated with fracture but have not been shown to cause
fracture.
This is a shotgun approach to find something we can change that will actually impact the
fracture rate.
What they found was that out of 14 risk factors for fracture, only 1, bone mineral density,
had strong evidence of causality.
Grip strength, a proxy for muscle mass, had weak evidence of causality.
Remember – they are not saying that these other things aren’t associated with fracture,
they are saying that changing the other things won’t change the rate of fracture.
So we get a ton of information from this study – it suggests that, for example, while those
who have earlier menopause are more likely to have a fracture, delaying menopause is
unlikely to make a difference in the fracture rate.
What about vitamin D?
Well – this study would suggest that all those vitamin D supplements we take aren’t
doing much to decrease the fracture rate, and that finding broadly aligns with randomized
trials that have examined vitamin D supplementation.
So that’s Mendelian randomization – I hope I’ve brought a bit of sunlight to the
issue.