Mendelian Randomization: How it Works, and What it Reveals about Vitamin D

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.

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5 thoughts on “Mendelian Randomization: How it Works, and What it Reveals about Vitamin D

  1. Can Mendelian randomization account for epigenetics? A person may have a gene for low vitamin D levels but is that gene being expressed?

  2. But what if the genotype associated with low serum D were also associated with some other mechanism that reduces the incidence of bone fractures (e.g., more efficient use of serum D)?

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