A Very Interesting Paper Using Mendelian Randomisation to Determine the Effect of Extra Years of Education on Heart Disease

It turns out that there are a number of genes, all associated with aspects of neurodevelopment, that predict how many years a person will spend in formal education.[1] It is already very well established that more years of education are associated with large reductions in coronary heart disease (CHD) (mediated by behaviour such as lower calorie intake, less smoking, more exercise).[2] So the authors of a recent well-written and most interesting BMJ paper did the obvious thing.[3] [4] They related the (random) presence or absence of educational propensity genes to CHD. Bingo, they measured a large effect (the genes that predispose to larger durations of formal education associate with reduced CHD). Now, the thing with Mendelian randomisation is that the genotype must not be linked to the outcome (CHD in this case), other than through the putative explanatory variable (duration of education in this case). The authors are aware that it is quite possible that education genes are linked to the outcome (CHD), net of (any) effect on education. To deal with this possibility they perform sensitivity analyses. They examine the association of genetic variates associated with education and the behaviours that lead to CHD. If the effects on education and on CHD behaviours are similar across the genetic variates this suggests that the effect on CHD is through education and not through another variable. And so it was. They also looked to see whether genetic variants already known to be associated with CHD (genes for high cholesterol, etc.) were also associated with education. If the genes associated with education do not associate with these other risk factors, then that favours a cause and effect explanation. There was no association. However, such an association would only be expected if there was a ‘massive’ effect of ‘education genes’ that bypassed education.

This all falls short of proof. Since the educational genes lead to education through mental processes, it is reasonable to suppose that almost all genetic variates that affect education also affect behaviour. Thus, they would affect CHD, even if there was no extra education. The authors say that their conclusion is strongly supported by identical twin studies where one twin stayed longer in education than the other, but this too ignores the fact that these twins are different, for all that their inherited genotype is the same, and so these differences could be the cause of both increased education and decrease in the behaviours that lead to heart disease.

One more point ­– even if years of education really are causative, this might well apply only to people genetically predisposed to more education and may not apply among those not so predisposed – there may be an interaction between the genes that predisposes to education and response to that education. After all, why would one persist in the classroom if you were not predisposed to benefit from the experience? People not predisposed would find being coerced to do so most unpalatable, and such an approach could even have a perverse effect. This is an excellent article and is beautifully presented. But I am a little more sceptical than the authors. I would like to see a debate on the issues.

— Richard Lilford, CLAHRC WM Director

References:

  1. Okbay A, Beauchamp JP, Fontana MA, et al. Genome-wide association study identifies 74 loci associated with educational attainment. Nature. 2016; 533(7604): 539–42.
  2. Veronesi G, Ferrario MM, Kuulasmaa K, et al. Educational class inequalities in the incidence of coronary heart disease in EuropeHeart. 201635895865.
  3. Tillmann T, Vaucher J, Okbay A, et al. Education and coronary heart disease: Mendelian randomisation study. BMJ. 2017; 358: j3542.
  4. Richards JB & Evans DM. Back to School to Protect Against Coronary Heart Disease? BMJ. 2017; 358: j3849.
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