Genetic influence on SSA significantly overestimated ?
N.E.Whitehead
April 2010
Summary:
Twin studies have been at the heart of estimations of the genetic influence on SSA. But a recent very important paper shows traditional twin studies have been over-estimating the genetic contribution of traits by 15% on average because of the effects in identical twins of a shared placenta. This should also impact SSA studies.
The paper by Kaminsky et al. (2009)(1) (which includes Gottesman, Martin and Petronis , some very well known figures in twin studies) studied 114 pairs of MZ twins and 80 fraternal (DZ) twins. They took samples from each of the twins and did a special kind of DNA analysis looking for differences between twin and co-twin. A previous post on this site mentioned in passing that this study pinpointed placenta differences as important. We can now give a number for the extent of the effect.
Methylation analysis
The DNA analysis was not looking at gene differences. Rather it was a recent type of analysis called methylation analysis. Methylation adds methane to proteins called histones which are attached to the DNA. Methane is Natural Gas. (This does not mean there are pockets of gas in our cells! Rather, other more complex biochemicals such as folic acid add the methane to the proteins). The amount of methylation controls how much of various gene products get produced. This change in protein production from the genes is called “epigenetic regulation” and you’re going to hear lots more about it.
It means, that the idea that identical DNA in identical twins will always produce the same adult organism identical in every detail is not accurate – the environment influences the pattern of expression of the DNA (in this case the womb environment, but the effect can be wider, eg in adults gene expression could be altered by what you eat.)
Shared placenta in one quarter of identical twins
The biochemical analysis by Kaminsky et al. is quite complex, but one of their important conclusions is that the placenta matters a great deal. It is known that MZ twins in about 25% of cases have a shared placenta, rather than individual ones. The shared placenta means the same blood circulates through both twins and acts as a kind of regulariser making the twins much more similar than if they didn’t share the one blood supply. The methylation patterns on the histones are also very similar, and their gene expression is very similar.
However if MZ twins have independent placentas there are lots of differences in gene expression, and they are much more like DZ twins.
Effect of 15% becomes zero
The authors worked out that if you have a mix of MZ and DZ twins in a volunteer sample like theirs then the shared placenta effect gives an artificial genetic effect of 15%. Thus if a mixed twin study showed the genetic contribution for some trait was 15% it might really be 0%. If the apparent genetic contribution was 65%, it should really be 50%. This matters particularly if the genetic contribution is already modest; it gets greatly reduced (eg 15% to 0 as above).
Kaminsky’s study looked at 6000 genetic locations in each individual and averaged the effects for the lot. For a particular trait the exaggerating effect from the shared placenta might be bigger or smaller. Thus each twin study will need to establish whether the MZ volunteers had a shared placenta or not. Unfortunately this is often not recorded, but it will be essential to establish this if genetic contributions to various traits are to be accurate.
One consequence of this research is that all twin studies to date on any trait have probably overestimated the genetic contribution.
We don’t know whether SSA studies are affected or not, but on average they will be, and the effect could be rather significant. Averaging the best twin studies to date the genetic contribution to SSA for men and women respectively is 20% and 35%. These could easily reduce to 5% and 20% - making them both weak effects. As discussed in chapter 10 of My Genes on this website, there are several factors likely to reduce this even further.
We await more definitive SSA twin studies, but it is very likely the genetic contribution has been significantly over-estimated.
Reference List
Kaminsky, Z.A., Tang, T., Wang, S.C., Ptak, C., Oh, G.H., Wong, A.H., Feldcamp, L.A., Virtanen, C., Halfvarson, J., Tysk, C., McRae, A.F., Visscher, P.M., Montgomery, G.W., Gottesman, I.I., Martin, N.G. and Petronis, A. (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nature Genetics 41, 240-245.