Pure Pedantry

I just thought this paper was kind of cool. It reviews the evidence from twin studies that shows that certain regions of the brain show very high levels of genetic heritability. Heritability, as I discussed in an earlier post, is a gross measure of the genetic as opposed to the environmental contribution to a particular trait. It is calculated by what are called the concordance rates between monozygotic and dizygotic twins for a particular trait — the concordance is the percentage of twins that share the trait. (I would hasten to point out that this is not a perfect measure by any stretch of the imagination. For it to have meaning, you have to assume that monozygotic and dizygotic twins have equivalent environments — each member of the twin set — which has been questioned. But still, it is a reasonably useful tool with some caveats.)

Anyway, Peper et al. in the journal Human Brain Mapping examined the evidence from MRI studies of twin to determine what role genetics have on the total and subregional variation of brain volumes.

Below is a graphic from one of the review papers. Red areas indicate very high levels of heritability; blue indicates low heritability. The upper graphic shows the gray matter; the lower shows the white matter. (Both are from Hulshoff Pol et al.)

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Areas of high heritability include the medial prefrontal cortex, Herschl’s gyrus, and the postcentral gyrus as well as large areas of white matter. The hippocampus showed only moderate heritability in most studies.

What is the significance of this work? Well there are a couple of things that are cool about it…

  • 1) Many of these areas with high heritability are involved in mental illness and neurological disease. Thus, we can be reasonably certain that genetics will play a role in these diseases as well. (We sort of knew that, but this is an interesting validation of it.)
  • 2) More and more, we are beginning to understand that a relatively small subset of genes controls brain development in a variety of different contexts. The identification of areas of the brain which are more genetically specified will help us identify these “master” genes more easily. The authors summarize the evidence for genetic regulation of brain volume:

    The few studies on polymorphisms in healthy subjects have revealed associations with brain volumes or densities. For example, Val/met (i.e., valine/methionine amino acids) variant carriers of the Brain Derived Neurotrophic Factor (BDNF)-gene (a gene involved in reducing the amount of naturally occurring neuronal cell death) were found to have a reduced size of the prefrontal cortex and hippocampus compared to val/val carriers. In addition, in met-BDNF carriers, a negative relation was found between volume of the dorsolateral prefrontal cortex and age, which was not present in the val-BDNF carriers. A study of allelic variants of the Apolipoprotein (ApoE)-gene – thought to be involved in cell growth and regeneration of nerves – showed that healthy elderly subjects who were homozygous for the Epsilon4 allele, i.e., e4-e4 genotype, had smaller hippocampal volumes than subjects heterozygous for that allele and than e4 noncarriers. Also, the presence of a single ApoE-epsilon4 allele was associated with an increased rate of hippocampal volume loss in healthy women. Two variants of the X-linked monoamine oxidase A-gene (MAOA) were recently associated with brain volumes in healthy subjects. The low-expression variant predicted volume reductions in cingulate gyrus, amygdala, insula, and hypothalamus, whereas the high expression variant was associated with changes in orbitofrontal volume. Overall, studying polymorphisms in healthy subjects yield valuable information on specific genes that may be involved in brain volume. (Citations removed.)

  • 3) While I will obligatorily add that it is exceptionally difficult to draw correlations between brain volume and function — if I remember correctly Stephen Jay Gould wrote a whole book on the chequered history of trying to correlate intelligence with brain volume, when taken with a grain of salt this line of research can prove fruitful. Furthermore, the causality in cases this correlation is even harder to infer:

    Importantly, the high heritability of brain volume is functionally relevant. For instance, the association between brain volumes and intelligence was found to be of genetic origin. Moreover, the association between frontal gray matter volume and intelligence was suggested to be due to genetic factors. Recently, the association of intelligence with gray matter of the frontal and occipital lobes, the parahippocampus and connecting white matter was found to be influenced by genes common to brain structure and intelligence. These findings demonstrate that a common set of genes may cause the association between brain structure and cognitive functions. However, in elderly twins, the associations between frontotemporal brain volumes and executive function were found to be because of common environmental influences shared by twins from the same family. These results point to the possibility that overlapping sets of genes or common environmental influences cause variation in two distinct phenotypes. However, other causal models are also consistent with the findings. It might be, for example, that a higher level of cognitive functioning leads a person to select an environment that also increases brain size. The genetic influence on brain size then simply reflects the genetic influences on cognition. Thus, the specific mechanism, pathways, and genes that are involved in human brain morphology and its association with cognitive functions remain elusive. (Citations removed. Emphasis mine.)

    What is interesting in spite of the caveat is that it might be possible in a crude way to delineate the progression of disease in these neural systems from baseline observations of changes in volume. This would not speak much to general intelligence — skirting the issue of an absolute relationship between volume and function. However, it would still increase significantly the power of imaging in the study of brain function if such links could be established.