Toward discovering genes affecting cognition

Citation: Common genetic variants influence human subcortical brain structures, Nature (2015) doi:10.1038/nature14101
Citation: Common genetic variants influence human subcortical brain structures, Nature (2015) doi:10.1038/nature14101
Here’s what we know. Intelligence, as defined by a general factor which explains variation across a range of cognitive tasks, is substantially heritable, with a narrow sense heritability on the order of 0.25 to 0.75 depending on who you talk to and what context.* Intelligence itself exhibits correlations with other traits, from those of social importance, such as education, as well as biological parameters, such as brain size. Additionally, the effect size of genetic variants associated with general intelligence are likely to be very small. This means that you should be immediately skeptical of claims that a common variant segregating in the population explains a large proportion of the variation in intelligence within the population. The history of this area of research, which goes back to linkage studies, is one of non-reproducibility. Large effect quantitative trait loci should already have been picked up by linkage studies decades ago, so I am usually rather skeptical when this old wine is presented again in a genomic guise. In short, the genetic architecture of general intelligence is likely to resemble height, with many loci of small effect.**

This is what Rietveld et al. found last fall in Common genetic variants associated with cognitive performance identified using the proxy-phenotype method. The same sizes were on the order of 10,000 to 100,000 within this study. The top associations within this study explain less than 1% of the variation within the data. It seems likely that the largest effect alleles which influence intelligence variation are about an order of magnitude smaller in impact than those for height. A new paper in Nature, Common genetic variants influence human subcortical brain structures, looks at the morphology of the brain, synthesizing imaging, cognitive neuroscience, and genomics. Here’s the abstract:

…To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Paul Thompson was involved in the research, so I am confident that it was be done thoroughly (and the author list is long enough that I hope they checked for obvious problems!). To correct for population stratification within this European sample they looked at the top for dimensions of variation, and used a regression model to capture other variables which might be confounded with the SNPs in question. The small proportion of variation explained actually increases my confidence, in that it seems to be in the same order of magnitude as the type of studies looking at endophenotypes.

Because of their sheer number I doubt that there’s a great short term likelihood of annotating all the genes responsible for variation in intelligence. Rather, I wonder if the ultimate goal is something similar to what occurred with statins. Find a small effect locus, and target a drug at that locus to help cure cognitive illnesses such as schizophrenia. It stands to reason that the same loci which impact general intelligence would also shape cognitive phenotypes which we term pathological.

* So if heritability in the narrow sense is 0.50 that means half the variation in intelligence in the population can be explained by variation of genes in the population. By way of comparison, height is 0.80 to 0.90 heritable in the narrow sense in the developed world. This does not mean that the correlation between parents and offspring is 0.80 or 0.90 for height. In fact the correlation is closer to 0.50 for height between parents and offspring and also between siblings.

** An alternative minority viewpoint is many rare alleles of somewhat larger effect.

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