PLoS ONE 5(7): e11504. doi:10.1371/journal.pone.0011504
A Genome-Wide Association Study of Neuroticism in a Population-Based Sample
Federico C. F. Calboli et al.
Abstract
Neuroticism is a moderately heritable personality trait considered to be a risk factor for developing major depression, anxiety disorders and dementia. We performed a genome-wide association study in 2,235 participants drawn from a population-based study of neuroticism, making this the largest association study for neuroticism to date. Neuroticism was measured by the Eysenck Personality Questionnaire. After Quality Control, we analysed 430,000 autosomal SNPs together with an additional 1.2 million SNPs imputed with high quality from the Hap Map CEU samples. We found a very small effect of population stratification, corrected using one principal component, and some cryptic kinship that required no correction. NKAIN2 showed suggestive evidence of association with neuroticism as a main effect (p less than 10−6) and GPC6 showed suggestive evidence for interaction with age (p≈10−7). We found support for one previously-reported association (PDE4D), but failed to replicate other recent reports. These results suggest common SNP variation does not strongly influence neuroticism. Our study was powered to detect almost all SNPs explaining at least 2% of heritability, and so our results effectively exclude the existence of loci having a major effect on neuroticism.
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Twin studies show perhaps 25% heritability or more for neutroticism. Brain scans show some statistically significant brain organ size relation. Longitudinal studies of children show that distinct traces of adult personality are already well established in the first few months of life. So, what is one to make of a finding that "our results effectively exclude the existence of loci having a major effect on neuroticism."
ReplyDeleteGive the fairly strong known heritability of the conditions and its apparent congenital basis, stability and biological basis, it is hard to make sense of a conclusion that "our results effectively exclude the existence of loci having a major effect on neuroticism." If this is true, how can the other data be explained?
Could neuroticism be a bit like emerging genetic models of bipolar, autism and schitzophrenia seem to be, a symptom of "accumulated junk" in the genome, sort one of the "fevers" of mental health, rather than deriving from particular genes?
In this view, the question would not be "which loci cause neuroticism," but "how many atypical loci (i.e. how much of a mutation load in the genome) produce a symptomatic mental health condition"?
In the mutation load model, once someone has enough mutation load in their genome to lead to some sort of symptoms, the manifestation of that mutation load in the form of a particularly disorder or personality might be more or less random in much the same way that the specific mental impairments that result from a stroke or brain injury are widely varied and more or less random. Seemingly indistinguishable mutation loads might produce Asperger's in one kid, neuroticism in another, and subclinical schitzophrenic symptoms in a third.
Another alternative would be that neuroticism is an in utero effect that is epigenetic rather than genetic effect fated at conception. Hormone levels in the mother, which might be partially cumulative from pregnancy to pregnancy, or might flow from paternal habits present in more than one pregnancy like stress levels or exposure to some substance, might mimic a hereditary pattern. This would resemble one of the leading biological models for male sexual orientation that suggests that in utero testosterone exposure, rather than genes, are key.
Given the multiple lines of evidence that point to in utero testosterone levels as impacting adult behavior (often traced through digit ratio) in addition to sexual orientation, it wouldn't be too far fetched for a similar mechanism to be at work in neuroticism.
Dienekes,
ReplyDeleteOn a related note, John Hawkes recently commented on his blog "Sergey Brin and genetic research":
"It remains unclear to me how much progress on health may be made by pattern-matching alone, and how much will require new theoretical advances."
I thought Hawke's observations timely and somewhat applicable to this paper on neuroticism.
Give the fairly strong known heritability of the conditions and its apparent congenital basis, stability and biological basis, it is hard to make sense of a conclusion that "our results effectively exclude the existence of loci having a major effect on neuroticism." If this is true, how can the other data be explained?
ReplyDeleteThe non-existence of loci having a major effect on neuroticism does not mean that there are not many loci (with smaller effects than 2%) that have a combined additive effect equal to the estimated heritability of the trait (e.g., from cryptic first-degree relatives as done in this paper).
However, it doesn't take a genius to figure out that if the authors of the paper had discovered that common SNPs accounted for a large fraction of the heritability of neuroticism, they would've published that fact, rather than what they did publish, as that is a much stronger and novel result.