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Friday, January 16, 2009

NOS1 - An Impulsivity Gene?

Neuroskeptic has warned before of the pitfalls of candidate gene association studies. With small sample sizes and multiple comparisons, false positive results are all too common, especially in behavioural genetics. Yet it's not all bad. The renowned Klaus-Peter Lesch and colleagues have just produced a paper which is a cut above the rest. They report on an association between a promoter region polymorphism in the gene NOS1 and "impulsive" traits.

NOS1 codes for the enzyme nitric oxide synthase 1, which is expressed in neurones and makes nitric oxide (Nitrogen monoxide, NO). NO is a small molecule with various roles in animals, most famously the ability to induce erections - Viagra works by enhancing this effect. NO is also known to act as a neurotransmitter, with widespread but poorly understood functions in the brain. It's therefore plausible that altered nitric oxide synthase function could affect behaviour, and several animal studies suggest that indeed it does.

The new paper, published in the Archives of General Psychiatry, reports on the characterization of a functional variant in the human NOS1 gene, and its association with behaviour in several large human samples. The polymorphism, which Lesch et. al. previously discovered and called NOS1 Ex1f VNTR, is a Variable Number Tandem Repeat in a promoter region of DNA. It can be either "short" (S) or "long" (L) (although note that these are arbitrary categories, since the length of the region varies along a range.)

The authors first established that Ex1f is a functional (biologically meaningful) variant, by showing that shorter forms of the Ex1f promoter are less active than the longer forms in vitro (see graphs). They then examined human brain tissue from post-mortem samples and found that the short/long polymorphism was associated with significant differences in the expression of a large number of proteins. Although most of the proteins in question were nothing to do with NO, this shows that the polymorphism does something, which is a start (many don't).

They then report on the association between the short form of the gene and what they call "impulsivity". Here's the exciting bit:

In two separate control samples of normal German adults (most of whom) were screened to exclude psychiatric disorders (n=640 and 1314), 21 and 20% carried two copies of the short allele (SS). I've helpfully highlighted that in green above. Then, in samples of German people who displayed various forms of impulsive behaviour, the SS genotype was more common: in 383 adults with ADHD (28% SS), 189 adults who had attempted suicide (25% SS), and adults with "Cluster B" personality disorders 26% SS, but not those with "Cluster C" disorders representing anxious traits. Also, in a sample of 182 criminals referred to a forensic psychiatry unit, those who had been assessed as "violent" were more likely to carry the SS genotype than those not (p=0.04). In a nutshell, SS is bad. There was a negative result in a family-wise association study in childhood ADHD, however.

As if that weren't enough data, in 1099 healthy volunteers, those carrying the S allele scored lower on the "Conscientiousness" factor of the NEO personality questionnaire than LL people, although the difference was only significant in women. Low conscientiousness could be seen as impulsiveness - although note that there are 5 personality factors on the NEO and the authors presumably checked for a genetic effect on all 5, so that's at least 5 comparisons.

Finally, they managed to work a bit of neuroimaging into the paper in the form of an EEG study in which SS subjects showed a greater posteriorization of the "no-go" centroid during a continuous performance task. The no-go centroid is an electrical signal which occurs in the brain during inhibition of an action; the authors claim that the fact that this signal occurred further back in the brain in SS subjects points "toward impaired function of the medial prefrontal cortex in these subjects, which probably underlies an improper cognitive control of initiated responses resulting in impulsive behaviors", but to be honest, that's very optimistic. What, if anything, this finding means is unclear.

Still, despite a couple of dodgy bits, the paper as a whole offers pretty good evidence that the NOS1 Ex1f variant is functional and influences personality. This is the first report linking NOS1 to behaviour in humans, although since the paper includes data from a number of different samples, it's more than just preliminary evidence. On the other hand, nothing in this field should be considered a fact until the exact effect in question has been replicated by independent researchers - at least, that's my rule of thumb.

The nature of the effect (the associated phenotype) is also unclear. The authors interpret it as increased "impulsivity", but that's a vague concept. Impulsivity in all situations? Only in social situations? Only when stressed? We don't know. Also, the authors seem to have only looked for associations with impulsive conditions. Were someone to look for an association with, say, depression, or schizophrenia, they might well find one, in which case this might be best seen as a resilience gene rather than an impulsivity one. No doubt someone will be doing such a study as we speak, so hopefully, we'll know soon.

History note: Klaus-Peter Lesch first attained fame as the lead author on the first paper associating the 5HTTLPR variant with personality. In the 12 years since this polymorphism has attracted more attention than any other in the field of behavioural genetics with several hundred papers at last count. So if that's anything to go by, we'll be hearing a lot more about NOS1. Stay tuned.

ResearchBlogging.orgAndreas Reif, MD; Christian P. Jacob, MD; Dan Rujescu, MD; Sabine Herterich, PhD; Sebastian Lang, MD;, Lise Gutknecht, PhD; Christina G. Baehne, Dipl-Psych; Alexander Strobel, PhD; Christine M. Freitag, MD;, Ina Giegling, MD; Marcel Romanos, MD; Annette Hartmann, MD; Michael Rösler, MD; Tobias J. Renner, MD;, Andreas J. Fallgatter, MD; Wolfgang Retz, MD; Ann-Christine Ehlis, PhD; Klaus-Peter Lesch, MD (2009). Influence of Functional Variant of Neuronal Nitric Oxide Synthase on Impulsive Behaviors in Humans Archives of General Psychiatry, 66 (1), 41-50

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