Posted in SLC1A1, tagged 23andMe, anti-psychotic, Biology, clozapine, DNA, economics, genetic association, Genetic testing, Glutamate, Health care, medication, Mental disorder, Mental health, obsessive-compulsive, Personalized medicine, side-effect on December 15, 2009|
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In their forecast “The World in 2010” special issue, the Economist points to “The looming crisis in human genetics” wherein scientists will reluctantly acknowledge that, even with super-cheap genome sequencing tools, we may not soon understand how genetic variation contributes to complex illness. The argument is a valid one to be sure, but only time will tell.
A paper I read recently, reminded me of the long hard slog ahead in the area of genomics and psychiatric illness. The authors in “Association of the Glutamate Transporter Gene SLC1A1 With Atypical Antipsychotics–Induced Obsessive-compulsive Symptoms” [Kwon et al., (2009) Arch Gen Psychiatry 66(11)] are trying to do something very important. They would like to understand why certain (most) psychiatric medications have adverse side-effects and how to steer patients clear of adverse side-effects. This is because, nowadays, a patient learns via a drawn-out trial-and-error ordeal about which medications he/she can manage the benefits/costs.
Specifically, the authors focused their efforts on so-called obsessive-compulsive symptoms that can arise from treatment with atypical antipsychotic medications. Working from 3 major medical centers (Samsung Medical Center, Seoul National University Hospital and Asan Medical Center) Kwon et al., were able to cobble together a mere 40 patients who display these particular adverse side-effects and matched them with 54 patients based on several demographic and medication-based criteria. Keep in mind that most genetic studies use upwards of 1,000 samples and still – hardly – are able to obtain significant effects.
Nevertheless, the authors note that the glutamate transporter gene (SLC1A1 or EAAC1) is a most logical candidate gene, being a located in a region mapped for obsessive-compulsive disorder risk and also a gene that appears to be down-regulated in response to atypical anti-psychotic treatment (particularly clozapine). A series of statistical association tests for 10 SNPs in this gene reveal that two SNPs (rs2228622 and rs3780412) and a 3-SNP haplotype (the A/C/G haplotype at rs2228622-rs3780413-rs3780412) showed modestly significant association (about 4-fold higher risk) with the adverse symptoms.
To me, this is a very noteworthy finding. A lot of work went into a very important problem – perhaps THE most pressing problem for patients on anti-psychotic medications today – and the results, while only of modest significance, are probably biologically valid. The authors point out that rs2228622 and rs3780412 have previously been associated with OCD in other studies.
But when you compare these modest results (that these authors fought hard to obtain) with the big promises of the genomic era (as noted in the Economist article), well then, the results seem rather diminutive. Will all patients who carry the risk haplotype be steered away from atypical antipsychotics? Will big pharma (the authors of this paper disclose a great many ties to big pharma) support the fragmentation of their blockbuster drug markets into a hundred sub-populations? I doubt it. But some doctors and patients will experiment and continue to explore this avenue of inquiry – and it will take a long time to work out. Better check back in 2020.
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Posted in ADRA2A, Locus coeruleus, Noradrenaline, SLITRK1, tagged ADRA2A, Development, medication, Mental disorder, Noradrenaline, SLITRK1 on January 9, 2009|
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A recent report by Katayama and colleagues [doi 10.1038/mp.2008.97] shows that the the gene slitrk1 – a known risk factor for the developmental disorders Tourette’s syndrome and trichotillomania gives rise to increased levels of noradrenaline when the gene is inactivated in a developing mouse model. In the U. S., the most frequently prescribed medications for these disorders are clonidine hydrochloride (Catapres®) and guanfacine (Tenex®), which inhibit the synaptic transmission from presynaptic nerve terminals that express the alpha 2-adrenergic receptor. Thus, the mouse model (mice with the inactive slitrk1 gene were healthy but showed behavioral abnormalities that were normalized upon treatment with clonidine) seems to validate the current form of treatment since a reduction in noradrenergic release, might counteract the higher levels of noradrenaline associated with the risk-promoting slitrk1 mutation.
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Image via Wikipedia Many of the unpleasant feelings and physiological changes associated with fear and anxiety can be traced back to a tiny brain region known as the amygdala. Neuroimaging studies often find this region abnormally active in people having difficulty down-regulating negative emotions. It is no surprise then, that when genes that regulate innate fear and the reactivity of this brain region are identified there is much hope for future medications that might target these biochemical pathways and relieve emotional suffering. So it is that Coryell and colleagues identify such a gene, ASIC1a, the acid sensing ion channel 1a, and report in their paper, “Targeting ASIC1a Reduces Innate Fear and Alters Neuronal Activity in the Fear Circuit” (DOI) and report that more expression of this gene results in mice with more innate fear and, that less expression or blockade of this gene results in less innate fear. The gene appears expressed in a well-studied fear circuit including the cingulate cortex, the amygdala and the bed nucleus of the stria terminalis, so any type of pharmacologic manipulation would be predicted to affect the entire fear circuit. The normal function of ASIC1a – a proton sensor – is presumably to regulate pH within and/or across cell membranes. Such changes in pH are known to affect synaptic transmission in a manner such that lower pH inhibits NMDA channels and higher pH activates NMDA channels, so it is possible that the effects of ASIC1a on fear may be ultimately due to effects on synaptic plasticity. An exciting candidate not to be feared.
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Image by Getty Images via Daylife Psychiatrists and families that cope with mental illness have long been aware of far reaching familial risk. Although the new genomics greatly accelerates the identification of specific risk alleles; the direct functional and mechanistic connections between these tiny bits of nucleic acid and large-scale changes in neural activity and behavior is more often a matter of hand waving than hard science. Monory et al., in their article, “Genetic Dissection of Behavioural and Autonomic Effects of d9-Tetrahydrocannabinol in Mice” (doi:10.1371/journal.pbio.0050269) provide an excellent example of how to relate the effects of a given gene (the CB1 receptor) to changes in behavior (getting stoned, to put it blunt-ly) by first beginning to determine what CB1 expressing cell-types are necessary. For example, ever-mellow GABA-ergic neurons are not involved in mediating the effects of cannabinoids whilst excitatory glutamatergic neurons mediate hypolocomotor effects. Similar analyses of specific (gene x circuit) interactions will build important bridges between genetics and psychiatry. Why do the mice get to have all the fun ?
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I much enjoyed the June 15th podcast “Blame it on my genes” hosted at the New York Academy of Sciences. Here, Professor Paul Appelbaum lays out a biological framework for behavioral genetics wherein genes influence an individual’s sensitivity to experience in ways that predispose or insulate them from illness. As the basic science begins to map specific (gene x environment) examples, how, then, might this knowledge play out in the justice system where it could be used in “determinations of culpability?” Indeed, as covered by Professor Appelbaum, our justice system allows individuals to be excused from culpability when they are incapacitated (insanity defense) or via automatism (a sleepwalker commits a crime but is not consciously aware of it). Can, or should, genetic background be used in this way (a genetic determinism defense)? Professor Appelbaum reviews a key Supreme Court ruling from “Robinson v. California” citing the opinions of Justice Hugo Black that recognize that just because someone is influenced by causal factors, does not mean that that person cannot choose rationally. This opinion is based on the principle of compatibilism (free will and determinism are compatible) which apparently is rooted in an ancient school of Greek philosophers. Nevertheless, there is a lot of action in the lower courts where genetic evidence is being proffered to mitigate or lessen culpability – interesting times ahead. Perhaps the judiciary is already subscribed to “The DNA Network!”
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