Genes 2 Brains 2 Mind 2 Me

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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