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WCPG 2011—Enter the Endophenotype on Day Four

11 October 2011. The last day of the 2011 World Congress on Psychiatric Genetics began with a plenary talk from David Goldman of the National Institute on Alcohol Abuse and Alcoholism about genetic factors contributing to impulsivity. Commonly associated with addiction and other psychiatric disorders, impulsivity may offer a useful intermediate phenotype lying closer to disease-related variants. Goldman described a recent exome sequencing study from his group in a genetically homogeneous Finnish population, which turned up a common variant in the serotonin HTR2B receptor that was necessary but not sufficient for severe impulsivity (Bevilacqua et al., 2010). This provides an opening to study how the gene modulates impulsivity, and exemplifies an approach that could prove useful to deconstructing the myriad behaviors related to psychiatric disease in the general population.

David Glahn of Yale University was then awarded the Theodore Reich Prize, which recognizes young investigators in the field of psychiatric genetics. Glahn described his work looking for endophenotypes that reflect the effects of genetic risk for disease, and which lie in between the pathway connecting genes to disease (see SRF Live Discussion on endophenotypes). Drawing from recent work linking three cognitive measures to genetic liability for bipolar disease (Glahn et al., 2010), Glahn proposed that demonstration of genetic determination of a trait related to disease ought to be enough to consider that trait as an endophenotype. As researchers continue to explore numerous and diverse measures as potential endophenotypes, Glahn proposed an Endophenotype Rating Value as a quantitative way to rank each one. He joked that the acronym for the term—"ERVĒ—fittingly echoes the name of Irv Gottesman, who helped bring the endophenotype concept to psychiatry. Glahn then used the ERV to evaluate a plethora of behavioral, neuroanatomical, and transcriptional characteristics measured in a study of major depressive disorder.

Pharmacogenetic finish
Though most of the meeting was oriented around finding genetic factors contributing to psychiatric disease, one of the last sessions was geared toward discovering factors predicting response to drug treatment. These pharmacogenetic factors may reflect a personís ability to metabolize a certain drug, or they may point to subtypes of disease, as suggested by findings presented by John Kelsoe of the University of California in San Diego. Looking retrospectively for genetic associations with lithium response in bipolar disorder among over 600 SNPs in 50 genes related to lithiumís cellular action, Kelsoe reported one implicating NTRK2, a receptor for BDNF, among individuals with elated mania and family history of bipolar, but not in those with a dysphoric form of the disorder. A prospective study showed that people homozygous for the T allele at this SNP responded better to lithium than those with one or no copies of the T allele. These findings suggest that the biological mechanisms behind this lithium responsiveness could be related to those that distinguish this clinical subtype of bipolar disorder.

After three talks focused on finding genetic variants associated with antidepressant treatment response, attention turned to antipsychotic-induced side effects, namely weight gain. Testing SNPs within molecules known to regulate feeding circuits in the brain, Daniel Mueller of University of Toronto reported associations between clozapine-induced weight gain in individuals with schizophrenia and SNPs within the gene encoding melanocortin receptor 4 (MC4R) and neuropeptide Y (NPY), both known for roles in human obesity. The risk allele in MC4R creates a transcription factor binding site, which might be a clue to how antipsychotics induce weight gain in carriers of this allele. Identifying such side effect-predicting alleles would help clinicians improve upon the current trial-and-error method to finding the most appropriate medications for a patient. The findings also highlight the need to look beyond a drugís purported mechanism (e.g., action at D2 receptors) in order to understand the full range of its effects.—Michele Solis.

Comments on Related News

Related News: Melanocortin Receptor Linked to Antipsychotic-Induced Weight Gain

Comment by:  Kristin Bigos
Submitted 15 May 2012
Posted 16 May 2012
  I recommend the Primary Papers

This study cohort is unique in that it comprises pediatric patients that are drug naive, and therefore an ideal sample in which to test pharmacogenetic predictors of weight gain. In their first 12 weeks on the drugs, one-quarter of the patients gained between 15 to 35 lbs. Patients who were previously treated with antipsychotics may have already gained their initial weight, making it difficult to detect small differences attributable to genetics. This is a beautiful example of how using an intermediate phenotype such as weight gain, which is a continuous variable, compared to the binary case-control GWAS paradigm, yields more powerful associations. I'm looking forward to future studies of MC4R and its potential as a drug target for blocking the metabolic side effects of antipsychotics.

View all comments by Kristin Bigos

Related News: Melanocortin Receptor Linked to Antipsychotic-Induced Weight Gain

Comment by:  Captain Johann Samuhanand
Submitted 17 May 2012
Posted 17 May 2012
  I recommend the Primary Papers

As a carer, I know that one of the principal reasons for noncompliance with antipsychotic medications is weight gain. This weight gain also seems to induce diabetes and other physical problems. So it is imperative that this particular aspect is researched more and answers found.

View all comments by Captain Johann Samuhanand