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PIP 2014—Pharmacogenetics in Psychiatry

7 Dec 2014

Editor's note: We thank Beatriz Carvalho Henriques and Brodie A. Heywood of the Unversity of Alberta in Edmonton, Canada, who produced this special report along with conference organizers Anil K. Malhotra of Zucker Hillside Hospital in Glen Oaks, New York, and Katherine J. Aitchison of the University of Alberta in Canada.

December 8, 2014. The 13th Annual Pharmacogenetics in Psychiatry meeting took place in Hollywood, Florida, on June 15, 2014. During the four sessions, 12 oral presentations were delivered on current topics of interest in the field, followed by a poster session where 20 projects from North America and Europe were highlighted.

Pharmacogenetics of antipsychotic drug-induced side effects

Anil Malhotra of Zucker Hillside Hospital in New York chaired the initial session, in which Daniel Muller of the Centre for Addiction and Mental Health, Ontario, Canada, presented the results found in a re-analysis of the CATIE GWAS data that used weight gain as the outcome variable, in which more stringent definitions for the sample (not obese at baseline and with no prior high-risk medication, and exposure to high-risk medication during the study) and ethnicity (Caucasian cluster selected) were employed. This new sample (n = 189) was submitted to a GWAS analysis where 328,733 SNPs were investigated. Although none reached genomewide significance, these data demonstrate a new avenue of investigation.

David Rossolatos of the University of Alberta in Canada presented on the association between a LEPR allele and weight gain in children and adolescents prescribed risperidone. The samples (n = 200) for the study were collected in the United Kingdom and Saudi Arabia, and the results suggested a greater degree of weight gain in male patients from the Saudi Arabian sample with the Arg223Arg genotype (p = 0.021). Replication in a relevant ethnic group is indicated.

The final presenter for the first session was James L. Kennedy of the Centre for Addiction and Mental Health, Ontario, Canada, who introduced data relevant for potential genetic markers that mediate clozapine-induced agranulocytosis (CIA). Agranulocytosis is the most significant side effect for clozapine to which the Finnish population may be particularly susceptible, leading investigators to work with samples of this ethnicity (n = 51). Tiwari et al. (2013) applied exome sequencing on a sample of 51 patients (24 with CIA and 27 without), which identified the genes PPF1A4, USP43, ACTN1, PODNL1, and SPATS1 as showing some degree of signal for association with agranulocytosis. A previous study had implicated the HLA region with this phenomenon (Lencz et al., 2014); however, because of poor quality in resequencing coverage of the above loci, the genes introduced don't exclude the involvement of HLA. The CIA Consortium (CIAC) is currently conducting a similar study subjecting over 200 samples of agranulocytosis or neutropenia to GWAS and sequencing.

Pharmacogenetics in Psychiatry organizers Alessandro Serretti, Kathy Aitchison, Anil Malhotra, Jim Kennedy, John Kelsoe. Image courtesy of A. Malhotra

Update on CRESTAR project

The following session, an update on the European CRESTAR project to develop pharmacogenetic biomarkers for schizophrenia, was chaired by James Kennedy. Alessandro Serretti of the University of Bologna, Italy, presented on a genomewide association analysis in a sample where patients were prescribed haloperidol (n = 96), and a larger sample (CATIE) where patients had been prescribed second-generation antipsychotics or perphenazine. The two samples were implicated SNPs in drug response in the genes RTKN2, ARID5B, and EIF2AK4.

Dan Cohen of the Mental Health Care Organization North-Holland North, the Netherlands, presented on side effects of clozapine that can be fatal. Even though possibly lethal clozapine-induced agranulocytosis (CIA) accounts for the caution seen within the medical community to prescribe clozapine and the accompanying required hematological monitoring, other side effects may show more potential to be fatal. In fact, CIA has a mortality rate of 2-4 percent following prescription of clozapine, while GIH (gastrointestinal hypomotility) has that of 15-27 percent, and of DKA (diabetic ketoacidosis), 20-30 percent. Based on these results, his analysis proposed closer monitoring for DKA and GIH, such as that already done for CIA, justified by the clozapine's efficacy in patients resistant to treatment.

Closing this session, James Walters of Cardiff University School of Medicine, Wales, UK, presented CLOZUK, a study focused on treatment-resistant schizophrenia. The study was conducted on treatment-resistant patients with schizophrenia who had been prescribed clozapine, a significantly large sample (n = 12,000), on which copy number variation (CNV) and GWAS analyses were run. The CNV analysis led investigators to the hypothesis that the phenomenology of schizophrenia may be correlated with dopaminergic pathways, while that of treatment-resistant schizophrenia might hold a relationship with glutamatergic ones.

Genetics and pharmacogenetics of neurocognitive function

Session three was chaired by John Kelsoe of the University of California, San Diego, and included three talks. Joey Trampush of Zucker Hillside Hospital in Glen Oaks, New York, presented a GWAS on general cognitive ability (g) which was led earlier in 2014 by the Cognitive Genomics Consortium (COGENT). The results for this study indicated that g and schizophrenia hold genetic markers in common (Lencz et al., 2014) and supported the classic endophenotype model of schizophrenia. In Phase 2 of the experiment, which is currently underway, investigators aim to increase the power of the study with the addition of several thousand more subjects.

For the next talk, Aristotle Voineskos of the University of Toronto discussed a gene-gene interaction in an early risk pathway for Alzheimer's disease that predicts cortical thickness and cerebral infarcts. His team used subjects from the Rush University Religious Orders Study and Memory and Aging Project (ROS/MAP), to show that individuals with combined APOE4 and SORL1 rs689021 A/A risk genotypes have the lowest average cortical thickness (p = 0.06) and the highest frequency of cerebral infarcts (p = 0.0005). APOE binds to SORL1 in a protein-protein interaction, though it was noted that each risk variant also has its own independent effect: SORL1 is involved in APP cleavage and APOE4 is a risk factor for hypertension, which, left untreated, leads to a substantial increase in amyloid-beta levels. Interestingly, although two APOE4 alleles increase risk for Alzheimer's disease 10-fold, young APOE4 carriers seem to have a cognitive advantage.

The third and final talk of the session was presented by Anil Malhotra. His group found that there was a significant correlation between fractional anisotropy (FA) in the left superior longitudinal fasciculus (SLF), a proxy measure of white matter integrity, and performance on a measure of verbal fluency (a measure that reflects cognitive function). Malhotra mentioned that those under the age of 45 with a C/C or C/T rs174853 FADS2 genotype, or other functional FADS1 SNPs, have greater white matter integrity, but his team also found a striking relationship between white matter integrity and membrane polyunsaturated fatty acids (PUFAs) in early schizophrenia patients. Currently, his team is augmenting treatment by PUFA supplementation in early-phase schizophrenia with an aim of enhancing cognitive ability.

Pharmacogenetics of bipolar disorder

Katherine Aitchison of the University of Alberta, Canada, chaired the fourth and final session. Alessandro Serretti presented the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, which focuses on elucidating the relationship between genetics and different patients' response seen for lithium/valproate. Based on the rates of acute hypomanic episodes within a sample of patients treated for six months, the study is investigating polymorphisms that account for the treatment's success. The study pointed to the gene ZNF516 as the most prominent marker for vulnerability to BD.

Katherine Burdick of the Icahn Mount Sinai School of Medicine in New York presented on the relationship between dopamine and cognition in patients diagnosed with bipolar disorder. She presented data from a study where the D2/D3 agonist pramipexole was found to provide some evidence for cognitive enhancement in patients with BD, albeit with a modest increase in risk taking as assessed with the Iowa Gambling task. In addition, overrepresentation of a DAT allele is common to BD, and this observation might have had an impact on the results, considering that carriers for the minor allele were perceived as healthier after being prescribed pramipexole.

Finally, John Kelsoe proposed the use of cellular models for drug development. He presented this strategy for lithium treatment, and found that the number of genes modulating efficacy of treatment in a responder was 10-20 times higher than a non-responder. In another experiment, neurons from induced pluripotent stem cells (iPSCs) that were then differentiated into prox1+ glutamatergic dentate gyrus granule cells demonstrated a hyperexcitable phenotype (as seen in a BD neural network). Lithium selectively changes mitochondrial activity in (lithium-responsive) BD neurons, and the hyperexcitability could be rescued by lithium treatment in responders. Further research will look for variants associated with lithium response by genotyping or sequencing the genes that changed expression levels after lithium treatment.

The meeting closed with a poster session and reception. Next year's Pharmacogenetics in Psychiatry meeting will be held in Toronto, Canada, in conjunction with the World Congress of Psychiatric Genetics in October 2015. (See the Pharmacogenetics in Psychiatry website for more details.)—Beatriz Carvalho Henriques, Brodie A. Heywood, Anil K. Malhotra, and Katherine J. Aitchison.