Pharmacogenomics – From Large Collaborations To Implementation and Drug Discovery

S766 effect as well as common variation: Rare variants of major effect can be a primary contributor to risk in a given individual, while common variation functions in a multifactorial context, including polygenic risk and other factors. Modeling etiologically complex disorders can be quite challenging. For rare variants, targeted disruption or mutation of a gene in cell and animal models will have strong construct validity. However, in the case of oligogenic and polygenic risk, such approaches are less relevant. Study of human samples from patients with oligogenic or polygenic risk represents a means of understanding pathobiology in such cases. However, given the etiological heterogeneity and the small effect size of common variation, large and even ultra-large cohorts will be required before studies are sufficiently powered. Over the past 5 years, we have been developing large cohorts of human samples from psychiatric disorders, while also piloting methods to robotically reprogram and differentiate these samples. We are taking three approaches to sample collection. First, for rare genetic disorders such as Phelan-McDermid Syndrome (PMS) – a severe neurodevelopmental disorder that presents with intellectual disability, autism, and additional neurological and psychiatric manifestations, we are collecting case-sibling pairs (n 18) for reprogramming. Second, idiopathic disorders, such as autism, schizophrenia, and PTSD, we are collecting large sample cohorts, targeting hundreds of samples for each disorder. Finally, in disorders where there are known or suspected dysregulated pathways, we can increase power by challenging cells with perturbing agents, including IGF-1 in PMS and cortisol in PTSD. In parallel with collection, we have piloted robotic reprogramming methods with these sample sets. NYSCF has developed automated protocols for fibroblast expansion, iPSC reprogramming and validation. In pilot studies with our schizophrenia cohort (n4120), 10% of the total sample is in the final stages of reprogramming on this automated platform, hence ensuring feasibility. For each individual, two clonal iPSC lines are validated and banked. Furthermore, we have developed robotic methods to induce neurons from iPSC. In pilot studies, we have already evaluated two automated protocols for rapid induction of excitatory neurons induces either iPSCs or NPCs into functional neurons with nearly 100% yield in less than 2 weeks by expression of doxycycline-inducible Ngn2 lentiviral vectors, combined with puromycin selection to increase the purity of the cultures. Over the next 3 years, we anticipate reprogramming, differentiating, and analyzing hundreds of iPSC lines derived from patients with autism, schizophrenia, PTSD, or rare genetic disorders associated with autism or schizophrenia.

Disclosure Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.06.124

Abstracts

Tuesday, October 17, 2017 8:30 a.m. - 10:00 a.m. Symposia Sessions PHARMACOGENOMICS – FROM LARGE COLLABORATIONS TO IMPLEMENTATION AND DRUG DISCOVERY Li-Shiun Chen (Chair)1, Daniel Mueller (Co-chair)2, Francis McMahon (Discussant)3 1

Washington University School of Medicine University of Toronto 3 NIH/NIMH 2

Overall Abstract Introduction: Recent genetic studies have identified variants in specific gene regions showing not only evidence of association but also biological mechanisms underlying the association. The goal of this symposium is to demonstrate how human genetic association findings can be translated into improved understanding of biological mechanism, disease prognosis, and treatment response using examples across different psychiatric disorders such as mood disorders, schizophrenia, eating disorder, and addiction. Methods: A variety of methods are used including randomized treatment trials, large genome wide association studies or meta-analyses, bioinformatics, and epigenetics. Results: The first talk by Dr. Schulze is on genotypephenotype relationships in bipolar and related traits. He will demonstrate how applying the friendly data sharing approach spanning five continents has helped pave the way for a better understanding of the genetic basis of response to lithium treatment, serving as an example for successful precision medicine research. The 2nd talk by Dr. Muller is on current evidence, evidence adjudication, implementation challenges of pharmacogenetics testing for antidepressants and antipsychotics use. He will present a review of the evidence that was considered in formulating that guidance, along with a summary of the main recommendations and associated ethical issues. He will also discuss the kinds of evidence still needed to incorporate genetic testing in clinical decision-making. The 3rd talk by Dr. Breen is on translation of genetic findings from large GWAS studies in Psychiatric Genomics Consortium (PGC) into druggable genomes. He will discuss how discovery of the biological pathways can not only reveal etiological pathways but also lead to drug discovery. The 4th talk by Dr. Chen demonstrates the significant genetic variants that predict nicotine dependence, smoking cessation, and response to cessation pharmacotherapy. These data suggest that genetic risks may predict smoking cessation outcomes and moderate the effect of pharmacological treatments. Some pharmacogenetic findings have been replicated in meta-analyses of multiple smoking cessation trials. The variation in efficacy between smokers with different genetic markers suggests that personalized smoking cessation pharmacotherapy based upon genotype could maximize the efficiency of such treatment while minimizing side effects. As a result, these genetic markers are useful to predict clinical predictor such

Abstracts

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as the number needed to treat (NNT) and the number needed to harm. Conclusion: Different psychiatric disorders serve as successful examples in how genetic findings in human association studies inform biological experiments to uncover the underlying mechanisms and treatments tailored to individual genetic background. Each presentation represents unique and complementary research paradigms in understanding how genomics inform personalized medicine by linking the biology and treatment in different psychiatric disorders. Learning Objectives: 1) human genetic studies inform the biological mechanisms of psychiatric disorders, 2) pharmacogenetic studies inform personalized treatments with maximized efficacy and minimized risk of side effects.

Disclosure Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.06.125

THE CONSORTIUM ON LITHIUM GENETICS (CONLIGEN): GENOME-WIDE APPROACHES TO BIPOLAR DISORDER PHARMACOGENETICS AND A TESTAMENT TO THE POWER OF INTERNATIONAL FRIENDLY DATA SHARING n

Thomas G. Schulze , Consortium on Lithium Genetics University of Munich Abstract This presentation will give the audience an overview of current efforts to identify biomarkers of response to lithium treatment in Bipolar Disorder (BD). First, building on the experience of the Consortium on Lithium Genetics (www. conligen.org), I will underscore how our approach of “friendly data sharing”, honoring the invaluable efforts by all researchers involved, clinicians and basic scientists alike, has been pivotal to the success of the ConLiGen GWAS in more than 2,500 individuals, i.e. and how it will shape the next steps. Second, I will present in-depth analyses on a potential link between lithium response and genes involved in circadian rhythms, based on stringent gene-set analyses. Finally, I will talk about latest transcriptomic approaches that might help shed light on lithium’s mechanism of action.

Disclosure Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.06.126

PHARMACOGENOMIC UPDATE ON ANTIDEPRESSANT AND ANTIPSYCHOTIC MEDICATIONS n

Daniel Mueller

University of Toronto Abstract Psychiatric medications continue to be prescribed on a ‘trial-and-error’ fashion, with virtually no predictive tools available allowing to select type and dose of medications for any given individual. An increasing amount of evidence support an important role for genetic markers to improve outcome to many antidepressant and antipsychotic used for depression and schizophrenia, respectively. High levels of clinical evidence in favor of genetic associations are particularly reported for drug metabolizing genes. Another example are patients of Asian ancestry who receive carbamazepine and where the HLA-B*1502 marker substantially increases risk of serious skin disorders (Stevens Johnson Syndrome and toxic epidermal necrolysis), leading to policies where genetic testing is now mandatory in some Asian countries. This presentation will begin by reviewing the state of the current research with a focus on drug metabolizing enzymes and highlight expert consensus guidelines and recommendations provided by national drug and safety administrative institutions. CYP450 enzymes, and in particular CYP2D6 and CYP2C19, are responsible for metabolizing most psychiatric medications. Data will be shown from 383 physicians (mostly psychiatrists and family general practitioners) from the greater Toronto area returning surveys following genetic testing for CYP2D6 and CYP2C19 genes (among others) of their patients treated with antidepressants and antipsychotic medications. Questionnaires where retrieved 6-8 weeks later and results indicate that whenever genetic information was considered in their treatment decisions, improvement of drug treatment was seen in 122 cases compared to only 2 cases where a slight symptom deterioration was reported (p o 0.01). Next, results from genetic analyses in noradrenergic and serotonergic genes will be shown from 350 adults diagnosed with late life depression (LLD). Participants received open-label venlafaxine, a serotoninnorepinephrine reuptake inhibitor, for up to 12 weeks. After adjusting for multiple comparisons, the norepinephrine variant rs2242446 (T-182C) was significantly associated with remission (odds ratio = 1.66, 95% CI = 1.13, 2.42). Individuals with the rs2242446 C/C genotype were more likely to remit (73.1%) than those with either the C/T (51.8%) or the T/T genotype (47.3%). Individuals with the C/C genotype also had a shorter time to remission than those with the C/T or T/T genotypes and had a greater percentage change in depressive symptom scores from baseline to end of treatment (up to week 12). We are currently testing selected microRNA