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Identification of Over 100 Schizophrenia-Associated SNPs and Certain Autism-Associated Rare Variants Reported at World Congress of Psychiatric Genetics in Boston

Today (Monday, October 21) was the last day of the five-day 2013 XXIst World Congress of Psychiatric Genetics in Boston and the tremendous success of the meeting and the enormous progress that has recently been made were remarked upon in a comment to BioQuick by Tom Insel (photo), M.D., Director of the National Institute of Mental Health (NIMH) since 2002. “This is a rapidly moving field. Five years ago, we had too few disease-associated variants. Now, perhaps, we have too many. At this meeting, we have heard reports of the identification of over 100 schizophrenia-associated SNPs, some overlapping with bipolar disorder. This is huge. In addition, we have heard about the identification of several rare variants associated with autism and intellectual disability. This is also huge,” Dr. Insel said. Many other new and exciting discoveries were described at the Congress and virtually all of the attendees would agree with Olli Pietilainen, Ph.D., from the Institute for Molecular Medicine at the University of Finland, and presenter of his group’s identification of a gene deletion associated with schizophrenia and intellectual disability, who commented to BioQuick that this was “absolutely the best of the many psychiatric congresses I have attended.” In keeping with the extremely high quality of the entire meeting. the final day’s opening plenary session featured lively presentations and a panel discussion involving four of the world leaders in their specialties, along with interactive audience participation on two questions--(1) how the field could continue the process of genetic discovery, and (2) what are the next steps to achieve biological understanding and translation of discoveries into the clinic. The panelists included Dr, Insel; Mark Daly, Ph.D., Chief of the Analytical and Translational Genetics Unit at Massachusetts General Hospital (MGH) and Co-Director of the Program in Medical and Population Genetics at the Broad Institute; Professor Peter Donnelly, Director of the Wellcome Trust Centre for Human Genetics and Professor of Statistical Genetics at the University of Oxford; and Patrick Sullivan, M.D., Distinguished Professor of Genetics, Director of Psychiatric Genomics, Professor of Psychiatry, and Adjunct Professor of Epidemiology, all at the University of North Carolina-Chapel Hill. The discussion was introduced by Congress co-organizer Lynn DeLisi, M.D., Professor of Psychiatry at the Veterans Affairs Boston Healthcare System, and moderated by the other co-organizer, Jordan Smoller, M.D., Sc.D., Director of the Psychiatric and Neurodevelopment Unit of the Center for Human Genetic Research at MGH. Dr. Sullivan was the first speaker and he said that the technology to move forward rapidly exists now and that one of the field’s goals should be to assemble a parts list that would constitute a comprehensive list of alleles having any effect in the various psychiatric disorders. He emphasized that the goal should not be to explain “heritability,” but rather to gain biological insight. He stressed that the assembly of this parts list requires consortia that have the power to accumulate the large sample sizes that are generally needed to yield meaningful discoveries. He said that he was conflicted about the utility of whole genome sequencing, noting that it is hard to justify the cost versus the limited gain of insight so far into the biology of psychiatric diseases. Professor Donnelly spoke next and he started by posing the question “why genetics?” He gave three answers: to learn key biology, to improve risk prediction, and to stratify populations for the purpose of personalized medicine. He stressed the overriding importance of learning key biology. He noted that genome-wide association studies (GWASs) work and cited as an example the over 100 schizophrenia-associated SNPs found by this process and described by the Psychiatric Genetics Consortium (PGC). Enough SNPs can point to key pathways that provide potential targets for disease intervention. He described how disease-associated SNPs had pointed to the autophagy pathway in Crohn’s disease and to cell-mediated immunity in multiple sclerosis. He acknowledged that going from associations to biology is difficult for many reasons, including the fact that gene regulation is not well understood, it is often not known which tissue is affected or when, the skill sets necessary to accomplish the task are varied and not often present in one group, and finally, there are very few examples of success. At least 5 to 10 such examples are needed, he said. He suggested that for pharmacologic purposes, it is necessary to know which gene is involved and which direction of modulation (up or down) is associated with disease. He emphasized that GWAS-identified variants of small effect can still point to important drug targets. He noted that low-frequency variants of large effect are simply not plentiful. Very few have been discovered by sequence-based investigations. He argued that there is a need to combine such variants to generate the power necessary to attain statistical significance. This might be possible with loss-of-function variants because they all have the same ultimate effect, but would be difficult with missense variants. He closed by noting that a genotyping and imaging study of 100,000 individuals will be launched soon in the UK. Dr. Daly and Dr. Insel then addressed question 2 on translating laboratory advances into clinical action. Dr. Daly spoke first and mentioned the 50-year lag in the development of effective drugs for psychiatric diseases. He noted that genetic findings are a first step toward identifying drug targets that may lead to effective therapies, and he also highlighted the great recent progress in schizophrenia with over 100 distinct genomic regions being associated with the disease. He said the goal is identify compounds that will effect a change that will be effective in patients and in the cell type the change needs to happen in. He emphasized that the problem is truly complex and that GWAS hits do not easily lead us to specific genes. He said that the capability to find rare mutations is key to diagnostic and therapeutic progress. He noted that we need to gain insights into what to target and what not to target. He gave the example of a CARD9 variant that provides as strong protective effect in Crohn’s disease and he cited evidence for involvement of the FMRP (fragile mental retardation protein) pathway in severe autism. Dr. Insel then took to the podium and said that it was “simply extraordinary to realize where we are now” compared to where we were in 2005 when the Congress was last held in Boston. He noted in particular the vast increase in the number of samples now available for study that are powering and accelerating progress. He emphasized the importance of the non-coding regions of the genome, noting that approximately 80% of the genome is transcribed and yet only 1% codes for genes. He said that we now know that spontaneous mutations are common and that we should consider the genome as a “transducer of environmental exposures.” He noted the importance of realizing that the genome is not a stable sequence, but rather is variable and dynamic, that blood DNA may not reflect DNA in other tissues. In moving from genomics to the clinic, he said that we must move from common variants, rare variants, and epistasis to risk architecture, diagnostics, and the development of new therapeutic targets. We must move from statistical association to an understanding of functional biology, he said. He described new projects that are moving us in that direction, including the Genetic Tissue Expression (GTex) Project, and he extolled the potential of iPS cell studies with tools such as TALENs, CRISPR, and LITE. He indicated that taking a genotype to phenotype approach, rather than the reverse, might have much merit and he mentioned Dr. Stephen Friend’s interesting concept of “superheroes” and the focus on studying populations that, despite having risk alleles, are resistant to the disease. He noted that many psychiatric diseases seem to be diseases of early development and that gaining clearer views into very early development is critical. Projects along this line include BrainSpan ( Dr. Insel further noted that the fetal brain is completely different from the adult brain and can almost be considered a different organ. He also emphasized the significant potential for somatic mutations in the fetal brain which goes through a remarkable phase in which it goes from 1,000 cells to 10 billion cells in a relatively short time. “There is no organ that divides that fast,” Dr. Insel stated. He concluded by stressing the needs for data standardization, data integration, data sharing, and crowd sourcing. He noted successes in these areas by the PGC, ENIGMA, the NDAR, and the NITRC. A lively panel discussion followed and then panelists fielded questions from the audience to close this highly informative session. In a morning concurrent symposia on functional genomics, Melanie P. Leussis, Ph.D., Assistant Professor of Psychology at Emmanuel College in Boston, spoke about her work to determine where alterations in the ankyrin 3 (Ank3) gene, which have been associated with bipolar disorder exert, their effect. She was able to show that knockdown on Ank3 induced changes in the synapse which could be normalized with lithium. Her results suggest that Ank3 can impact the synapse, but Dr. Leussis noted that direct evidence that these alterations affect the disorder is still needed. Sevilla Detera-Wadleigh, Ph.D., Staff Scientist at the NIMH, gave a fascinating presentation of using the new iPS cell approach to develop an assay for studying drug effects on bipolar disease, for which there is currently no animal model. She used now-standard methods to convert patient-specific fibroblasts first to iPS cells and then to neural stem cells. She used the malaria drug mefloquine (Larium), which is now known to be associated with numerous psychiatric side effects including mania, psychosis, suicidal behavior, and violence, as a way to simulate a psychiatric-type impact on the neural stem cells and which did lead to cell death. Pretreatment of the neural stem cells with either of the two standard bipolar treatments (lithium or valproate) protected against the negative effects of mefloquine. Dr. Detera-Wadleigh believes this system can be used to screen potential drugs for the treatment of bipolar disorder. Olli Pietilainen, Ph.D., from Finland, presented a study of a Finnish population in which some individuals showed a deletion of a region of chromosome 22.q11.22 that was associated with both schizophrenia and intellectual disability in affected individuals. The deletion was shown to disrupt the gene TOP3, which is a component of cytosolic messenger ribonucleoproteins and forms a complex with FMRP1. The day continued with many other exciting reports and then the attendees headed home, eagerly looking forward to next year’s 2014 World Congress of Psychiatric Genetics, “Pathways to Therapy and Prevention,” which will take place in Copenhagen, Denmark, October 12-16. [World Congress of Psychiatric Genetics 2013] [2014 World Congress of Psychiatric Genetics] [by Michael D. O'Neill]