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Autism Gene Studies, PsychChip Development, and Substance Abuse Genetics Featured in Saturday Session of World Congress of Psychiatric Genetics in Boston

Day 3 (Saturday, October 19) of the XXIst World Congress of Psychiatric Genetics, taking place in Boston, began with a spectacular plenary session featuring two world-class scientists as speakers—Christopher A. Walsh, M.D., Ph.D., Bullard Professor of Psychiatry at Harvard Medical School, Chief of the Division of Genetics at Children’s Hospital Boston, and Howard Hughes Medical Institute (HHMI) Investigator, and Kevin Eggan, Ph.D., Associate Professor in the Harvard University Department of Stem Cell Biology and Regenerative Medicine, an HHMI Investigator, and an acknowledged world leader in stem cell biology. Dr. Walsh described recent results in the world-wide and genome-wide hunt for inherited genes for autism spectrum disorders (ASDs), with an emphasis on studies looking for recessive genes in consanguineous families having members with ASDs. Dr. Eggan detailed the technical difficulties in working to create pure specific brain cell type populations from human embryonic stem cells, induced pluripotent stem (iPS) cells, or transfer factor treatment of fibroblasts. While not minimizing the problems, he described progress along the road to this goal and indicated the enormous potential that success in the technical challenges will have in the study of disease mechanisms, particularly in psychiatric disorders. Dr.Walsh said that autism has an incidence of 1-2 per 1,000, while ASDs have an incidence of 6 per 1,000. ASDs have comorbidities of 50-60% with cognitive impairment, 10-25% with regression, and 30% with seizures/epilepsy suggesting that they are developmental disorders associated with abnormal brain development, he added. ASDs are highly heritable, Dr. Walsh said, and yet genetic causes have been identified for only a small fraction of the totality of the disorders. These genetic causes include de novo point mutations that have recently been identified and associated with an estimate 5-15% of ASDs. Many ASD-associated mutations are de novo, Dr. Walsh noted. Identified genetic associations for these disorders also include copy number variations (CNVs). But still, the genetic bases of the vast majority of ASDs remain a mystery. Given the high heritability of the disorders, Dr. Walsh reasoned that it might be fruitful to look for associated recessive mutations. The odds of finding such mutations is highly increased by examining consanguineous families that are by the rules of genetics enriched in recessive mutations and have a higher incidence of recessive disease than non-consanguineous families. In screening such families having members with an ASD for ASD-associated genes, Dr. Walsh successfully identified a number of such genes, including Cc21A (previously identified in other studies), SYNE1 (previously identified in a study of de novo mutations and a complex locus with multiple splice forms and interactions with CPG2, a candidate plasticity gene associated with spine shape and regulation of spine size in spiny neurons), and a homozygous I1308F point mutation in the AMT (amino methyl transferase gene). This latter mutation has the mildest effect of any allele every associated with ASDs, Dr. Walsh noted. He went on to say that an alternative, faster way to identify recessive mutations in families not known to be consanguineous is to look for excessive homozygosity in affected families by whole exome sequencing. Using this approach, he and colleagues identified UBE3B (previously related to Angelman syndrome) as a gene in which null mutations caused severe intellectual deficiency (ID). Dr. Walsh also mentioned that an excess of CNVs might suggest that this type of mutation might be causative. He concluded by stating that there is tremendous locus and allelic heterogeneity in ASDs and that partial loss of function may be the rule and may reinforce the complex nature of ASDs. Levels of gene expression may be key to disease severity. Dr. Eggan followed with his discussion of the huge potential of stem cell approaches to studying disease mechanism, especially of psychiatric diseases, while also describing the sobering reality of the technical difficulties of establishing pure populations of the particular cell sub-type of interest. He noted the need for additional biomarkers that can be used to identify and segregate different cell types. As an indication of the great potential of stem cell-based approaches, he mentioned an example where work had been done to genetically repair one of the mutations of SOD1 associated with ALS (Lou Gehrig’s disease) in a stem cell-derived model of ALS. Later, in a concurrent symposium session, Daniel Howrigan, Ph.D., a post-doctoral fellow at Massachusetts General Hospital (MGH), described pathway and cross-disorder analysis and also outlined progress on the PsychChip, a custom array being developed by Illumina in collaboration with the Psychiatric Genetics Consortium (PGC), and intended to be made commercially available by the end of 2013. The PsychChip is designed to target extant association among both common and rare variant approaches in psychiatric genetics, with fine-mapping of known associations and increased coverage of suggestive regions. Despite the targeted nature of the PsychChip, imputation analysis of the base HumanCore content of the chip (~250K SNPs) is able to capture 93% of the common variation (minor allele frequency greater than 1%) to that of the more extensive OmniExpress chip (~730K SNPs), meaning that much of the common variation genome-wide is still captured by the targeted array. The day closed with an electrifying plenary presentation on substance abuse studies by Yasmin Hurd, Ph.D., Professor of Psychiatry, Professor of Neuroscience, and Professor of Pharmacology and Systems Therapeutics at Mount Sinai Hospital in New York. Dr. Hurd spoke about her work that many told her was not possible to be done, namely studying gene expression in post-mortem brains from deceased victims of heroin overdoses. In particular, she was able to show that there is a significant impairment in the gene ELK1 which codes for a transfer activator that targets regulatory genes in the brain’s nucleus acumbens. Dr. Hurd was previously, in 2002, able to show that prodynorphin (proenkephalin B) amygdala impairment is associated with mood disorder. Prodynorphin is an opioid polypeptide involved in chemical signal transduction and cell communication. She has more recently shown that SNVs in prodynorphin expression in a specific brain sub-region are found in victimsof heroin abuse. She also showed that post-mortem brains could be used in molecular studies for epigenetic marks. Dr. Hurd is hopeful that such advances will ultimately lead to a better understanding of the complexities of substance abuse and guide the development of effective interventions. The World Congress of Psychiatric Genetics will run through Monday, October 21, 2013. [World Congress of Psychiatric Genetics 2013] [by Michael D. O'Neill]