At the MOHB this morning, Pamela Sklar of Massachusetts General Hospital presented data from the Psychiatric Genome-wide Association Study Consortium (PGC). One of its projects on bipolar disorder looked at the genomes of more than 7,000 cases of the disorder against 10,000 or so matched controls trying to find differences that correlate with an increased risk for the disease. What they’ve found was not different from what many genome-wide association studies have found. Four strongly associated genetic regions popped up in their study, but the individual amount of risk for the disorder that they contribute is quite low. For this reason and because many of the variants they find associated with bipolar and other psychiatric disorders aren’t necessarily gene mutations (many have been genetic duplications and deletions), says Sklar, it’s been hard to convince biologists with experience in model systems to delve in and look at how the gene variants might be contributing.
Nevertheless, working with a collaborator with expertise in fly genetics, Sklar presented data on the function of three genes that might be linked to bipolar disorder. They manipulated versions of the genes in Drosophila melanogaster and observed the formation of synapses between neuron and muscle. At these synapses the long neuron cells form little bulbous protrusions known as boutons and these form in well documented ways in Drosophila larvae. When the researchers knocked out expression of their suspect genes in the flies, the neurons formed some normal looking boutons but also some “ghost” boutons that appeared to be immature non-functioning synapses. The results will require more follow up, but are interesting. The GWAS and genome sequencing studies that Sklar and others are doing are producing “real risk genes in schizophrenia and bipolar disorder,” she said to an audience filled with researcher who work primarily on model systems. “They need people like you to study them.”