The quest to understand the brain, and its role in behavior and disease, is no small task. Over the past decade, labs like Nicholas Katsanis’ at Duke University have shown that genetic and genomic approaches can be extremely beneficial to our understanding of neurobiology. He organized a short course for the Neuroscience 2015 conference in Chicago to help researchers gain a better understanding of genomic applications.
The first speaker was Shamil Sunyaev, a computational genomics researchers at the Genetics Division of Brigham & Women’s Hospital and Harvard Medical School in Boston. He started his presentation, Computational Approaches to Annotating Neurodevelopment and Neurodegenerative Disease Genomes, with a discussion of simple and complex phenotypes—and how, historically, researchers have tried to study heritability of disease states in animal models and in human studies. He said that advances in technology, particularly the advent of next-generation sequencing (NGS) techniques, are finally allowing researchers to identify polymorphic markers, map those markers, and identify causal mutations simultaneously. New discoveries are important, Sunyaev argued, but there are still many unknowns, and discoveries should be bolstered by supporting research.
Next to the podium was Benjamin Neale, a genetics researcher with a focus on psychological biology at the Broad Institute. He started his presentation, Leveraging Genome Data in Psychiatric Illness, with an emphasis on the idea of continuous variability in population statistics. He stated that with diseases like schizophrenia or autism (or any complex trait for that matter) there is never just one cause. The idea of Mendelian genetics may be quite attractive, however, it just doesn’t play for most of the things we want to study. It’s like height, he argued. “There’s no one gene for 5 feet 10 inches. Your height is not due to one single genetic effect but rather many that conspire together to give this normal distribution to the population. Heritability is a calculation, not an individual—if there is a genetic effect, and biological processes that a gene is acting upon, it is contributing to the variability we see within the population.”
Exploring genetic contributions to disease is a way of taking an unbiased approach to one’s research. Such studies help identify new leads to better understand the biology behind psychiatric disorders. He discussed the genetic study of schizophrenia, from early genome-wide association studies to more advanced inquiries using NGS technologies today. Group research consortia have been invaluable to understanding of this disease; by increasing the sample size, researchers have discovered several new leads. Dr. Neale cautions there are still thousands of effects still yet to be identified—and each of those effects are going to be quite small. “The ability to assay genetic variation in a high-throughput way is great, but we need to work on the biology to figure out what’s really going on here,” he says. “There is new neurobiology to be found through these studies. We need to assay and interrogate these new leads to really understand what is happening.”
To that end, Dr. Neale was very optimistic about the 1000 Genomes Project, which he hopes will open up the possibility for different paradigms and methods to look at newly arising de novo mutations.
The short course’s third speaker, Steven McCarroll, is a geneticist at Harvard Medical School. In his talk, The Role of MHC in Schizophrenia, he introduced a technique called Drop-Seq to study the genetic alterations between different cell types present in complex tissues like the brain. The end result of Drop-Seq is RNA libraries from the different isolated cell types, which his lab has validated with retinal studies.
Using Drop-Seq, Dr. McCarroll and his lab are uncovering new biological insight regarding schizophrenia. A SNP in a complement gene called C4 had been associated with the disorder, but it did not correspond with any known variant. He and his collaborators used molecular assays to detect different C4 gene types and discovered four common variants across those families, and then measured expression in post-mortem brain samples. They found schizophrenia risk was significantly increased with the C4A variant. Further work showed this protein is a part of the complement cascade that tags cells and debris for elimination. This evidence suggests that this variant may alter the protein’s behavior during critical periods of synaptic pruning, giving rise to the disorder.
“This is only one story, of course. But I hope it gives encouragement, even with these complex, polygenic illnesses, that these techniques can help seed new hypotheses about what might be going on,” he says. “And offer new possibilities for treatment.”
Albert La Spada, from the University of California San Diego’s Institute for Genomic Medicine, then gave his own example of how careful, mechanistic study of a genetic variant can lead to novel therapies. His work on Huntington’s Disease has brought a potential therapy to clinical trial. This drug, KD3010, FDA-approved for diabetes and metabolic disease, may help stop the disease’s debilitating progression. Dr. La Spada emphasized that his work is not yet finished—and emphasized that careful phenotyping is a huge barrier to genomic success with brain disorders.
“If you are studying a disease process, you really need to sit down to the task of being a systems biologist. It’s going to require the application of a variety of approaches to move forward,” Dr. La Spada said. “Second, whether you realize it or not, genetics is there along with you at every step, allowing you to define a disorder, redefine it, and then deconstruct it so you can hopefully develop a therapy.”
Alison Goate, a genetics researcher at the Icahn School of Medicine at Mount Sinai, then took the stage to discuss her work on Genetics of Alzheimer’s Disease. Like her colleagues before her, she championed a systems approach, stating those avenues of approach have yielded the best results in the Alzheimer’s field. To date, work in genetics supports the amyloid-beta hypothesis, or the theory that the disease’s terrible symptoms are caused by amyloid-beta plaques that build up in the brain. But new research is suggesting that there may be different types of processes, and different types of cells, that go awry and lead to those plaques. New studies are implicating genes beyond amyloid precursor genes and presenilin 1, including SPI1 and TREM2. What’s most interesting about some of these genes, Dr. Goate argues, is that they may not be Alzheimer’s-specific.
“These genes, when we look at what they do, may influence the risk for neurodegenerative disease in general—they are linked to amyotrophic lateral sclerosis (ALS), fronto-temporal dementia, and Parkinson’s disease,” she said. “So, what we’re learning is that their role may not be specific to clearing amyloid beta but perhaps to clearance of debris in general.”
Goate also gave a nod to the National Institute of Aging’s Alzheimer’s Disease Sequencing Project.This project may identify new genes implicated in the condition, both of a problematic and of a protective nature. “There’s a lot to be learned from protective factors,” she says. “If we can find these genes that are protective, there may be a way to mimic that protection when we design drugs.”
Nicholas Katsanis closed the day with a presentation on copy number variants in neuropsychiatric disorders. He cautioned that true genetic penetrance is a bit of a “unicorn”, and that researchers may not know how to measure if it actually exists. He hopes to see scientists spend more time on the study of protective alleles, and emphasized the need to get to the point where we can use genetic findings to help us treat disease. Geneticists and neuroscientists need to work together to truly understand the effects different alleles have disease phenotypes. “Medical resequencing is not enough. We have to look at functional assessments,” Dr. Katsanis noted. “There are no white hats and black hats here. Alleles exert their effects in a context-dependent way. So we have to do the work to figure it all out.”