{"id":13191,"date":"2023-09-18T15:26:39","date_gmt":"2023-09-18T19:26:39","guid":{"rendered":"https:\/\/www.med.unc.edu\/genetics\/?p=13191"},"modified":"2023-09-18T15:26:39","modified_gmt":"2023-09-18T19:26:39","slug":"scientists-take-next-big-step-in-understanding-genetics-of-schizophrenia","status":"publish","type":"post","link":"https:\/\/www.med.unc.edu\/genetics\/scientists-take-next-big-step-in-understanding-genetics-of-schizophrenia\/","title":{"rendered":"Scientists Take Next Big Step in Understanding Genetics of Schizophrenia"},"content":{"rendered":"

Led by Hyejung Won, PhD, UNC School of Medicine researchers and colleagues developed a new research model to glean a deeper understanding of the genetic variants implicated in schizophrenia, including how genes are turned on or off to affect health and disease.<\/p>\n

\n
\"Hyejung<\/a>
Hyejung Won, PhD<\/figcaption><\/figure>\n

CHAPEL HILL, NC \u2013 Genetically speaking, we are individuals different from each other because of slight variations in our DNA sequences \u2013 so-called genetic variants \u2013 some of which have dramatic effects we can see and comprehend, from the color of our eyes to our risk for developing schizophrenia \u2013 a debilitating psychiatric condition affecting many millions worldwide. For several years, scientists have studied the entire genomes of thousands of people \u2013 called genome-wide association studies, or GWAS \u2013 to find approximately 5,000 genetic variants associated with schizophrenia.<\/p>\n

Now, UNC School of Medicine scientists and colleagues are figuring out which of these variants have a causal effect in the development of schizophrenia. They are finding that some of the genetic variants regulate or alter the expression of genes involved in the condition.<\/p>\n

Published in the journal\u00a0Cell Genomics<\/em><\/a>, this research marks a big step forward in our understanding of the genetic basis of schizophrenia.<\/p>\n

\u201cOur findings not only provide insights into the intricate regulatory landscape of genes, but also propose a groundbreaking approach to decoding the cumulative effect of genetic variants on gene regulation in individuals with schizophrenia,\u201d said senior author\u00a0Hyejung Won, PhD<\/a>, associate professor of genetics at the UNC School of Medicine and member of the UNC Neuroscience Center. \u201cThis comprehension could potentially pave a path for more precise interventions and therapies in the future. Right now, therapeutic options are limited, and some people do not respond to drugs available.\u201d<\/p>\n

\"\"
Sool Lee<\/figcaption><\/figure>\n

For this study, Won and first authors Jessica McAfee and Sool Lee, both UNC-Chapel Hill graduate students, led a team of researchers from UCLA, Harvard, the University of Michigan, and Human Technopole in Italy to explore the genetic variants already linked to the risk of schizophrenia through GWAS research. Their goal was to figure out a way to tease apart meaningless variants from those with potential for biological activity important for developing schizophrenia. This isn\u2019t easy for a few reasons, one of which is that genetic variants are often inherited together from parents. So, right next to each other could be two genetic variants associated with the condition \u2013 one might be important for gene expression that plays a major role in the condition, but the other variant might not have any role in the condition.<\/p>\n

To tackle this problem, the researchers used a special technique called a massively parallel reporter assay (MPRA) \u2013 essentially a genetic sequencing technique that can parse which variants trigger gene expression and which ones don\u2019t. To use this method, the researchers introduced the 5,000 variants into human brain cells in a dish, cells that are essential for early brain development. These variants may or may not cause the expression of their downstream gene and genetic barcode.\u00a0 The barcode, a 20bp DNA sequence, is unique to each variant. This is what the group uses to distinguish the variant sequences. The MPRA revealed 439 genetic variations with actual biological effects, meaning they can alter expression of gene.<\/p>\n

\"\"
Jessica McAfee<\/figcaption><\/figure>\n

\u201cTraditionally, scientists have used other epigenetic data, such as transcription factor binding and biochemically defined enhancers, to identify variants with biological effects,\u201d Won said.
\n\u201cHowever, these conventional methods failed to predict a large portion of variants we identified to have biological effects. Our work points to a wealth of unexplored variants with biological effects.\u201d<\/p>\n

To understand how these variants work together to influence gene activity, Won and colleagues developed a new model that combines data from MPRA with chromatin architecture of brain cells \u2013 that is, the genetic information important for how brain cell DNA is organized. By doing this, the researchers could connect these 439 variants to how genes are turned on or off.<\/p>\n

\u201cSchizophrenia is a complex condition that is highly heritable,\u201d Won said. \u201cTo find these 439 potentially causal variants is a big step, but we still have a lot of work ahead to figure out the complicated genetic architecture that leads an individual to develop this condition. With that information in hand, we could begin to understand the biological mechanism underlying this complex disorder, which may eventually lead to targeted therapies.\u201d<\/p>\n

This research was funded by the National Institutes of Health and the Brain and Behavior Research Foundation.<\/em><\/p>\n

This article originally appeared in the UNC Health Newsroom<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"

Led by Hyejung Won, PhD, UNC School of Medicine researchers and colleagues developed a new research model to glean a deeper understanding of the genetic variants implicated in schizophrenia, including how genes are turned on or off to affect health and disease.<\/p>\n","protected":false},"author":28418,"featured_media":13192,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":"","_links_to":"","_links_to_target":""},"categories":[2],"tags":[128,203,42],"class_list":["post-13191","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-news","tag-lee","tag-mcafee","tag-won","odd"],"acf":[],"yoast_head":"\nScientists Take Next Big Step in Understanding Genetics of Schizophrenia | Department of Genetics<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" 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