Mount Sinai Researchers Identify More Than 400 Genes Associated With Schizophrenia Development
In the largest study of its kind, involving more than 100,000 people, researchers at the Icahn School of Medicine at Mount Sinai have applied a novel machine learning method to identify 413 genetic associations with schizophrenia across 13 brain regions. As described in the February issue of Nature Genetics, examining gene expression at the tissue level allowed researchers to not only identify new genes associated with schizophrenia, but also pinpoint the areas of the brain in which abnormal expression might occur.
While affecting less than two percent of the global population, schizophrenia is one of the leading causes of disability worldwide. Despite its low prevalence, the disease has major public health and socioeconomic impact, primarily due to hospital readmission and treatment costs. What’s more, while it is widely believed that numerous genes contribute to increased risk of schizophrenia development, the exact genetic underpinnings are poorly understood.
Nonetheless, such ambiguity serves as fuel for many researchers, as the discovery of disease-associated genes is crucial for understanding the mechanisms involved in any illness. Accordingly, Mount Sinai researchers used genome-wide association study findings coupled with transcriptomic imputation to identify schizophrenia-associated disease with tissue-level resolution. Genome-wide association studies are an increasingly common study type in biomedical research; they look at differences at various points in a genetic code to see whether a variation is found more often in those with a particular trait, such as schizophrenia. Transcriptomic imputation is a novel machine learning technique that allows researchers to test associations between disease and gene expression in otherwise inaccessible tissues, such as those of the brain.
Studying 40,299 people with schizophrenia and 62,264 matched controls, the researchers used this sharp resolution to discover that genes associated with schizophrenia are expressed throughout development: some during specific stages of pregnancy, and others during adolescence or adulthood. The researchers also learned that different regions of the brain confer different risks for schizophrenia, with most associations coming from the dorsolateral prefrontal cortex.
“Our new predictor models gave us unprecedented power to study predicted gene expression in schizophrenia, and to identify new risk genes associated with the disease,” said Laura Huckins, PhD, Assistant Professor of Genetics and Genomic Sciences, and Psychiatry, at the Icahn School of Medicine at Mount Sinai. “In particular, it was fascinating to see schizophrenia risk genes expressed throughout development, including in early pregnancy.”
“By laying the groundwork for combining transcriptomic imputation and genome-wide association study findings, our hope is to not only elucidate gene development as it relates to schizophrenia, but also shape the future of research methods and design.”
This work was partially funded by grant U01MH109536. Full acknowledgements are available in our manuscript.
Dr. Huckins has recently been awarded an R01 (R01MH118278) to develop these transcriptomic imputation models further, and to apply these to elucidate the genetic architecture of schizophrenia, bipolar disorder, and anorexia nervosa.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Gynecology, Nephrology, Neurology/Neurosurgery, and Orthopedics in the 2019-2020 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology, Mount Sinai St. Lukes and Mount Sinai West are ranked 23rd nationally for Nephrology and 25th for Diabetes/Endocrinology, and Mount Sinai South Nassau is ranked 35th nationally for Urology. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and Mount Sinai South Nassau are ranked regionally.