Biological Insights from Schizophrenia-associated Loci in Ancestral Populations.

Autor: Bigdeli TB; VA New York Harbor Healthcare System, Brooklyn, NY.; Department of Psychiatry and Behavioral Sciences and SUNY Downstate Health Sciences University, Brooklyn, NY.; Institute for Genomics in Health (IGH), SUNY Downstate Health Sciences University, Brooklyn, NY.; Department of Epidemiology and Biostatistics, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY., Chatzinakos C; Department of Psychiatry and Behavioral Sciences and SUNY Downstate Health Sciences University, Brooklyn, NY.; Institute for Genomics in Health (IGH), SUNY Downstate Health Sciences University, Brooklyn, NY., Bendl J; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, NY.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY., Barr PB; VA New York Harbor Healthcare System, Brooklyn, NY.; Department of Psychiatry and Behavioral Sciences and SUNY Downstate Health Sciences University, Brooklyn, NY.; Institute for Genomics in Health (IGH), SUNY Downstate Health Sciences University, Brooklyn, NY.; Department of Epidemiology and Biostatistics, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY., Venkatesh S; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, NY.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY.; Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, NY, USA., Gorman BR; Massachusetts Area Veterans Epidemiology, Research, and Information Center (MAVERIC), Jamaica Plain, MA., Clarence T; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, NY.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY., Genovese G; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA.; Harvard Medical School, Boston, MA., Iyegbe CO; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY., Peterson RE; VA New York Harbor Healthcare System, Brooklyn, NY.; Department of Psychiatry and Behavioral Sciences and SUNY Downstate Health Sciences University, Brooklyn, NY.; Institute for Genomics in Health (IGH), SUNY Downstate Health Sciences University, Brooklyn, NY., Kolokotronis SO; Institute for Genomics in Health (IGH), SUNY Downstate Health Sciences University, Brooklyn, NY.; Department of Epidemiology and Biostatistics, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY.; Division of Infectious Diseases, Department of Medicine, College of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY.; Department of Cell Biology, College of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY., Burstein D; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, NY.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY.; Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, NY, USA.; Mental Illness Research, Education and Clinical Center VISN2, James J. Peters VA Medical Center, Bronx, NY, USA., Meyers JL; Department of Psychiatry and Behavioral Sciences and SUNY Downstate Health Sciences University, Brooklyn, NY.; Institute for Genomics in Health (IGH), SUNY Downstate Health Sciences University, Brooklyn, NY.; Department of Epidemiology and Biostatistics, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY., Li Y; Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, CT.; Yale University School of Medicine, New Haven, CT., Rajeevan N; Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, CT.; Yale University School of Medicine, New Haven, CT., Sayward F; Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, CT.; Yale University School of Medicine, New Haven, CT., Cheung KH; Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, CT.; Yale University School of Medicine, New Haven, CT., DeLisi LE; Department of Psychiatry, Cambridge Health Alliance, Cambridge, MA., Kosten TR; Michael E. DeBakey VA Medical Center, Houston, TX.; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX., Zhao H; Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, CT.; Yale University School of Medicine, New Haven, CT., Achtyes E; Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI., Buckley P; University of Tennessee Health Science Center in Memphis, TN., Malaspina D; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY., Lehrer D; Department of Psychiatry, Wright State University, Dayton, OH., Rapaport MH; Huntsman Mental Health Institute, Department of Psychiatry, University of Utah, Salt Lake City, UT., Braff DL; Department of Psychiatry, University of California, San Diego, CA.; VA San Diego Healthcare System, San Diego, CA., Pato MT; Department of Psychiatry, Robert Wood Johnson Medical School, New Brunswick, NJ., Fanous AH; Department of Psychiatry, University of Arizona College of Medicine-Phoenix, Phoenix, AZ.; Department of Psychiatry, VA Phoenix Healthcare System, Phoenix, AZ., Pato CN; Department of Psychiatry, Robert Wood Johnson Medical School, New Brunswick, NJ., Huang GD; Office of Research and Development, Veterans Health Administration, Washington, DC., Muralidhar S; Office of Research and Development, Veterans Health Administration, Washington, DC., Michael Gaziano J; Massachusetts Area Veterans Epidemiology, Research, and Information Center (MAVERIC), Jamaica Plain, MA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA., Pyarajan S; Massachusetts Area Veterans Epidemiology, Research, and Information Center (MAVERIC), Jamaica Plain, MA., Girdhar K; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, NY.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY., Lee D; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, NY.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY., Hoffman GE; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, NY.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY.; Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, NY, USA.; Mental Illness Research, Education and Clinical Center VISN2, James J. Peters VA Medical Center, Bronx, NY, USA., Aslan M; Clinical Epidemiology Research Center (CERC), VA Connecticut Healthcare System, West Haven, CT.; Yale University School of Medicine, New Haven, CT., Fullard JF; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, NY.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY., Voloudakis G; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, NY.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY.; Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, NY, USA.; Mental Illness Research, Education and Clinical Center VISN2, James J. Peters VA Medical Center, Bronx, NY, USA., Harvey PD; Bruce W. Carter Miami Veterans Affairs (VA) Medical Center, Miami, FL.; University of Miami School of Medicine, Miami, FL., Roussos P; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, NY.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, NY.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY.; Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, NY, USA.; Mental Illness Research, Education and Clinical Center VISN2, James J. Peters VA Medical Center, Bronx, NY, USA.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2024 Aug 28. Date of Electronic Publication: 2024 Aug 28.
DOI: 10.1101/2024.08.27.24312631
Abstrakt: Large-scale genome-wide association studies of schizophrenia have uncovered hundreds of associated loci but with extremely limited representation of African diaspora populations. We surveyed electronic health records of 200,000 individuals of African ancestry in the Million Veteran and All of Us Research Programs, and, coupled with genotype-level data from four case-control studies, realized a combined sample size of 13,012 affected and 54,266 unaffected persons. Three genome-wide significant signals - near PLXNA4 , PMAIP1 , and TRPA1 - are the first to be independently identified in populations of predominantly African ancestry. Joint analyses of African, European, and East Asian ancestries across 86,981 cases and 303,771 controls, yielded 376 distinct autosomal loci, which were refined to 708 putatively causal variants via multi-ancestry fine-mapping. Utilizing single-cell functional genomic data from human brain tissue and two complementary approaches, transcriptome-wide association studies and enhancer-promoter contact mapping, we identified a consensus set of 94 genes across ancestries and pinpointed the specific cell types in which they act. We identified reproducible associations of schizophrenia polygenic risk scores with schizophrenia diagnoses and a range of other mental and physical health problems. Our study addresses a longstanding gap in the generalizability of research findings for schizophrenia across ancestral populations, underlining shared biological underpinnings of schizophrenia across global populations in the presence of broadly divergent risk allele frequencies.
Databáze: MEDLINE