{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:20Z","timestamp":1792790360009,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,17]]},"group-title":"Genomics","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Human Genome Research Institute","award":["UM1-HG012053"],"award-info":[{"award-number":["UM1-HG012053"]}],"id":[{"id":"https:\/\/ror.org\/00baak391","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Human Genome Research Institute","award":["RM1-HG011123"],"award-info":[{"award-number":["RM1-HG011123"]}],"id":[{"id":"https:\/\/ror.org\/00baak391","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute of Mental Health","award":["R01-MH125236"],"award-info":[{"award-number":["R01-MH125236"]}]},{"name":"National Institute of Mental Health","award":["F31MH138142"],"award-info":[{"award-number":["F31MH138142"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Schizophrenia (SCZ) is a highly heritable complex disorder influenced by coding and noncoding genetic variation. Its genetic causes, particularly those involving noncoding variation, are largely unknown. High-throughput CRISPR screens enable dissection of disease-associated loci and identification of noncoding regulatory elements and variants that modulate gene expression. We screened SCZ GWAS loci linked to genes that are also associated in whole-exome sequencing studies to identify regulatory elements and variants impacting expression of disease-relevant genes. We used CRISPRi paired with HCR-FlowFISH to epigenetically silence 333 putative regulatory elements and measure the downstream effects on gene expression of causal SCZ genes,\n                  <jats:italic>FAM120A<\/jats:italic>\n                  ,\n                  <jats:italic>SV2A<\/jats:italic>\n                  , and\n                  <jats:italic>STAG1<\/jats:italic>\n                  , in iPSCs and iPSC-derived neurons (iNeurons). We identified 78 regulatory elements that significantly alter expression of a SCZ gene, including noncoding enhancers\/silencers as well as promoters of genes and lncRNAs. Pooled prime editing screens interrogated noncoding variant influence on gene expression for SCZ-associated variants and uncharacterized common variants from diverse population studies. We find that a common variant in the promoter of\n                  <jats:italic>SV2A<\/jats:italic>\n                  , rs112851681:A&gt;G (MAF = 3.56%, 1000 Genomes) enhances transcriptional activity in iPSCs and iNeurons. These findings show distinct noncoding mechanisms that map within GWAS signals, and provide a path forward for interrogating noncoding regulatory elements and variants in disease loci.\n                <\/jats:p>","DOI":"10.64898\/2026.09.03.749158","type":"posted-content","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:20:18Z","timestamp":1789647618000},"source":"Crossref","is-referenced-by-count":0,"title":["Interrogation of noncoding schizophrenia risk variants using CRISPR-based functional genomics"],"prefix":"10.64898","author":[{"given":"Marisa C.","family":"Hamilton","sequence":"first","affiliation":[{"name":"University Program in Genetics and Genomics, Duke University Medical Center, Durham, NC, USA"},{"name":"Center for Advanced Genomic Technologies, Duke University, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia W.","family":"Riley","sequence":"additional","affiliation":[{"name":"Center for Advanced Genomic 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S.","family":"Allen","sequence":"additional","affiliation":[{"name":"University Program in Genetics and Genomics, Duke University Medical Center, Durham, NC, USA"},{"name":"Department of Biostatistics & Bioinformatics, Duke University, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Shen","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard I.","family":"Sherwood","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael I.","family":"Love","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 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