Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

• 成果类型: Article
• 署名作者: Wen, Cindy; Margolis, Michael; Dai, Rujia; Zhang, Pan; Przytycki, Pawel F.; Vo, Daniel D.; Bhattacharya, Arjun; Matoba, Nana; Tang, Miao; Jiao, Chuan; Kim, Minsoo; Tsai, Ellen; Hoh, Celine; Ayguen, Nil; Walker, Rebecca L.; Chatzinakos, Christos; Clarke, Declan; Pratt, Henry; Peters, Mette A.; Gerstein, Mark; Daskalakis, Nikolaos P.; Weng, Zhiping; Jaffe, Andrew E.; Kleinman, Joel E.; Hyde, Thomas M.; Weinberger, Daniel R.; Bray, Nicholas J.; Sestan, Nenad; Geschwind, Daniel H.; Roeder, Kathryn; Gusev, Alexander; Pasaniuc, Bogdan; Stein, Jason L.; Love, Michael I.; Pollard, Katherine S.; Liu, Chunyu; Gandal, Michael J.
• 署名单位: University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; State University of New York (SUNY) System; SUNY Upstate Medical University; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; McLean Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Yale University; University of Massachusetts System; University of Massachusetts Worcester; Yale University; Yale University; Yale University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; Johns Hopkins University; Cardiff University; Yale University; Yale University; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; Carnegie Mellon University; Carnegie Mellon University; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of California System; University of California San Francisco; Chan Zuckerberg Initiative (CZI); Central South University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9797
• DOI: 10.1126/science.adh0829
• 发表日期: 2024-05-24
• 关键词: transcriptome; mechanisms; association; expression; variants; colocalization; quantification; schizophrenia; disorders; networks

摘要

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.