Integrative analyses highlight functional regulatory variants associated with neuropsychiatric diseases

Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, bor...

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Bibliographic Details
Published in:	Nature genetics Vol. 55; no. 11; pp. 1876 - 1891
Main Authors:	Guo, Margaret G., Reynolds, David L., Ang, Cheen E., Liu, Yingfei, Zhao, Yang, Donohue, Laura K. H., Siprashvili, Zurab, Yang, Xue, Yoo, Yongjin, Mondal, Smarajit, Hong, Audrey, Kain, Jessica, Meservey, Lindsey, Fabo, Tania, Elfaki, Ibtihal, Kellman, Laura N., Abell, Nathan S., Pershad, Yash, Bayat, Vafa, Etminani, Payam, Holodniy, Mark, Geschwind, Daniel H., Montgomery, Stephen B., Duncan, Laramie E., Urban, Alexander E., Altman, Russ B., Wernig, Marius, Khavari, Paul A.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-11-2023 Nature Publishing Group
Subjects:	38/91 42/70 631/208/191 692/699/476 Agriculture Animal Genetics and Genomics Anxiety Anxiety disorders Attention Deficit Disorder with Hyperactivity - genetics Attention deficit hyperactivity disorder Autism Autism Spectrum Disorder - genetics Binomial distribution Biomedical and Life Sciences Biomedicine Bipolar disorder Bipolar Disorder - genetics Borderline personality disorder Cancer Research Chromatin Depressive Disorder, Major - genetics Disease Gene expression Gene Function Gene mapping Generalized anxiety disorder Genes Genetic modification Genome editing Health risks Heritability Human Genetics Humans Magnesium Mental disorders Network analysis Neuroses Nucleotides Obsessive compulsive disorder Obsessive-Compulsive Disorder - genetics Obsessive-Compulsive Disorder - psychology Panic attacks Post traumatic stress disorder Psychological stress Schizophrenia Schizophrenia - genetics Signs and symptoms Transcriptomics
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Summary:	Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types. Expression-gene mapping, network analyses and chromatin looping nominated candidate disease-relevant target genes modulated by these daSNVs. Follow-up integration of daSNV gene editing with clinical cohort analyses suggested that magnesium transport dysfunction may increase neuropsychiatric disease risk and indicated that common genetic pathomechanisms may mediate specific symptoms that are shared across multiple neuropsychiatric diseases. Epigenomic profiling and massively parallel reporter assays identify 892 functional differentially-active single-nucleotide variants (daSNVs) linked to ten neuropsychiatric diseases. CRISPRi and gene editing approaches show magnesium transport dysfunction as a common genetic pathomechanism.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 M.G.G., M.W., and P.A.K. conceptualized the project. M.G.G., D.L.R, C.E.A., Y.L., Y.Y., Y.Z., L.N.K., L.K.H.D., X.Y., L.M., T.F., I.E., A.H., Z.S., Y.P., V.B., and N.A. performed experiments and analyzed the data. M.G.G., P.A.K., M.W., R.B.A., L.E.D., A.E.U., S.B.M., P.E., M.H., and D.H.G. guided methodology development, experiments, and data analysis. M.G.G. and P.AK. wrote the manuscript with input from all authors. Author contributions
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-023-01533-5