Dynamic stress- and inflammatory-based regulation of psychiatric risk loci in human neurons.

Autor:	Retallick-Townsley KG; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Lee S; Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT 06511.; Department of Genetics, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT 06511., Cartwright S; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Cohen S; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029., Sen A; Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT 06511.; Department of Genetics, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT 06511., Jia M; Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT 06511.; Department of Genetics, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT 06511., Young H; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Dobbyn L; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Deans M; Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT 06511.; Department of Genetics, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT 06511., Fernandez-Garcia M; Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT 06511.; Department of Genetics, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT 06511., Huckins LM; Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT 06511., Brennand KJ; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, New Haven, CT 06511.; Department of Genetics, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT 06511.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 09. Date of Electronic Publication: 2024 Jul 09.
DOI:	10.1101/2024.07.09.602755
Abstrakt:	The prenatal environment can alter neurodevelopmental and clinical trajectories, markedly increasing risk for psychiatric disorders in childhood and adolescence. To understand if and how fetal exposures to stress and inflammation exacerbate manifestation of genetic risk for complex brain disorders, we report a large-scale context-dependent massively parallel reporter assay (MPRA) in human neurons designed to catalogue genotype x environment (GxE) interactions. Across 240 genome-wide association study (GWAS) loci linked to ten brain traits/disorders, the impact of hydrocortisone, interleukin 6, and interferon alpha on transcriptional activity is empirically evaluated in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons. Of ~3,500 candidate regulatory risk elements (CREs), 11% of variants are active at baseline, whereas cue-specific CRE regulatory activity range from a high of 23% (hydrocortisone) to a low of 6% (IL-6). Cue-specific regulatory activity is driven, at least in part, by differences in transcription factor binding activity, the gene targets of which show unique enrichments for brain disorders as well as co-morbid metabolic and immune syndromes. The dynamic nature of genetic regulation informs the influence of environmental factors, reveals a mechanism underlying pleiotropy and variable penetrance, and identifies specific risk variants that confer greater disorder susceptibility after exposure to stress or inflammation. Understanding neurodevelopmental GxE interactions will inform mental health trajectories and uncover novel targets for therapeutic intervention. Competing Interests: CONFLICT OF INTEREST STATEMENT K.J.B is a scientific advisor to Rumi Scientific Inc. and Neuro Pharmaka Inc. All other authors declare no conflicts of interest
Databáze:	MEDLINE
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