Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Retallick-Townsley KG

PROVIDER: S-EPMC11257632 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Dynamic neuro-immune regulation of psychiatric risk loci in human neurons.

Retallick-Townsley Kayla G KG Lee Seoyeon S Williams Sarah E SE Cartwright Sam S Cohen Sophie S Sen Annabel A Jia Meng M Young Hannah H Dobbyn Lee L Deans Michael M Fernandez-Garcia Meilin M Huckins Laura M LM Brennand Kristen J KJ

bioRxiv : the preprint server for biology 20250825

The prenatal environment influences neurodevelopment and subsequent clinical trajectories for psychiatric outcomes in childhood and adolescence. Yet it remains unclear if the impact of maternal and fetal immune activation varies with distinct polygenic risk profiles. Therefore, here we catalogue genotype and environment (GxE) interactions, contrasting allele-specific regulatory activity between inflammatory contexts. We report a cue-specific neuronal massively parallel reporter assay (MPRA) of 2 ...[more]

PMID: 39026810

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Dataset Information

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

Publications

Dynamic neuro-immune regulation of psychiatric risk loci in human neurons.

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