Clinical, cellular, and genomic consequences of a population-enriched SETD1A missense variant

ABSTRACT: Rare coding variants in dozens of genes confer substantial risk for neuropsychiatric disorders, yet variant-specific and multi-scale mechanisms remain poorly defined. Rare variants in SETD1A, encoding a histone H3K4 methyltransferase, are among the strongest genetic risk factors for schizophrenia. Exome sequencing (n=3,736) revealed a population-enriched SETD1A missense variant (P596L) in the Lancaster Old Order Amish founder population associated with bipolar disorder and allele dose–dependent cognitive deficits in adulthood. Leveraging this enrichment, we integrated human genetics with patient-derived stem cell models to define clinical, cellular, and genomic consequences of this naturally occurring allele. Induced pluripotent stem cells (iPSCs) from homozygous carriers exhibited signatures of SETD1A hypofunction, including reduced proliferation and heightened susceptibility to replication stress and DNA double-strand breaks. During forebrain-directed differentiation, homozygous mutant cells displayed premature activation of neurodevelopmental transcriptional programs but impaired neural rosette formation, reduced neurite complexity, and early progenitor senescence. Multi-omic profiling revealed dysregulation of gene modules converging on replication stress pathways and neuronal regulatory networks enriched for autism and psychiatric risk genes. Pharmacologic inhibition of the H3K4 demethylase KDM5 partially rescued replication stress and neurite deficits, supporting an epigenetic mechanism and suggesting therapeutic tractability. Together, these findings link a population-enriched missense variant to disrupted chromatin regulation, genome stability, and neurodevelopmental timing, bridging human genetic risk with cellular pathophysiology. Our results demonstrate the power of founder populations to enable variant-level mechanistic dissection and identify epigenetic intervention strategies for psychiatric disease.

SUBMITTER: Robert Lease 

PROVIDER: S-BIAD3289 | bioimages |

REPOSITORIES: bioimages