Multiple genes in a single GWAS risk locus synergistically mediate aberrant synaptic development and function in human neurons

Siwei Zhang; Hanwen Zhang; Marc P Forrest; Yifan Zhou; Xiaotong Sun; Vikram A Bagchi; Alena Kozlova; Marc Dos Santos; Nicolas H Piguel; Leonardo E Dionisio; Alan R Sanders; Zhiping P Pang; Xin He; Peter Penzes; Jubao Duan

doi:10.1016/j.xgen.2023.100399

Multiple genes in a single GWAS risk locus synergistically mediate aberrant synaptic development and function in human neurons

Cell Genom. 2023 Aug 28;3(9):100399. doi: 10.1016/j.xgen.2023.100399. eCollection 2023 Sep 13.

Authors

Siwei Zhang^{1

2}, Hanwen Zhang¹, Marc P Forrest^{3

4}, Yifan Zhou⁵, Xiaotong Sun⁵, Vikram A Bagchi^{3

4}, Alena Kozlova¹, Marc Dos Santos^{3

4}, Nicolas H Piguel^{3

4}, Leonardo E Dionisio^{3

4}, Alan R Sanders^{1

2}, Zhiping P Pang⁶, Xin He⁵, Peter Penzes^{3

4

7

8}, Jubao Duan^{1

2}

Affiliations

¹ Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL 60201, USA.
² Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637, USA.
³ Department of Neuroscience, Northwestern University, Chicago, IL 60611, USA.
⁴ Center for Autism and Neurodevelopment, Northwestern University, Chicago, IL 60611, USA.
⁵ Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
⁶ Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
⁷ Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
⁸ Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Abstract

The mechanistic tie between genome-wide association study (GWAS)-implicated risk variants and disease-relevant cellular phenotypes remains largely unknown. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons as a neurodevelopmental model, we identify multiple schizophrenia (SZ) risk variants that display allele-specific open chromatin (ASoC) and are likely to be functional. Editing the strongest ASoC SNP, rs2027349, near vacuolar protein sorting 45 homolog (VPS45) alters the expression of VPS45, lncRNA AC244033.2, and a distal gene, C1orf54. Notably, the transcriptomic changes in neurons are associated with SZ and other neuropsychiatric disorders. Neurons carrying the risk allele exhibit increased dendritic complexity and hyperactivity. Interestingly, individual/combinatorial gene knockdown shows that these genes alter cellular phenotypes in a non-additive synergistic manner. Our study reveals that multiple genes at a single GWAS risk locus mediate a compound effect on neural function, providing a mechanistic link between a non-coding risk variant and disease-related cellular phenotypes.

Keywords: CRISPR-Cas9 gene editing; CROP-seq; GWAS; Micro-C; allele-specific open chromatin; chromatin accessibility; common risk variants; human iPS cells; isogenic; neuron; neuropsychiatric disorders; noncoding variants; scRNA-seq; schizophrenia; synergistic.

Abstract

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