Single-cell multiomics of neuronal activation reveals context-dependent genetic control of brain disorders

Despite hundreds of genetic risk loci identified for neuropsychiatric disorders (NPD), most causal variants/genes remain unknown. A major hurdle is that disease risk variants may act in specific biological contexts, e.g., during neuronal activation, which is difficult to study in vivo at the population level. Here, we modeled neuronal activation in human iPSC-induced excitatory and inhibitory neurons from 100 donors. Single-cell multiomics analyses of over a million neurons uncovered complex activity-dependent transcriptomic and epigenomic regulation and significantly expanded the repertoire of stimulation-specific causal variants/genes for NPD. We identified thousands of genetic variants associated with activity-dependent gene expression (i.e., eQTL) and chromatin accessibility (i.e., caQTL). These caQTL explained considerably larger proportions of NPD heritability than the eQTL. Integrating the multiomic data with GWAS revealed NPD risk variants/genes whose effects were only detected ..., Human iPSC lines and cell culture
We initially started with 107 iPSC lines (European ancestry) of which 100 lines were successfully differentiated into both excitatory and inhibitory neurons (Table S1). Of the 100 iPSC lines used for data production, 58 with their IDs starting with “CD” were reprogrammed  at Rutgers University Cell and DNA Repository (RUCDR)-NIMH Stem Cell Center using the cryopreserved lymphocytes (CPLs) of donors of Molecular Genetics of Schizophrenia (MGS) cohort, and have been used in previous studies(65, 66, 78, 80, 81). The rest were purchased from the California Institute of Regenerative Medicine (CIRM).  28 iPSC lines are from SCZ cases and 72 are from healthy controls. The donors’ average age is 52 (+/-17) years old, and 56 of them are males. For TF-Knockout by CRISPR-based DNA base editing, two donor iPSC lines, CW20107 from CIRM and KOLF2.2J from Jackson Lab (JAX), were used as part of the SSPsyGene consortium(81).  All iPSC lines were verified..., , # Single-cell multiomics of neuronal activation reveals context-dependent genetic control of brain disorders

## Description of the data and file structure

*Single-cell multiomics of neuronal activation reveals context-dependent genetic control of brain disorders*. 

**Authors:** Lifan Liang^1,*, Siwei Zhang*^*2,*, Zicheng Wang^1,*, Hanwen Zhang*^*2,*, Chuxuan Li^2,3,*^, Christina Thapa^2,^, Emily Oh^2^, David Sirkin^2^, Xiaotong Sun^1^, Alexandra Barishman^2^, Ada McCarroll^2^, Alexandra C. Duhe^2^, Sheng Qian^1^, Xiaoyuan Zhong^1^, Brendan Jamison^1,2^, Whitney Wood^2^, Alena Kozlova^2^, Zhiping P. Pang^4^, Alan R. Sanders^2,5^, Xin He^1,#^, Jubao Duan^2,5,#^

**Affiliations:**

^1^Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.

^2^Center for Psychiatric Genetics, Endeavor Health Research Institute, Evanston, IL 60201, USA.

^3^Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia,..., , **Changes after Mar 2, 2025:** 

Updated tables after the 2nd round of revision

**Note on changes made in the current version:** (1) Table S1 with added sample information related to genotype access. (2) Table  S25 with updated candidate risk gene lists for BP GWAS and MDD GWAS. (3) Table S4: removed worksheets with comparisons between 6 hrs vs. 1 hr.  (4) Table S9 with updated OCR_gene pairs. (5) Table S18 with updated TF list. (6) Table S19 with added columns to indicate which eGenes are in vivo ERG or LRG. (7) Table S20 with updated dynamic eGene lists. (8) Table S21 with updated eQTL-based cTWAS result. (9) Table S22 with updated GO-terms enriched in cTWAS risk genes for NPD. (10) Table S24 with updated ASoC SNP lists using new sequencing depth cutoff (i.e., >10 reads per sample). (11) Table S27, 28 and 29 with updated ASoC SNPs that are also GWAS risk SNPs for SCZ, BP and MDD, respectively. (12) Table S30 with updated caQTL-based cTWAS risk genes for NPD. (1...