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

Authors: 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, and Jubao Duan

Cell Genomics, 28 August 2023

Scientists use Axion’s noninvasive Maestro MEA to assess functional differences in iPSC-derived neurons in vitro.   

Many risk loci have been identified for neuropsychiatric disorders via genome-wide association studies (GWAS), but causal genes and mechanisms remain unidentified for most risk loci. In this study, scientists generate a neurodevelopmental model with hiPSC-derived and NEUROG2 (NGN2)-induced excitatory neurons (NGN2-Glut) and use allele-specific open chromatin (ASoC) as a metric to identify potentially functional risk factors for schizophrenia. After identifying a potential causal risk factor, the authors used Axion’s noninvasive Maestro multielectrode array (MEA) platform to assess functional differences in vitro among iPSC-derived neurons expressing allelic differences in this specific gene. Taken together with other findings, the researchers conclude 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.”