Fig. 1: KO effects of 21 NDD risk genes are most strongly correlated in mature neurons.
a, List of rare-variant target risk genes associated with NDDs separated by chromatin modifiers and neuronal communication genes. Bold gene names indicate strong associations with ASD based on ref. 5. Gene targets of rare variants associated with SCZ, epilepsy (EPI) and bipolar disorder (BIP) are annotated. b, Strength of association with ASD, as estimated by distribution of posterior probability (p.p.) scores from ref. 5; 4 of 29 NDD genes were more strongly associated with DD (blue; p.p. ≤ 0.1) while 16 of 29 were more strongly associated with ASD (red; p.p. ≥ 0.9). Further annotations of individual risk genes are shown in Supplementary Figs. 1 and 2. c, One-sided, positive MAGMA GSEA of targeted genes across GWAS for anorexia nervosa (AN), chronic pain, amyotrophic lateral sclerosis (ALS), SCZ, BIP, BIP-I (bipolar subtype 1) and BIP-II (bipolar subtype 2). FDR multiple testing correction was performed to adjust for multiple gene set comparisons: #Nominal P < 0.05, *FDR < 0.05, **FDR < 0.01, ***FDR < 0.001. Error bars indicate the standard error of beta (the regression coefficient). d, Schematic of hiPSC-derived cell-type-specific scCRISPR-KO screen. Representative immunofluorescence for markers of NPCs (DAPI/Nestin), mature iGLUTs (DAPI/MAP2/vGLUT) and mature iGABAs (DAPI/MAP2/GABA). e, Transcriptomic impact of NDD gene KO represented as two-tailed Pearson’s correlation across nominally significant (P < 0.01) DEGs. (i) Pearson’s correlation matrix of log2FC DEGs across all NDDs and cell types. (ii) Cross-cell-type correlation network diagram (based on Pearson’s correlations) across NDD perturbations (number of NDD gene KO perturbations resolved indicated in parentheses); the mature iGLUT cluster was most dense, and the iNPC most sparse. Illustrations in d and e created in BioRender; Townsley, K. https://biorender.com/rvk1zn2 (2026). PCC, Pearson’s correlation coefficient.
