Fig. 3: Heritability enrichment for schizophrenia risk genes 22q11.2 deletion neurons.

a Marginal enrichment in Heritability (+/− SE) explained by common (MAF > 5%) variants within 100 kb of genes differentially expressed, estimated by LD Score regression. Six traits were analyzed: SCZ schizophrenia, BP bipolar disorder, EA educational attainment, MDD major depressive disorder, ASD autism spectrum disorder, ADHD attention deficit hyperactivity disorder, at all three cell stages, showing enrichment for schizophrenia most prominently in genes upregulated in 22q11.2 deletion neurons. DE differentially expressed. Three groups of DE genes were analyzed. Left, all nominally significant DE genes (p < 0.05, N (DE genes in stem cells) = 2346, N (DE genes in NPCs) = 2076, N (DE genes in neurons) = 3370). Middle, all nominally significant upregulated DE genes (p < 0.05, N (genes in stem cells) =1521, N (genes in NPCs) = 964, N (genes in neurons) =2173). Right, all nominally significant downregulated DE genes (p < 0.05, N (genes in stem cells) =825, N (genes in NPCs) = 1112, N (genes in neurons) =1197). The standard errors in LD score regression are derived from block Jackknife that are then used to calculate z scores and P values (two-sided). A significant heritability enrichment for schizophrenia was found for all DEgenes and upregulated genes in neurons (p = 0.00018 and p = 1.6 × 10⁻⁵, LD score Regression). The test statistic for each comparison is presented in Supplementary Data 6. b DE genes (two-sided Wald-test implemented in DEseq2) in 22q11.2 neurons with nominally significant gene-wise association to schizophrenia from MAGMA (p_g < 0.05, F-test implemented in MAGMA, two-sided). c qq plot of p-values (t-test, linear regression, two-sided) with 95% confidence interval for the enrichment of rare coding LoF, missense damaging or synonymous variants in schizophrenia patients in genes upregulated in deletion neurons (circled) and 100 random gene sets matched by expression level to the upregulated genes.