Fig. 5: Localizing the heritability signals of neuropsychiatric disorders using DMRs and chromatin loops.
From: Temporally distinct 3D multi-omic dynamics in the developing human brain
a, k-means clustering of DMRs reveals specificities for cell lineages and developmental stages. b, Schematic of the maturation of MGE-derived ERBB4-expressing inhibitory neurons (Inh-MGE-ERBB4). c, Numbers of trajectory-DMRs identified for Inh-MGE-ERBB4 maturation between adjacent developmental stages. d, Enriched TF-binding motifs in trajectory-DMRs for the maturation of Inh-MGE-ERBB4 neurons. The enrichment of TF-binding motif is determined using hypergeometric tests with a q value threshold of 0.01 for display. e, Schematic of the specification of RG-1-derived cell types. f, Numbers of branch-DMRs found during RG-1 differentiation. g, TF-binding motif enrichments in branch-DMRs associated with RG-1 differentiation. h, The enrichment of schizophrenia polygenic heritability in DMRs and loop-connected DMRs. The P value was computed using a two-sided paired t-test. i, Numbers of schizophrenia-associated loci containing at least one fine-mapped variant that overlaps with DMRs or loop-connected DMRs. j, Spearman’s correlation and two-sided P value between the enrichment of polygenic heritability and fine-mapped schizophrenia variants. k, Enrichment of polygenic heritability for schizophrenia and bipolar disorder in PDZRN4-expressing layer 5–6 excitatory neurons across developmental stages. Error bars indicate standard errors estimated by the linkage disequilibrium score regression block jackknife method (n = 200 blocks). l, Statistical significance of differential heritability enrichment between development stages. P values were computed using two-sided t-tests. Red and blue colours show developmentally increased or decreased heritability enrichment, respectively. NS, not significant. m, Meta-analysis of heritability enrichment for schizophrenia and bipolar disorder in excitatory neuron populations. Error bars indicate standard deviations across cell types included in the meta-analysis. n = 5 cell types for the second trimester, n = 9 for the third trimester, n = 16 for infant, n = 17 for adult.
