In a study published in Molecular Psychiatry on September 4, 2026, a team led by Xiao Xiao from the Kunming Institute of Zoology (KIZ) of the Chinese Academy of Sciences, along with collaborators from Jinan University and Xi'an Jiaotong University First Affiliated Hospital, integrated genome-wide association study data, whole-exome sequencing data, and human brain cortical developmental multi-omics data to identify cortical cell types underlying schizophrenia genetic risk.

The researchers built an atlas of approximately 3 million nuclei from 325 neurotypical donors, using 22 public single-nucleus RNA sequencing datasets. The data spanned from early embryonic development to adulthood, covering the cingulate, frontal, motor, temporal, and visual cortices.

The researchers found that common genetic risk for schizophrenia concentrated in excitatory and inhibitory neurons, with excitatory neurons being the most prominent. Intracortical projection (IT) neurons emerged as a major convergence point, involved in information transmission and associative processing across cortical areas. Deep-layer L6b excitatory neurons showed significant enrichment, connecting to higher-order thalamic structures and participating in arousal, attention, and brain state regulation.

Developmental analysis showed that genetic risk concentrated in early neurodevelopment, during neurogenesis and neuronal migration. Early excitatory neuron differentiation stage cells and specific early inhibitory neuron lineages showed genetic risk associations. The researchers validated these findings with single-nucleus chromatin accessibility sequencing, showing heritability enriched in open chromatin of mature excitatory neuron subtypes, with IT and L6b neurons most prominent.

The researchers also analyzed postmortem frontal cortex samples from 31 patients and 170 controls, profiling approximately 1.1 million nuclei. They identified 3,510 differentially expressed genes concentrated in IT excitatory neurons, while L6b, VIP, PVALB, and SST inhibitory neurons also showed transcriptome changes.

These findings establish a refined cortical vulnerability framework linking schizophrenia genetic risk to mature associative circuits and early neurodevelopment.

Paper link: https://www.nature.com/articles/s41380-026-03862-3