Abstract

Numerous variants associated with increased risk for SCZ have undergone positive selection and were associated with human brain development, but which brain regions and developmental stages were influenced by the positive selection for SCZ risk alleles are unclear. We analyzed SCZ using summary statistics from a genome-wide association study (GWAS) from the Psychiatric Genomics Consortium (PGC). Machine-learning scores were used to investigate two natural-selection scenarios: complete selection (loci where a selected allele has reached fixation) and incomplete selection (loci where a selected allele has not yet reached fixation). Based on the p value of single nucleotide polymorphisms (SNPs) with selection scores in the top 5%, we formed five subgroups: p < 0.0001, 0.001, 0.01, 0.05, or 0.1. We found that 48 and 29 genes (p < 0.0001) in complete and incomplete selection, respectively, were enriched   for the transcriptional   co-expression   profile   in the   prenatal dorsolateral prefrontal cortex (DFC), inferior parietal cortex (IPC), and ventrolateral prefrontal cortex (VFC). Core genes ( GNA13, TBC1D19 , and ZMYM4 ) involved in regulating early brain development were identified in these three brain regions. RNA sequencing for primary cortical neurons that were transfected Gna13 overexpressed lentivirus demonstrated that 135 gene expression levels changed in the Gna13 overexpressed groups compared with the controls. Gene-set analysis identified important associations among common variants of these 13 genes, which were associated with neurodevelopment and putamen volume [p = 0.031; family-wise error correction (FWEC)], SCZ (p = 0.022; FWEC). The study indicate that certain SCZ risk alleles were likely to undergo positive selection during human evolution due to their involvement in the development of prenatal DFC, IPC and VFC, and suggest that SCZ is related to abnormal neurodevelopment.