Association of MAP2 gene polymorphisms and altered expression with schizophrenia risk in a Chinese Han population

Schizophrenia (SCZ) is a highly heritable primary psychotic disorder. The microtubule-associated protein 2 (MAP2) gene is essential for dendritic integrity and synaptic plasticity, positioning it as a key candidate for bridging genetic risk and neuropathology. Nevertheless, the role of common genetic variations within MAP2 in SCZ susceptibility remains to be elucidated.

We conducted a candidate gene association study of MAP2 in a Han Chinese cohort comprising 418 SCZ patients and 418 matched healthy controls. Targeted sequencing was used to genotype single nucleotide polymorphisms (SNPs). MAP2 mRNA levels were quantified by RT-qPCR and correlated with genotypes and clinical symptoms. Bioinformatic tools (such as GTEx, BrainSeq, 3DSNP, HaploReg, RegulomeDB and SNP2TFBS database) were employed for functional annotation of risk loci.

We identified multiple MAP2 SNPs associated with SCZ risk in a Han Chinese cohort. Specifically, the AA genotype of rs288057 and the GG genotype of rs288087 were significantly associated with increased disease risk (OR = 2.393 and 2.258, respectively). Expression analysis revealed a marked reduction in peripheral MAP2 mRNA levels in patients compared to controls. This downregulation was genotype-dependent: the risk AA at rs288057 and GG at rs288087 were correlated with lower mRNA levels, a finding supported by its significant eQTL effect in the GTEx and BrainSeq database. In silico annotation suggested rs288087 resides within a putative enhancer region, while rs288057 may affect a promoter-proximal regulatory site. Clinically, MAP2 expression showed a significant positive correlation with the severity of negative symptoms (SANS score). Furthermore, ROC analysis indicated that MAP2 expression levels distinguished patients from controls with an AUC of 0.728.

This study identifies MAP2 as a schizophrenia risk gene, wherein non-coding variants likely reduce its expression via distinct regulatory mechanisms, linking this downregulation to core negative symptoms. These findings highlight MAP2's pathophysiological and translational relevance.