Differential genome-wide association analysis of schizophrenia and post-traumatic stress disorder identifies opposing effects at the MAPT/CRHR1 locus.

BACKGROUND

Schizophrenia (SCZ) and post-traumatic stress disorder (PTSD) are severe psychiatric conditions with overlapping yet distinct symptomatology and pathophysiology.

METHODS

We conducted a differential genome-wide association study (GWAS) to directly compare the genetic architectures of SCZ and PTSD using publicly available GWAS summary statistics from the Psychiatric Genomics Consortium (PGC).

RESULTS

We identified four independent loci reaching genome-wide significance (P < 5 × 10-8) for differential associations between SCZ and PTSD in individuals of European ancestry. These loci (rs62062288, rs58120505, rs12536395, and rs11057189) showed genome-wide significant associations with SCZ and nominal associations with PTSD (all Ps < 0.05) but with opposite directions of effect. Among these, only rs62062288 retained genome-wide significance for PTSD in trans-ancestry meta-analysis, whereas the other three loci showed markedly attenuated PTSD associations (all Ps > 0.001). rs62062288 maps to the 17q21.31 MAPT/CRHR1 locus, exhibiting a risk effect for PTSD and a protective effect for SCZ. GTEx analyses revealed that MAPT and CRHR1 are highly expressed across multiple brain tissues and that rs62062288 shows opposite regulatory effects on MAPT and CRHR1 expression in the brain tissue caudate basal ganglia, with the PTSD risk allele associated with increased MAPT expression and decreased CRHR1 expression. Additional brain-region-specific expression quantitative trait locus (eQTL) effects on CRHR1 were observed in frontal cortex BA9, hippocampus, and spinal cord, indicating tissue-dependent regulation.

CONCLUSION

These findings provide evidence for distinct and opposing genetic contributions to SCZ and PTSD. The identification of the MAPT/CRHR1 locus with brain-region-specific and gene-specific regulatory effects highlights divergent neurodevelopmental and stress-related pathways underlying these disorders.