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We examined whether common variants from the extended major histocompatibility complex (xMHC) region contribute to the response to antipsychotic drugs (APDs) in patients with schizophrenia with persistent psychosis. Subjects participated in a prospective longitudinal study of the effect of APDs on psychopathology were temporally split into discovery ( n  = 88) and replication ( n  = 42) cohorts. The primary endpoint was a change in Brief Psychiatric Rating Scale at 6-week or 6-month after treatment. rs204991 ( β  = 3.917,  p  = 3.72 × 10 −6 ), the strongest signal associated with response at 6-week was located near  C4A/C4B  after a linear regression adjusted for covariates. xMHC SNP imputation disclosed much stronger signals (rs9268469,  β  = 5.140,  p  = 1.57 × 10 −7 ) and other weaker signals ( p  &lt; 1 × 10 −5 ) spanning the entire xMHC region. All the variants were previously identified schizophrenia risk loci. Conditional fine-mapping revealed three subgroups of SNPs which were the eQTLs ( p  &lt; 1 × 10 −7 ) for  C4A, HLA-C , and  BTN3A2  in disease-relevant tissue. Epistasis between  HLA-C  and  C4A  was observed ( p  = 0.019). Minor allele (G) carriers of rs204991, eQTL for  C4A , having decreased risk for schizophrenia and lower imputed expression of C4A, had a better response to APDs. Some imputed HLA alleles associated with a decreased risk for schizophrenia had a positive association with improvement in psychotic symptoms. An independent cohort validated the association of change in psychosis with  C4A . We provide evidence that genetic risk factors for schizophrenia from the xMHC region are associated with response to APDs and those variants significantly alter the imputed expression of  C4A, HLA-C , and  BTN3A2 . The minor alleles predicting higher C4A level are associated with diminished improvement in psychotic symptoms after APD treatment.

translational psychiatry

Schizophrenia risk loci from xMHC region were associated with antipsychotic response in chronic schizophrenic patients with persistent positive symptom