Approximately 30% of patients with schizophrenia are treatment resistant (TRS), i.e. have persistent psychotic symptoms despite adequate trials of at least two antipsychotic drugs (APDs). Most TRS patients are candidates for clozapine treatment which is underutilized because of its side effects and difficulty in identifying TRS. We conducted a genome-wide association study (GWAS) of 79 TRS and 95 non-treatment resistant (NTRS) Caucasian schizophrenia patients to identify possible biomarkers for TRS, which might also provide insight into the pathobiology of TRS. The single nucleotide polymorphism, rs2237457, located in 7p12.2, a region reported to have imprinted inheritance, was found to have the lowest p value in an allelic association test (unadjusted p = 5.53 × 10(-6)). Haploview disclosed a 30 kb block flanking this SNP within GRB10, 70 kb upstream of l-dopa decarboxylase (DDC), an enzyme which is rate-limiting in the synthesis of trace amines and neurotransmitters implicated in schizophrenia and the action of APDs. This SNP or haplotype was identified as an exclusive cis-acting eQTL for DDC in human dorsolateral prefrontal cortex by BrainCloud®. A replication sample genotyped for this SNP produced a weaker result, but in the same direction. After combining the two samples, rs2237457 remained significantly associated with TRS (unadjusted p = 5.66 × 10(-7) in recessive mode; 9.42 × 10(-5) in allelic association). If replicated in an independent sample, rs2237457 may provide a biomarker to identify a significant proportion of Caucasian TRS. The results implicate trace amines and their synthesis in the pathophysiology of TRS.
Keywords: Clozapine; Dopa decarboxylase; Genetic; Genome-wide association study; Schizophrenia; Treatment resistant.
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