The DRD2 rs1076560 polymorphism and schizophrenia-related intermediate phenotypes: A systematic review and meta-analysis

•Alternative DRD2 rs1076560 allele carrier status negatively affects all investigated intermediate phenotypes, except brain morphology.•The strongest evidence of association was found for its implication in altered brain activity and connectivity.•Healthy alternative rs1076560 allele carriers show inefficient recruitment, particularly in fronto-striatal regions.•Schizophrenia patients carrying this allele show decreased brain recruitment.

Intermediate phenotypes may contribute to elucidate the genetic determinants of schizophrenia. A regulatory dopamine 2-receptor gene (DRD2) polymorphism (rs1076560; G > T) has been identified as a genetic risk factor for schizophrenia. Studies report conflicting results on its involvement in schizophrenia intermediate phenotypes and no systematic review on this topic has been published. Therefore, we aimed to assess whether this polymorphism is implicated in schizophrenia intermediate phenotypes by performing a systematic review and meta-analysis. Alternative allele carrier status negatively affected all intermediate phenotypes except for brain morphology, for which inconsistent genotype effects were found. Specifically, alternative allele carriers showed inefficient brain recruitment in healthy subjects and decreased brain recruitment in schizophrenia patients. Finally, significant results of the meta-analysis on functional magnetic resonance imaging in healthy subjects pinpointed rs1076560-associated brain regions, in particular the fronto-striatal network. To increase homogeneity and thus improve comparability in future genetic studies investigating SCZ intermediate phenotypes, we highlight methodological caveats and provide suggestions to circumvent such pitfalls.