rs10503929

This fMRI study found significantly attenuated ventral striatal activation during reward anticipation in healthy first-degree relatives of schizophrenia patients (FWE-corrected P < .03) compared to matched controls, supporting striatal dysfunction as an intermediate phenotype for schizophrenia genetic risk. The phenotype was reliable (ICC 0.59-0.73), independent of brain structure, and influenced by the NRG1 rs10503929 variant, with C-allele carriers showing higher striatal responses.

This comprehensive review examines the genomics of schizophrenia and pharmacogenomics of antipsychotic drugs, synthesizing evidence on over 200 genes associated with psychotic disorders. The authors discuss five categories of genes relevant to antipsychotic response: disease-associated genes, mechanism-of-action genes, drug metabolism genes (particularly CYP2D6, CYP2C19, CYP2C9, CYP3A4), drug transporter genes, and pleiotropic genes. The review details pharmacogenomic profiles of 20+ antipsychotic drugs and demonstrates significant ethnic and interindividual variation in drug metabolism phenotypes, with examples including CYP2D6 extensive metabolizers (55.71% of population), intermediate metabolizers (34.7%), poor metabolizers (2.28%), and ultra-rapid metabolizers (7.31%).

This study examined epistatic interactions between SNPs in NRG1 and genes in the NMDA-glutamate pathway (ERBB4, AKT1, DLG4, NOS1, NOS1AP) in schizophrenia using case-control and neuroimaging approaches. In two independent samples (US sibling study: 296 cases/365 controls; German sample: 905 cases/1323 controls), significant gene-gene interactions were identified, including rs4560751 × rs3802160 (OR=4.56, p=0.0002), NRG1 rs10503929 × ERBB4 rs1026882 (OR=2.25, p=0.035), and a three-way interaction in NRG1-ERBB4-AKT1. These interactions were biologically validated by showing that risk allele carriers had inefficient dorsolateral prefrontal cortex (DLPFC) activation during working memory fMRI tasks.

This comprehensive review synthesizes genomic and pharmacogenomic research in schizophrenia, discussing over 200 candidate genes associated with psychotic disorders, genetic mechanisms including copy number variants and microRNA alterations, and pharmacogenomic factors affecting antipsychotic efficacy and safety. Key genes covered include dopamine receptors (DRD1-5), dysbindin (DTNBP1), DISC1, neurotrophic factors, and metabolic enzymes such as CYP2D6, CYP3A4, and COMT, with emphasis on genotype-phenotype correlations in antipsychotic response and side effects.

A targeted sequencing study of 115 patients with bipolar disorder and depression identified genetic variants in NRG1, PIP4K2A, and HTR2C associated with treatment response and disease severity. The allele C of rs35641374 (NRG1) was associated with longer intervals between depressive episodes (p=4.37e-07), while the allele C of rs10508649 (PIP4K2A) was associated with longer intervals between manic/mixed episodes (p=0.000309) and treatment resistance assessed by CGI-I scale (p=0.000943). The allele A of rs2248440 (HTR2C) was associated with higher depression severity (p=0.003).

This targeted sequencing association study of 115 psychiatric patients and 34 controls identifies NRG1, PIP4K2A, and HTR2C as candidate biomarker genes for antidepressant treatment response and mood disorder recurrence. Key findings include rs35641374 (NRG1) associated with longer time to depressive recurrence in bipolar disorder (p=4.37e-07), rs61731109 and rs10508649 (PIP4K2A) associated with antidepressant non-response (p=0.00111 and p=0.000943), and rs2248440 (HTR2C) associated with higher depression severity (p=0.003).