rs6994992

An imaging genetics study of 144 healthy Caucasian controls examining NRG1 genetic variation and brain network small-worldness properties measured via EEG during an auditory odd-ball task. Three NRG1 SNPs (rs6468119, rs6994992, rs7005606) were significantly associated with small-worldness modulation in different frequency bands (alpha, beta1, theta), with risk allele carriers showing larger modulation than non-carriers (p-values ranging from 0.019–0.048).

This systematic review and validation study examined psychosis-associated SNPs and their effects on brain volumetry in 113 subjects (schizophrenia, bipolar disorder, at-risk mental state, and healthy controls). Of 25 studies identified in the systematic review implicating 7 SNPs in 5 genes, the authors tested these variants using voxel-based morphometry. They found FWER-corrected associations for CACNA1C rs769087-A with larger bilateral hippocampus and thalamus white matter (p = 0.026 and p = 0.036) and with larger superior frontal gyrus volume. Higher replication concordance was found for CACNA1C, ZNF804A, and BDNF variants, supporting their involvement in psychosis and brain structure.

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 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.

This study extended genetic linkage analysis to 3D diffusion tensor images (DTI) in 258 twins and siblings to map single gene effects on brain fiber architecture. The BDNF Val66Met polymorphism (rs6265) significantly influenced fractional anisotropy (FA) in the posterior cingulate gyrus, accounting for 90-95% of local FA variance. Raw FA images without smoothing provided greatest sensitivity for detecting gene effects when corrected for multiple comparisons using false discovery rate procedures.

This study examined NRG1, DAOA, and DISC1 gene polymorphisms and expression in 195 Chinese Han individuals (18 ultra-high risk for psychosis, 61 first-degree relatives, 55 first-episode psychosis, 61 healthy controls). Rs3918341 in DAOA was associated with UHR susceptibility (OR=3.68, p<0.001). Epistatic analysis showed interactions between NRG1 and DAOA, and NRG1 and DISC1 genes in UHR risk. NRG1 mRNA was significantly downregulated in the UHR group compared to healthy controls and first-episode psychosis patients.

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).

This case-control association study of 738 schizophrenia cases from CATIE and 733 matched controls failed to replicate previous associations between the NRG1 promoter SNP rs6994992 and schizophrenia, age at onset, or neurocognitive function. The T allele showed a weak and non-significant association in the opposite direction (χ²=3.96, p=0.046, did not survive multiple comparison correction) compared to prior reports, and found no associations with WRAT-3 scores (proxy for premorbid IQ) or neurocognitive summary scores.