rs6314

This dissertation examined pharmacogenetic associations with clozapine adverse effects in 237 Finnish schizophrenia patients. ADRA2A rs1800544 was associated with clozapine-induced sialorrhea (OR 2.13, 95% CI: 1.17-3.88, p=0.013). Eight HNMT SNPs in complete linkage disequilibrium (r²=1) were associated with sedation. CHRM3 rs685548 and weighted genetic risk scores from HTR4, HTR7, TPH1, CHRM2, ABCB1, and OPRM1 were associated with anticholinergic symptoms.

Association study of 55 SNPs in 887 Hungarian adults examining genetic predisposition to aggression measured by the Buss-Perry Aggression Questionnaire. The HTR2A rs7322347 intronic variant showed significant association with aggression after Bonferroni correction (p = 0.0007), with carriers of the minor A allele showing lower aggression levels. The DRD4 rs916455 variant also showed nominal significance (p = 0.0275) but did not survive multiple testing correction.

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%).

A candidate gene study of 34 patients with neuropathic pain found significant association between the serotonin receptor 2C gene (HTR2C rs6318 C allele) and pain relief during escitalopram treatment, with an odds ratio of 15.5 (p=0.014) in men and 10.6 (p=0.010) in combined analysis. Additional genes in the serotonergic pathway including HTR2A, SLC6A4 (5-HTTLPR), CYP2C19, and ABCB1 were also analyzed, with 5-HTTLPR showing a borderline association.

Meta-analytic review of candidate gene studies for childhood ADHD examining 19 genes. Significant associations identified for DAT1 (3' UTR VNTR: OR=1.12, p=0.028; rs27072: OR=1.20, p=0.006), DRD4 (exon 3 VNTR: OR=1.33, p=0.00007; rs1800955: OR=1.21, p=0.007), DRD5, 5HTT, HTR1B (rs6296: OR=1.11, p=0.010), and SNAP25 (rs3746544: OR=1.15, p=0.030).

A family-based association study of 12 SNPs in the HTR2A serotonin receptor gene in 1,408 Irish subjects from 270 high-density schizophrenia families (755 with psychotic illness, 127 with suicidal ideation). Testing for association with psychosis and suicidal ideation using FBAT and PDTPHASE, the authors found two SNPs reaching nominal significance in psychosis (rs659734 p=.05 in FBAT, rs2070037 p=.05 in PDTPHASE) and several haplotypes with modest association (p=.02 to .04), but no significant associations in the suicidal ideation subset and no surviving multiple testing correction. The study does not provide support for HTR2A as a susceptibility gene for psychotic illness or suicidal ideation.

Analysis of 554 SNPs across 47 candidate genes in 590 families from the IMAGE ADHD genetics study found no overall parent-of-origin effect (χ² = 1.82, P = 0.117) for ADHD transmission. Five SNP markers in DDC, TPH2, and SLC6A2 showed nominal associations (P < 0.01) with ADHD combined subtype when restricted to maternal or paternal transmission only, but these findings likely represent false positives given multiple comparisons.

This dissertation investigated the genetic basis of violent criminal behavior, antisocial personality disorder (ASPD), and broader antisocial behavior through GWAS and meta-analyses in Finnish and international populations. Study I identified an intronic CDH13 variant (rs11649622, OR=2.7, p=4.19×10⁻⁶) associated with extremely violent offending, replicated in homicide offenders (p=5.3×10⁻⁷, OR=2.17). Study II revealed the first genome-wide significant association between LINC00951 variant rs4714329 (OR=1.59, p=1.6×10⁻⁹) and ASPD. Study III meta-analysis of 16,400 individuals found no genome-wide significant associations with broader antisocial behavior, though polygenic risk scores explained ~5% of phenotypic variance.

Family-based association study in 42 Antioquia families examining serotonergic gene variants and autism. Found significant associations with SLC6A4 variants rs4583306 (OR=2.6, p=0.004) and rs2066713 (OR=2.2, p=0.03), and evidence of epistasis between SLC6A4 and HTR2A (p<0.001) in autism etiology. The haplotype 5HTTLPR-rs4583306 (S-G) showed tripled autism risk (OR=3.4, p=0.01).

A case-control study (N=99: 49 patients with major depressive disorder, 50 controls) conducted in Mexican mestizo population analyzing 8 genetic variants in serotonin and dopamine receptors (HTR1A rs6295, HTR2A rs6311/rs6313/rs6314, HTR6 rs1805054, DRD2 rs1801028/rs1800497, DRD3 rs6280) using PCR-RFLP genotyping. The study characterized genotype and allele frequencies in depressed patients versus healthy controls and evaluated associations with antidepressant treatment response using Hamilton Depression Scale.

This association study examined 20 polymorphisms from 12 candidate genes in 163 ADHD probands and 129 controls, finding significant associations with two genes: NET1 (rs998424 P=0.009, rs3785157 P=0.002) and DRD1 (rs4532 OR=1.63 P=0.006, rs265981 OR=1.61 P=0.008). The study used both family-based transmission disequilibrium tests and case-control analyses. No significant effects were detected on cognitive, behavioral, or brain MRI measurements.