rs6323

A twin study of 1,312 children investigating genetic mediation of endophenotypes in ADHD. Using candidate gene SNPs from dopaminergic, noradrenergic, and serotonergic pathways, the study found the strongest association between rs7984966 in HTR2A and reaction time variability (P=0.007), and rs3785157 in SLC6A2 with commission errors. Mediation analyses revealed that commission errors mediated 38% of the SLC6A2-inattention association, and reaction time variability mediated 44% of the HTR2A-inattention association, suggesting these cognitive measures are intermediate phenotypes on the genetic pathway to ADHD.

This international doctoral thesis examined gene-physical activity interactions in fibromyalgia through six studies analyzing 64 SNPs across 34 candidate genes in Spanish women. The case-control study (314 fibromyalgia cases vs. 112 controls) identified associations of rs841 (GCH1), rs1799971 (OPRM1), and rs2097903 (COMT) with fibromyalgia susceptibility (p=0.04, p=0.02, and p=0.04 respectively). Cross-sectional studies (n=274-276 fibromyalgia patients) found that SCN9A rs4453709 and other genetic polymorphisms interacted with physical activity to influence pain, fatigue, and resilience outcomes.

This case-control study examined associations between MAOA and MAOB SNPs (rs909525, rs6323, rs2064070, rs1799836) and anger-related traits in 261 suicidal participants (171 attempters, 90 completers) and 317 healthy controls. Three MAOA variants showed significant associations with outward anger expression in males (p<0.001), with the rs909525 A allele associated with suicidality (p<0.007). The rs6323 C allele showed association with anger-out in females (p=0.002).

A case-control study in a Chinese Han population examined the role of the MAOA gene in paranoid schizophrenia by genotyping 1 VNTR polymorphism and 41 SNPs in 555 patients and 567 controls. While individual SNP alleles showed marginal associations (e.g., rs6323-G: OR=0.81, p=0.03; rs1137070-C: OR=0.77, p=0.01), these did not survive multiple testing correction. Haplotypic analysis revealed significant associations in females, particularly for VNTR(L)-rs6323(T) (p=0.03, OR=1.78) and VNTR(L)-rs1137070(C) (p=0.02, OR=2.71) haplotypes showing increased schizophrenia risk. Gene expression analysis of MAOA mRNA in 73 drug-free patients found no significant differences by genotype, suggesting haplotypic interactions may contribute to disease susceptibility through mechanisms other than altered mRNA expression.

A pharmacogenetic study of 446 schizophrenic patients (221 males, 225 females) from West Siberia investigating associations between 41 SNPs in dopaminergic genes and antipsychotic-induced hyperprolactinemia. The study found rs1799836 in MAOB gene associated with hyperprolactinemia in males (OR=0.748, p=0.048), and rs40184 and rs3863145 in SLC6A3 gene associated with hyperprolactinemia in the risperidone/paliperidone subgroup (OR=0.341, p=0.021 and OR=0.362, p=0.043, respectively), indicating protective effects.

Development and validation of a targeted NGS panel for diagnosing familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA2), CADASIL, and migraine with aura. In 149 patients across 4 cohorts (55 FHM, 44 CADASIL, 31 EA2, 19 migraine families), the panel identified novel and known mutations in genes CACNA1A, ATP1A2, SCN1A, and NOTCH3, increasing mutation detection rate from 7.7% to 28.5%. Notably, ATP1A2 and NOTCH3 mutations were identified in typical migraine with aura families for the first time, demonstrating aetiological overlap with FHM.

A pharmacogenetic association study of 446 schizophrenia patients from West Siberia examined 41 SNPs in dopamine pathway genes (DRD1, DRD2, DRD3, DRD4, SLC6A3, MAOA, MAOB) for association with antipsychotic-induced hyperprolactinemia (HPRL). rs1799836 in MAOB showed significant protective association with HPRL in men (OR=0.748, p=0.048), while rs40184 (OR=0.341, p=0.021) and rs3863145 (OR=0.362, p=0.043) in SLC6A3 showed protective effects specifically in risperidone/paliperidone-treated patients.

This doctoral thesis conducted multiple candidate gene association studies in 274-426 southern Spanish women with fibromyalgia to investigate gene-physical activity/sedentary behavior interactions with pain, fatigue, and resilience. Study III identified rs841 (GCH1) GG genotype (OR=0.61, p=0.04) and rs2097903 (COMT) AT/TT genotypes (OR=1.66, p=0.04) associated with fibromyalgia susceptibility, and confirmed rs1799971 (OPRM1) GG genotype (OR=0.58, p=0.02) confers genetic risk. Study IV found rs6311/rs6313 (HTR2A) polymorphisms individually associated with algometer pain score, and gene-sedentary behavior interactions involving rs4680/rs165599 (COMT), rs1383914 (ADRA1A), rs12994338/rs4453709 (SCN9A), and rs6860 (CHMP1A) significantly associated with pain outcomes. SCN9A emerged as most robust gene for fibromyalgia phenotype.