The dopaminergic network and genetic susceptibility to schizophrenia

摘要: Background: Schizophrenia is a disabling illness with unknown pathogenesis. Estimates of heritability suggest substantial genetic contribution; however studies to date have been equivocal. Uncovering liability loci may therefore require analyses functionally related genes. Rooted in this assumption, dissertation describes series investigating epidemiological foundation for the commonly cited hypothesis suggesting dopaminergic dysfunction schizophrenia pathogenesis, i.e. 'dopamine hypothesis'. Studies: The initial study investigated DRD3 and identified novel associations across gene. second considered larger network genes two independent Caucasian samples, detecting replicated epistatic interactions. This proposed risk model centered on dopamine transporter. Study #3 precursor, phenylalanine hydroxylase, four identifying single SNP (rs1522305) that was significantly samples. #4 motivated by shared etiology bipolar disorder. comprehensively evaluated network, selecting 431 'tag' SNPs from 40 among large cohorts contrasted adult controls. Across all 60% nominally significant factors were also associated results supported variations as both disorders, confirmed several previously reported associations, new targets future research. Conclusion: These gene could play an etiological role pathogenesis possibly 1 Additional replicate are warranted. Public Health Significance: (SZ) devastating. When Global Burden Disease calculated disability adjusted life years, weighted severity disability, they determined active psychosis seen produces equal quadriplegia. has estimated be top ten causes worldwide. As common (roughly 1% point prevalence worldwide), economic burden society substantial. Pathogenesis treatment palliative. Therefore understanding facilitate development promising therapeutics.