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The dopaminergic network and genetic susceptibility to schizophrenia

Talkowski, Michael E (2008) The dopaminergic network and genetic susceptibility to schizophrenia. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Talkowski, Michael
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee CoChairFeingold, Eleanorfeingold@pitt.eduFEINGOLD
Committee CoChairNimgaonkar, Vishwajit Lnimga@pitt.eduNIMGA
Committee MemberDevlin, Berniedevlinbj@upmc.eduDEVLINBJ
Committee MemberTorres, Gonzalogtorres@pitt.eduGTORRES
Committee MemberBarmada, M. Michaelbarmada@pitt.eduBARMADA
Date: 28 September 2008
Date Type: Completion
Defense Date: 24 July 2008
Approval Date: 28 September 2008
Submission Date: 31 July 2008
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: association; dopamine; gene; polymorphism; schizophrenia
Other ID:, etd-07312008-153245
Date Deposited: 10 Nov 2011 19:55
Last Modified: 19 Dec 2016 14:36


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