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Genetics of age-related maculopathy & Score statistics for X-linked quantitative trait loci

Jakobsdóttir, Jóhanna (2009) Genetics of age-related maculopathy & Score statistics for X-linked quantitative trait loci. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Age-related maculopathy (ARM) is a common cause of irreparable vision loss in industrialized countries. The disease is characterized by progressive loss of central vision making everyday tasks challenging. The etiology is complex and has both an environmental and a strong genetic components. The public health relevance of the work is to improve the understanding genetic causes in the disease etiology and ultimately to lead to better disease management and prevention. From my ARM work, I present four papers covering range of statistical approaches. The first paper presents fine-mapping efforts, using both linkage and association methods, under previously identified linkage peaks on chromosomes 1q31 and 10q26. We replicate the discovery of the complement factor H (CFH) gene on 1q31 and identify a novel locus, harboring three closely linked genes (PLEKHA1, LOC387715, and HTRA1), on 10q26. Both discoveries have been widely replicated. In the next paper I present meta-analysis of 11 CFH and 5 LOC387715 data sets. We also replicate these findings in two independent case-control cohorts, including one cohort, where ARM status was not a factor in the ascertainment. In the third paper we replicate discoveries of new complement related loci (C2 and CFB) on chromosome 19p13 as well as developing classification models based on SNPs from CFH, LOC387715, and C2. The last paper focuses on applying statistical techniques from the diagnostic medicine literature to ARM. We comment on the importance of understanding the difference and similarities between different goals of genetic studies: improving etiological understanding or finding variants that discriminate well between cases and controls. This work is particularly relevant today when there has been explosion in the availability of direct-to-consumer DNA tests.In addition to carrying out linkage and association analysis, I also have extended the statistical theory behind score-based linkage analyses for X chromosomal markers. This work has public health relevance because many complex common diseases have sex-specific differences, such as prevalence and age of onset. Modeling those appropriately with powerful and robust methods will bring an improved understanding of their genetic basis.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Jakobsdóttir, Jó, jjakobsdottir@gmail.comJOJ8
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWeeks, Daniel Eweeks@pitt.eduWEEKS0000-0001-9410-7228
Committee MemberFeingold, Eleanorfeingold@pitt.eduFEINGOLD
Committee MemberWeissfeld, Lisa Alweis@pitt.eduLWEIS
Committee MemberMazumdar, Satimaz1@pitt.eduMAZ1
Date: 29 June 2009
Date Type: Completion
Defense Date: 1 April 2009
Approval Date: 29 June 2009
Submission Date: 7 April 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Biostatistics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: age-related macular degeneration; age-related maculopathy; AMD; ARM; complex disease; genetics; QTLs; quantitative trait loci; score statistics; x-linked traits
Other ID:, etd-04072009-094825
Date Deposited: 10 Nov 2011 19:34
Last Modified: 30 Jun 2022 16:19


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