The Proteomic Landscape of Human Disease: Construction and Evaluation of Networks Associated to Complex Traits

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The Proteomic Landscape of Human Disease: Construction and Evaluation of Networks Associated to Complex Traits

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dc.contributor.advisor Daly, Mark Joseph
dc.contributor.advisor Hirschhorn, Joel Naom
dc.contributor.author Rossin, Elizabeth Jeffries
dc.date.accessioned 2012-11-15T15:59:42Z
dash.embargo.terms 2014-10-05 en_US
dash.embargo.terms 2014-10-05
dc.date.issued 2012-11-15
dc.date.submitted 2012
dc.identifier.other http://dissertations.umi.com/gsas.harvard:10514 en
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:9909632
dc.description.abstract Genetic mapping of complex traits has been successful over the last decade, with over 2,000 regions in the genome associated to disease. Yet, the translation of these findings into a better understanding of disease biology is not straightforward. The true promise of human genetics lies in its ability to explain disease etiology, and the need to translate genetic findings into a better understanding of biological processes is of great relevance to the community. We hypothesized that integrating genetics and protein- protein interaction (PPI) networks would shed light on the relationship among genes associated to complex traits, ultimately to help guide understanding of disease biology. First, we discuss the design, testing and implementation of a novel in silico approach (“DAPPLE”) to rigorously ask whether loci associated to complex traits code for proteins that form significantly connected networks. Using a high-confidence set of publically available physical interactions, we show that loci associated to autoimmune diseases code for proteins that assemble into significantly connected networks and that these networks are predictive of new genetic variants associated to the phenotypes in question. Next, we study variation in the electrocardiographic QT-interval, a heritable phenotype that when prolonged is a risk factor for cardiac arrhythmia and sudden cardiac death. We show that a large proportion of QT-associated loci encode proteins that are members of complexes identified by immunoprecipitations in mouse cardiac tissue of proteins known to be causal of Mendelian long-QT syndrome. For several of the identified proteins, we show they affect cardiac ion channel currents in model organisms. Using replication genotyping in 17,500 individuals, we use the complexes to identify genome-wide significant loci that would have otherwise been missed. Finally, we consider whether PPIs can be used to interpret rare and de novo variation discovered through recent technological advances in exome-sequencing. We report a highly connected network underlying de novo variants discovered in an autism trio exome-sequencing effort, and we design, test and implement a novel statistical framework (“DAPPLE/SEQ”) to analyze rare inherited variants in the context of PPIs in a way that significantly boosts power to detect association. en_US
dc.language.iso en_US en_US
dash.license LAA
dc.subject GWAS en_US
dc.subject network en_US
dc.subject protein-protein interaction en_US
dc.subject proteomics en_US
dc.subject sequencing en_US
dc.subject genetics en_US
dc.title The Proteomic Landscape of Human Disease: Construction and Evaluation of Networks Associated to Complex Traits en_US
dc.type Thesis or Dissertation en_US
dash.depositing.author Rossin, Elizabeth Jeffries
dc.date.available 2014-10-06T07:30:37Z
thesis.degree.date 2012 en_US
thesis.degree.discipline Biological and Biomedical Sciences en_US
thesis.degree.grantor Harvard University en_US
thesis.degree.level doctoral en_US
thesis.degree.name Ph.D. en_US
dc.contributor.committeeMember Regev, Aviv en_US
dc.contributor.committeeMember Stranger, Barbara en_US
dc.contributor.committeeMember Kraft, Peter en_US

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