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dc.contributor.advisorSpritz, Richard A.
dc.contributor.authorRoberts, Genevieve Heather Linnea
dc.contributor.committeememberHendricks, Audrey
dc.contributor.committeememberSantorico, Stephanie
dc.contributor.committeememberTaylor, Matthew
dc.contributor.committeememberLeach, Sonia
dc.contributor.committeememberSpritz, Richard
dc.date.accessioned2019-11-21T16:05:37Z
dc.date.available2020-09-25T16:05:40Z
dc.date.submitted2019
dc.descriptionIncludes bibliographical references.
dc.descriptionSummer
dc.description.abstractVitiligo is an autoimmune disease that results in destruction of skin melanocytes and patches of white skin and hair. Family studies demonstrated a strong, but complex inherited basis for vitiligo. Subsequent genome-wide linkage and association studies identified over 50 vitiligo susceptibility loci, with most loci harboring genes involved in immune regulation, apoptosis, or melanocyte function. The identified loci fit together in a model of melanocyte-directed autoimmunity and suggest shared pathobiology between vitiligo and many other autoimmune diseases. In this work, I advance understanding of vitiligo’s etiology beyond the “molecular parts list” found by previous gene-mapping studies by exploring clinical variation among vitiligo cases and the genetic architecture of vitiligo. In summary, I find that early- and late-onset vitiligo represent distinct genetic subtypes differentiated by one extreme-risk Major Histocompatibility class II allele. I additionally find that vitiligo that clusters in families is fundamentally similar to vitiligo that occurs sporadically, though with increased polygenic burden of known common risk alleles segregating in multiplex vitiligo families. Finally, I report that the total proportion of vitiligo risk attributable to genetic factors (or heritability) of vitiligo in Europeans is ~0.8. I find that we can capture nearly all relevant genetic variation with dense SNP arrays and “deep” imputation, but only ~15-20% of total heritability is accounted for by the confirmed known vitiligo susceptibility loci. From this, I conclude that vitiligo is one of the best-understood genetically complex diseases, but a great deal still remains to be discovered. Leveraging what I’ve found, I suggest multiple strategies for the future identification of novel vitiligo risk factors. Furthermore, my analyses underscore the importance of additional investigation into environmental triggers for vitiligo, about which little is currently known.
dc.identifierRoberts_ucdenveramc_1639D_10659.pdf
dc.identifier.urihttps://hdl.handle.net/10968/4589
dc.languageEnglish
dc.publisherUniversity of Colorado at Denver, Anschutz Medical Campus. Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 09/25/2020
dc.subjectFamily Clustering
dc.subject.meshAutoimmune Diseases
dc.subject.meshVitiligo
dc.subject.meshMultifactorial Inheritance
dc.subject.meshAge of Onset
dc.subject.meshQuantitative Trait, Heritable
dc.titleGenetic architecture of vitiligo and vitiligo subtypes, The
dc.typeThesis
dcterms.embargo.expires2020-09-25
thesis.degree.disciplineHuman Medical Genetics & Genomics
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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