Defense Date


Document Type


Degree Name

Doctor of Philosophy


Human Genetics

First Advisor

Michael C. Neale


Etiological models of complex disease are elusive[46, 33, 9], as are consistently replicable findings for major genetic susceptibility loci[54, 14, 15, 24]. Commonly-cited explanations invoke low-frequency genomic variation[41], allelic heterogeneity at susceptibility loci[33, 30], variable etiological trajectories[18, 17], and epistatic effects between multiple loci; these represent among the most methodologically-challenging issues in molecular genetic studies of complex traits. The response has been con- sistently reactionary—hypotheses regarding the relative contributions of known func- tional elements, or emphasizing a greater role of rare variation[46, 33] have undergone periodic revision, driving increasingly collaborative efforts to ascertain greater numbers of participants and which assay a rapidly-expanding catalogue of human genetic variation. Major deep-sequencing initiatives, such as the 1,000 Genomes Project, are currently identifying human polymorphic sites at frequencies previously unassailable and, not ten years after publication of the first major genome-wide association find- ings, re-sequencing has already begun to displace GWAS as the standard for genetic analysis of complex traits. With studies of complex disease primed for an unprecedented survey of human genetic variation, it is essential that human geneticists address several prominent, problematic aspects of this research. Realizations regarding the boundaries of human traits previously considered to be effectively disparate in presentation[44, 39, 35, 27, 25, 12, 4, 13], as well as profound insight into the extent of human genetic diversity[23, 22] are not without consequence. Whereas the resolution of fine-mapping studies have undergone persistent refinement, recent polygenic findings suggest a less discriminant basis of genetic liability, raising the question of what a given, unitary association finding actually represents. Furthermore, realistic expectations regarding the pattern of findings for a particular genetic factor between or even within populations remain unclear. Of interest herein are methodologies which exploit the finite extent of genomic variability within human populations to distinguish single-point and cumulative group differences in liability to complex traits, the range of allele frequencies for which common association tests are appropriate, and the relevant dimensionality of common genetic variation within ethnically-concordant but differentially ascertained populations. Using high-density SNP genotype data, we consider both hypothesis-driven and agnostic (genome-wide) approaches to association analysis, and address specific issues pertaining to empirical significance and the statistical properties of commonly- applied tests. Lastly, we demonstrate a novel perspective of genome-wide genetic “background” through exhaustive evaluation of fundamental, stochastic genetic processes in a sample of matched affected and unaffected siblings selected from high- density schizophrenia families.


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Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

February 2012