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Imaging genetics of MECP2

Abstract

The gene MECP2 is a profound mediator of both brain structure and disease. While it is known that MECP2 causes 90% of Rett Syndrome patients in women, its role in determining both brain structure in normal populations and in the etiology of autism in boys is largely unknown. This dissertation focuses on the integration of genetic and brain imaging data, with mass-computing and statistics, to further understand the role that this crucial CNS gene plays on the outcome of human brain volume and morphology in humans. The first study examined common variation in MECP2 derived from genotyping in an ethnically homogeneous population of 300 Norwegians in various disease states from the TOP study. A highly significant association was detected, in males only, between variation in MECP2 and brain structure measures including cortical surface area and overall brain volume, along with subcortical structures. The cortical surface area association replicated in an independent sample from the ADNI study, and several specific cortical regions were significant in both studies. This finding led to the next-generation deep sequencing of MECP2 in autistic boys, in the search for both exonic and regulatory mutations that may cause or modify autism. A synonomous exonic variant and 9 3'UTR variants, undetected in controls, were discovered. Haplotype association combining data from AGRE, the Wellderly Study, and HapMap showed enrichment of a rare haplotype in autistics and a possibly protective haplotype enriched in controls. Many novel single nucleotide and indel variants were discovered, some in putative functional elements. The final study attempts to link genetic sequence data with brain imaging data, using construction of genetic variables for input into morphology analysis, and a sequence-based multivariate distance matrix regression method (MDMR) for in silico functional characterization of the many variants detected. The rare enriched haplotype, possessed by nine autism patients, showed significant morphology differences, usually lateral to medial ingrowth, in the hippocampus, thalamus, cerebellum, and pallidum. The protective haplotype showed lateral hippocampal outgrowth. Sequence- based association picked up two potential functional indels in the promoter region that were associated with multiple brain measures. It is the hope of this author that this work has contributed to an understanding of the etiology of autism, and provided a method to use next- generation sequencing data to uncover variants that affect any potential phenotype examined

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