نبذة مختصرة : To understand complex phenotypes, medical research has evolved from the study of single genes and proteins to approaches that encompass more comprehensive catalogues of molecules. Among the more widely used are genome-wide expression and high-throughput genotyping, the latter primarily making use of single nucleotide polymorphisms (SNPs) in what has been termed genome-wide association studies (GWAS). Because of the scale of the data sets that are being produced, unique problems have emerged that necessitate the extensive use of bioinformatics tools. This thesis has entailed the analysis of several such large data sets in the context of biological pathways and introduces several bioinformatics solutions. Paper III, IV, and V deal with this topic. This thesis is primarily oriented around the study of Alzheimer disease (AD) and aging. The questions about the etiology of AD are often concurrent with questions about the biology of aging. This thesis pursues insight on genomic factors pertaining to both inquiries, acknowledging that both the AD state and aging itself are complex and multi-factorial. Two constituent papers (I and III) address aging and two papers (II and V) deal with genetic models in the study of AD. In paper I, we examined the association of age with several genetic markers in the insulin degrading enzyme (IDE) and explored possible molecular mechanisms. In contrast to women, both age-at-sampling and age-at-death of the males were significantly lower in individuals that were heterozygous at genetic loci spanning the IDE locus. Plasma insulin levels and the expression levels of the gene were found to be higher in those same heterozygous males. In paper II, SNPs in 25 genes involved in cholesterol metabolism were tested for association with AD and dementia. Genetic markers in a large linkage disequilibrium block spanning SREBF1, TOM1L2, and ATPAF2 were significantly associated with disease. Gene expression and gene network analyses supported the findings. In paper III, we investigated the biological ...
Relation: I. Mun-Gwan Hong, Chandra Reynolds, Margaret Gatz, Boo Johansson, Jennifer C. Palmer, Harvest F. Gu, Kaj Blennow, Patrick G. Kehoe, Ulf de Faire, Nancy L. Pedersen and Jonathan A. Prince. Evidence that the gene encoding insulin degrading enzyme influences human lifespan. Human Molecular Genetics. (2008) 17:2370-2378. ::doi::10.1093/hmg/ddn137 ::pmid::18448515 ::isi::000257788300012; II. Chandra A. Reynolds, Mun-Gwan Hong, Ulrika K. Eriksson, Kaj Blennow, Fredrik Wiklund, Boo Johansson, Bo Malmberg, Stig Berg, Andrey Alexeyenko, Henrik Grönberg, Margaret Gatz, Nancy L. Pedersen and Jonathan A. Prince. Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk. Human Molecular Genetics. (2010) 19:2068-2078. ::doi::10.1093/hmg/ddq079 ::pmid::20167577 ::isi::000277238200019; III. Mun-Gwan Hong, Amanda J. Myers, Patrik K. E. Magnusson and Jonathan A. Prince. Transcriptome-wide assessment of human brain and lymphocyte senescence. PLoS ONE. (2008) 3:e3024. ::doi::10.1371/journal.pone.0003024 ::pmid::18714388 ::isi::000264420900046; IV. Mun-Gwan Hong, Yudi Pawitan, Patrik K. E. Magnusson and Jonathan A. Prince. Strategies and issues in the detection of pathway enrichment in genome-wide association studies. Human Genetics. (2009) 126:289-301. ::doi::10.1007/s00439-009-0676-z ::pmid::19408013 ::isi::000269056500006; V. Mun-Gwan Hong, Andrey Alexeyenko, Jean-Charles Lambert, Philippe Amouyel and Jonathan A Prince. Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease. Journal of Human Genetics. (2010) 55:707–709. ::doi::10.1038/jhg.2010.92 ::pmid::20668461 ::isi::000283379600014; http://hdl.handle.net/10616/40433
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