A genetic-epidemiologic study of Alzheimer’s disease

摘要: textabstractAlzheimer's disease (AD) is the most frequent cause of dementia and thus a major public-health problem. Age genetic predisposition to are important risk factors. In 2001 more than 24 million people in western world had dementia. This number expected double every 20 years up 81 2040 because anticipated increase life expectancy. Genetically, AD heterogeneous disorder with both familial sporadic forms. Chapter 1 general introduction on epidemiological factors also describes different studies performed this thesis. In chapter 2 linkage presented. Chapter 2.1 whole genome screen 112 patients their first-degree relatives from Genetics Research Isolated Populations (GRIP) study. Of patients, 103 could be connected into an extremely large complex pedigree. pedigree cannot analyzed available software. study, we developed algorithm for splitting pedigrees allow us conduct analysis. Then determined wide significance thresholds analysis using sub obtained by our cutting finally, sing these pedigrees. The strongest evidence was chromosome 1q21 (HLOD = 5.20, at marker D1S498), which locus identified earlier. We confirmed 10q24 4.15, D10S185). There significant chromosomes 3q23 4.44 D3S1569) and! 18q12 3.68, D18S1152). Several single families contributed strong signals 1, 3 18. Multiple moderate signal locus. Finally, there suggestive 11q24 3.29, D11S1320).. sequenced obvious candidate genes nicastrin (NCST) C-reactive protein (CRP) but no mutations were found. 21 including transferrin gene, gene encoding butyrilcholinesterase, neprilysin somatostatin gene. screened variants found. In 2.2 present combined association study between microtubule associated tau (MAPT) granulin (GRN) AD. investigated region MAPT plus other eight (including GRN gene) five putative GRIP studied 122 85 control subjects extensive Single Nucleotide Polymorphism (SNP) panel. No found any individual SNP 7 tagging SNPs excluded linkage. Nominally two located 722 kb upstream N-myristoyltransferase (NMT1) 17 meta all conducted date associations stratified APOE*4. very modest non-signif! icant carriers H2 haplotype compared H1/H1 carriers, only those APOE*4 allele. These findings suggest that do not play role population. Aiming find involved AD, 2.3 extended Dutch family nine affected individuals. Two peaks above 1.0 7. A further analyses individuals yielded LOD score 2.92 combination loci suggesting epistatic effect loci. used literature mining strategy prioritize selection defined Our approach suggested as potential regions CASP9, TNFRSF1B MTHFR CDK5 NOS3 have been previously apoptosis. CASP9 selected sequencing. coding exons or splice sites rare allele rs9872 pres! ent maybe family. Chapter thesis. Three carried out Rotterdam Study (chapters 3.1-3.3) prospective determinants diseases elderly one (chapter 3.4). 3.1 tested 5 significantly increased GG genotype rs2069442 (OR=1.8, 95% CI 1.16-2.79, p=0.009) without showed C, G rs2069442, (p=0.05) result alterations expression Cdk5 may relevant neurodegenerative processes Taken together, results chapters underscore relevance AD. We evaluated relationship cholesteryl ester transfer (CETP) 3.2. Here show positive VV I405V polymorphism CETP independently APOE systemic HDL levels. Since lower levels higher HDL, compatible view low through reduction neuronal repair capacity. In 3.3 ubiquilin (UBQLN1) Parkinsonâ?Ts (PD) cognitive function. ubiquitination machinery, related degradation. downstream exon 8 (rs12344615) UBQLN1 has difference PD CC 12344615 overall Study. did based detected data it unlikely function. Chapter 3.4 shows 14-kb deletion extending DJ-1 case-control controls ascertained 191 demented 129 non-demented controls. presence heterozygous (two control) within generations suggestion common origin deletion. Form exclude developing Variations However, haploinsufficiency factor isolated population. Finally, 4 provides discussion presented thesis put perspective future studies.