Download or read book Identification of Functional Variants in Alzheimer s Disease associated Genes written by Sheng Chih Jin and published by . This book was released on 2014 with total page 210 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alzheimer's disease (AD) is the most common form of dementia affecting the health of more than 5 million Americans in 2013. Understanding how genetic variants contribute to AD is important to develop effective therapeutics for delaying and eventually curing the disease. Recent sequencing studies have identified rare variants p.V232M in PLD3 and p.R47H in TREM2 significantly associated with AD risk. Additionally, genome-wide association studies (GWAS) uncovered common variants in ABCA7, BIN1, CD33, CD2AP, CLU, CR1, EPHA1, MS4A4A, and PICALM that contribute to AD; however, the most-significant variants in these loci are located within non-coding regions and have no direct functional impact on AD pathogenesis. We hypothesized that if PLD3 and TREM2 are truly AD risk genes, they will carry additional functional variants that can substantially affect AD risk. Moreover, we hypothesized that GWAS genes carry additional risk alleles across the frequency spectrum so that common, low frequency or rare variants within these genes may contribute to AD risk. We undertook pooled sequencing of exonic and flanking intronic sequence for the aforementioned genes in 3,730 European Americans (EA) (2,082 AD cases and 1,648 controls) and 336 African Americans (AA) (204 AD cases and 132 controls). We found rare variants in PLD3 and TREM2 are more frequently seen in cases than in controls of EA descent. Single-variant analyses showed that p.M6R and p.A442A in PLD3 and p.R62H in TREM2 are significantly associated with AD risk besides p.V232M in PLD3 and p.R47H in TREM2. We found rare variants in PLD3 (P[subscript SKAT-O]1.44 x 10−11) and TREM2 (P[subscript SKAT-O]5.37 x 10−7) are genome-wide significantly associated with AD. Additionally, we found a significant association for PLD3 coding variants with AD risk in AA (P[subscript SKAT-O]1.40 x 10−3). However, we did not find evidence of association for TREM2 variants with AD risk in AA. We validated 90 coding variants in GWAS-identified genes and bioinformatic analyses implicated that a large proportion of these variants are functional. The International Genomics of Alzheimer's Project recently performed meta- and gene-wide analyses and identified 23 loci associated with AD risk, of which 13 were novel. However, these loci's role in affecting the molecular pathways of AD remains unknown. To determine whether these loci are also associated with cerebrospinal fluid (CSF) amyloid-beta 1-42 (A[beta]42) and phosphorylated tau11 (ptau11) levels, we combined CSF biomarker datasets from several studies and performed single-variant, set-based, and conditional analyses for each locus. In the APOE locus, rs769449 is genome-wide significantly associated with CSFA[beta]42 and ptau11 levels independently of APOE-[epsilon]2 and APOE-[epsilon]4 SNPs and the association for CSF ptau181 levels was not driven by A[beta] metabolism. We found rs7937331, within the CELF1 fine-mapping region, tags the same signal as the IGAP top SNP (rs62003531) and is significantly associated with CSF A[beta]42 levels and AD risk. Additionally, rs62003531, located in the intronic region of FERMT2, tags the same association as the IGAP top SNP (rs17125944) and is associated with CSF A[beta]42 levels. None of the SNPs within the IGAP-identified AD risk loci except the APOE locus are significantly associated with CSF ptau181 levels after multiple test correction. In investigating the potential regulatory functions associated with IGAP top SNPs and CSF top SNPs, most of GWAS top SNPs have no significant regulatory potential and are unlikely to be functional variants for AD risk. However, RegulomeDB predicts that several proxy SNPs in linkage disequilibrium (LD) with rs7937331 may be cis-acting expression quantitative trait loci (eQTLs) for nearby genes. The IGAP study also identified an intergenic polymorphism near TREML2 suggestively associated with AD risk; however, due to the study design, it was not possible to uncover the underlying functional variant or to determine whether this observed association was driven by the known AD risk allele, TREM2 p.R47H, or represented a novel locus. We performed analyses using whole-exome sequencing data, CSF biomarker analyses and meta-analyses to demonstrate that the AD risk association is likely driven by a TREML2 variant p.S144G (rs3747742) independently of TREM2 p.R47H risk for AD. Finally, we sought to functionally characterize the effects of novel TREM2 variants on TREM2 cell surface transport. We transduced a T cell hybridoma cell line with virus containing TREM2 wild type (WT) and risk variants and measured TREM2 cell surface expression with a TREM2-specific monoclonal antibody. We found cells expressing p.T66M and p.R136W have a robust effect on TREM2 cell surface expression but cells expressing p.R47H and p.R62H are similar to hTREM2 WT. Additionally, since polymorphisms in the CELF1 fine-mapping region were implicated to be eQTLs for nearby genes, we performed cis-eQTL analysis for mRNA expression levels in several brain regions using four publicly available datasets to identify genetic determinants of gene expression in human brains. We found several C1QTNF4-expression-associated SNPs which tag the same signal are in LD with rs7937331, the top CSF A[beta]42 SNP in the CELF1 fine-mapping region. Additionally, we found evidence of differential expression in the C1QTNF4 transcript between AD cases and controls in human brains. These findings provide additional evidence that genes involved in the inflammatory response play an important role in AD pathogenesis.

Download or read book Genetic Variants in Alzheimer s Disease written by Kevin Morgan and published by Springer Science & Business Media. This book was released on 2013-06-22 with total page 257 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alzheimer’s Disease is the most common form of dementia. The disease is characterised by the loss of synapses and neurons in the cerebral cortex and certain subcortical regions. In the last three years, the genetics of Alzheimer’s Disease has made significant advances; in fact, one could argue more than in the previous two decades. This has resulted in the identification of nine new genes and perhaps more importantly the realization that new pathways could be involved in the pathogenesis of Alzheimer’s. These new pathways are now legitimate targets for therapeutic intervention, which can possibly lead to treatment or a possible cure. The aim of this book is to put all of the recent genetic data on these new genes into context. Different genetic variants will be discussed, as well as biomarkers and future possibilities. ​

Download or read book Identification of Functional Variants in the Alzheimer s Disease Candidate Gene ABCA7 written by Naomi Susan Clement and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Exploring Potential Functional Variants in the Alzheimer s Disease Associated Genes CD2AP EPHA1 and CD33 written by Anne Braae and published by . This book was released on 2016 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Alzheimer s and Parkinson s Diseases written by Israel Hanin and published by Springer Science & Business Media. This book was released on 2013-06-29 with total page 690 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book represents the third in a series of International Conferences related to Alzheimer's (AD) and Parkinson's (PD) diseases. The first one took place in Eilat, Israel, in 1985; and the second one in Kyoto, Japan, in 1989. This book contains the full text of oral and poster presentations from the Third International Conference on Alzheimer's and Parkinson's Diseases: Recent Developments, held in Chicago, Illinois, U.S.A. on November 1-6, 1993. The Chicago Conference was attended by 270 participants. The Scientific Program was divided into nine oral sessions, a keynote presentation, and a poster session. The conference culminated in a Round Table Discussion involving all of the participants in the conference. The four and one-half day meeting served as an excellent medium for surveying the current status of clinical and preclinical developments in AD and PD. There were 59 oral presentations and 93 posters. This book incorporates a majority of both.

Download or read book Identification of Novel Variants Associated with Alzheimer s Disease Using Quantitative Traits written by Yuetiva Karenina Robles and published by . This book was released on 2017 with total page 235 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alzheimer's disease (AD) is the most common neurodegenerative disease causing dementia in more than 5.4 million individuals in the United States. AD is a complex disease with a large genetic factor. Genetic linkage studies identified three causal genes for the Mendelian form of AD, and genome-wide association studies (GWAS) have discovered more than 25 genetic loci associated with AD risk. However, it is unclear how these loci influence AD, or if they are associated with other AD phenotypes such as age at onset (AAO) or disease progression. Loci identified thus far explain less than half of the estimated genetic influence on risk, suggesting there are many more to be identified. Genetic studies of endophenotypes, biomarkers that are genetically correlated with disease and part of the causal pathway, have successfully identified novel genetic loci associated with AD risk and other phenotypes. We hypothesized that genetic studies using potential and well-validated endophenotypes may reveal novel associations with disease and provide important information about biology underlying the genetic architecture shared between the endophenotype and disease, not only with risk but also disease modifiers such as AAO or rate of cognitive decline. We also hypothesized that we could identify novel endophenotypes by unbiased genetic studies of a variety of biologically relevant protein levels.To identify plasma proteins that may be biomarkers for complex traits, including AD, we performed single-variant analyses on 818 individuals with levels of 146 plasma proteins measured using a multiplex immunoassay. This multiplex assay included a wide variety of proteins such as markers of various diseases and biological mechanisms. Although we did not identify novel AD biomarkers, we did identify promising novel biomarkers for multiple sclerosis and stroke, among others. We also observed evidence of complex genetic regulation of several proteins including potential pleiotropy and loci with multiple variants independently influencing protein levels.Several putative CSF biomarkers for AD have emerged the past few years, including angiotensin-converting enzyme (ACE), clusterin (CLU), and chitinase-3-like protein 1 (also known as YKL-40, encoded by CHI3L1). We wanted to determine whether these potential biomarkers could also be AD endophenotypes; therefore, we analyzed these proteins in addition to known endophenotypes for AD: CSF amyloid-beta (A[beta]42), phosphorylated tau (ptau181), tau, and apolipoprotein E (ApoE). ACE, ApoE, and YKL-40 levels were associated with the respective protein encoding genetic loci (ACE, APOE, and CHI3L1 respectively). The top loci for ACE and ApoE were also associated with AD risk and AAO, suggesting these may be informative for pathogenesis influencing disease onset. We did not find evidence that YKL-40 is an AD endophenotype, but CSF levels of YKL-40 positively correlated with both tau and ptau181 and the strength of the correlation significantly increased after including the genetic information from the associated locus. This suggests that biomarker studies may benefit by including genetic information. Our genetic analyses of CSF tau, ptau181, and A[beta]42 replicated results published previously from a smaller cohort and revealed two novel loci associated with ptau181. For the first time, we also identified two loci outside the APOE region that were associated with A[beta]42 which were also associated with AD risk (GLIS1 on 1p32.3: [beta] = 0.100, P = 3.43x10−2), disease progression (GLIS1: [beta] = 0.277, P = 1.92x10−2), and AAO (SERPINB1 on 6p25: [beta] = 0.043, P = 4.62x10−3).Most of the loci identified were non-coding; therefore, requiring additional analyses to determine the functional genetic traits affecting protein levels and potentially influencing AD phenotypes. We analyzed CSF levels of ACE and ApoE with available exome-chip and whole-genome data to identify coding variants. ApoE levels appeared to be driven by APOE genotype, there were no additional variants associated with ApoE levels. Several variants for ptau181 and A[beta]42 were predicted to alter regulatory motifs and affect protein binding. In order to ascertain the functional genes potentially driving the genetic association, we searched for SNPs with expression quantitative trait locus effects in human tissues. Analyses indicated that the same variant on 6p25 influenced A[beta]42 levels and expression of SERPINB1, which is a key regulator for neutrophil activity. Recently A[beta]42 was reported necessary to trigger infiltration of neutrophils into the brain, and with our findings, adds to the growing evidence that immune response plays a key role in AD pathogenicity. By utilizing quantitative traits such as endophenotypes in genetic studies we obtained results that will inform future studies.

Download or read book MicroRNAs in Diseases and Disorders written by Philip V Peplow and published by Royal Society of Chemistry. This book was released on 2019-05-07 with total page 500 pages. Available in PDF, EPUB and Kindle. Book excerpt: From pathology to treatment, MicroRNAs in Diseases and Disorders highlights the role of microRNAs (miRNAs) in the development and progression of a variety of diseases, including cancer, neurological disease, endocrine disease and autoimmune disease, and underscores the utilization of miRNA targets in the treatment of these conditions. Providing a comprehensive account, this book also includes the identification of miRNAs as diagnostic and prognostic biomarkers for disease, as well as evaluates translational value from clinical trials using synthesized and functionalized miRNA mimics and inhibitors. With a global contribution list and chapters from leading experts across the field, MicroRNAs in Diseases and Disorders is an invaluable reference to miRNA researchers and health professionals in a variety of disease areas in government, academia and industry. The book will also appeal to pharmaceutical and medicinal chemists with an interest in miRNA targeting therapeutics, as well as to advanced students in chemical biology and drug discovery.

Download or read book Molecular Biology of Alzheimer s Disease written by Christian Haass and published by CRC Press. This book was released on 2003-09-02 with total page 350 pages. Available in PDF, EPUB and Kindle. Book excerpt: Highlighting the latest and the most timely aspects of Alzheimer's disease research, this text will enable scientists in related research fields, as well as physicians working with Alzheimer's disease patients, to obtain a quick and complete overview of the current state of the art in one of the most exciting fields in neuroscience research. Leading scientists have contributed articles focusing on key developments in this field. This includes an overview about the pathology, the genetics of familial Alzheimer's disease, proteolytic generation and aggregation of amyloid -peptide, presenilins, risk factors such as ApoE, and transgenic animal models. Some of the latest developments in Alzheimer's disease research, including the effect of presenilin knock outs on amyloid -peptide generation, are also included.

Download or read book Identification and Functional Characterization of Genetic Risk Factors in Alzheimer s Disease written by Kerstin Eckart and published by . This book was released on 2009 with total page 442 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Medical Genetics of Alzheimer s Disease written by Garden Grove Garden Grove Press and published by . This book was released on 2017-04-05 with total page 232 pages. Available in PDF, EPUB and Kindle. Book excerpt: This article collection reviews the medical genetics of Alzheimer's disease and includes 25 papers by various authors. Topics include: Genetics ignite focus on microglial inflammation in Alzheimer's disease; DYRK1A genetic variants are not linked to Alzheimer's disease in a Spanish case-control cohort; A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer's disease in males carrying an apolipoprotein E epsilon4 allele; Genetic variants conferring susceptibility to Alzheimer's disease in the general population; do they also predispose to dementia in Down's syndrome; Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer's disease; Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham study; Allele-specific polymerase chain reaction for the detection of Alzheimer's disease-related single nucleotide polymorphisms; Current concepts in Alzheimer's Disease: molecules, models and translational perspectives; Association of MAPT haplotypes with Alzheimer's disease risk and MAPT brain gene expression levels; Active immunotherapy options for Alzheimer's disease; The role of exosomes in the pathogenesis of Alzheimer's disease; TP73 allelic expression in human brain and allele frequencies in Alzheimer's disease; Genetics of vascular dementia - review from the ICVD working group; The algorithm for Alzheimer risk assessment based on APOE promoter polymorphisms; Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer's disease; Caspase-1 genetic variation is not associated with Alzheimer's disease risk; Would you want to know? Public attitudes on early diagnostic testing for Alzheimer's disease; A loss of function variant in CASP7 protects against Alzheimer's disease in homozygous APOE epsilon4 allele carriers; Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer's disease; Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease; Aneuploidy-driven non-heritable genomic variations demonstrate area-specific distribution in the Alzheimer's disease brain; The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease; Genetic effect of interleukin-1 beta (C-511T) polymorphism on the structural covariance network and white matter integrity in Alzheimer's disease; ZnT3 mRNA levels are reduced in Alzheimer's disease post-mortem brain; Data mining of high density genomic variant data for prediction of Alzheimer's disease risk. Proceeds from the sale of this book go to the support of an elderly disabled person.

Download or read book Epigenetics of Aging written by Trygve O. Tollefsbol and published by Springer Science & Business Media. This book was released on 2009-11-11 with total page 462 pages. Available in PDF, EPUB and Kindle. Book excerpt: Recent studies have indicated that epigenetic processes may play a major role in both cellular and organismal aging. These epigenetic processes include not only DNA methylation and histone modifications, but also extend to many other epigenetic mediators such as the polycomb group proteins, chromosomal position effects, and noncoding RNA. The topics of this book range from fundamental changes in DNA methylation in aging to the most recent research on intervention into epigenetic modifications to modulate the aging process. The major topics of epigenetics and aging covered in this book are: 1) DNA methylation and histone modifications in aging; 2) Other epigenetic processes and aging; 3) Impact of epigenetics on aging; 4) Epigenetics of age-related diseases; 5) Epigenetic interventions and aging: and 6) Future directions in epigenetic aging research. The most studied of epigenetic processes, DNA methylation, has been associated with cellular aging and aging of organisms for many years. It is now apparent that both global and gene-specific alterations occur not only in DNA methylation during aging, but also in several histone alterations. Many epigenetic alterations can have an impact on aging processes such as stem cell aging, control of telomerase, modifications of telomeres, and epigenetic drift can impact the aging process as evident in the recent studies of aging monozygotic twins. Numerous age-related diseases are affected by epigenetic mechanisms. For example, recent studies have shown that DNA methylation is altered in Alzheimer’s disease and autoimmunity. Other prevalent diseases that have been associated with age-related epigenetic changes include cancer and diabetes. Paternal age and epigenetic changes appear to have an effect on schizophrenia and epigenetic silencing has been associated with several of the progeroid syndromes of premature aging. Moreover, the impact of dietary or drug intervention into epigenetic processes as they affect normal aging or age-related diseases is becoming increasingly feasible.

Download or read book Neurodegeneration and Alzheimer s Disease written by Ralph N. Martins and published by John Wiley & Sons. This book was released on 2019-07-10 with total page 548 pages. Available in PDF, EPUB and Kindle. Book excerpt: Understanding the impact of diet, exercise, genetics, and hormones on the risk and development of Alzheimer’s and other neurogenerative diseases Diet is widely known to impact on neurological function. Nevertheless, academic texts discussing this relationship are relatively few in number. This book therefore fills an important gap in the current literature. Opening with an overview of neurodegenerative diseases, particularly Alzheimer’s disease, the text then focuses on explaining the means by which glycemic control and lipid metabolism – and associated nutritional and lifestyle variables – may factor into such disorders’ prevention and treatment. An international group of experts in the fields of food science and neurodegeneration have contributed chapters that examine Alzheimer’s disease within a broad range of contexts. Offering dietary, genetic, and hormonal perspectives, the authors explore topics ranging from sugar consumption to digestive fermentation, and Alzheimer’s disease animal models to the cognition-enhancing effects of physical exercise. Also included are overviews of the latest research into current and developing methods of treatment and diagnosis, as well as differential diagnostics. This groundbreaking book: Explores how glucose metabolism, insulin resistance, lipid metabolism, and high intake of refined carbohydrates are linked to Alzheimer's disease Discusses how genetic makeup can impact risk of Alzheimer’s and Parkinson’s disease Examines cognitive changes in neurodegeneration, lists current tests for determining cognitive impairment, and provides information concerning differential diagnosis Discusses potential advantages of increasing antioxidant and micronutrient intake Reviews hormonal influences on neurodegeneration Examines the links between protein intake and Alzheimer’s disease. Neurodegeneration and Alzheimer's Disease is an essential resource for researchers, medical practitioners, dietitians, and students with an interest in neurological diseases and their diagnosis and risk factors, as well as diet-related conditions such as diabetes and obesity. Lifestyle and diet influence neurodegeneration risk, and a better understanding of this evidence amongst health professionals will hopefully lead to greater public awareness of how to reduce the likelihood of these widespread conditions.

Download or read book Apolipoprotein E and Alzheimer s Disease written by A.D. Roses and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 208 pages. Available in PDF, EPUB and Kindle. Book excerpt: There is now considerable genetic evidence that the type 4 allele of the apolipoprotein E gene is a major susceptibility factor associated with late-onset Alzheimer's disease, the common form of the disease defined as starting after sixty years of age. The role of apolipoprotein E in normal brain metabolism and in the pathogenesis of Alzheimer's disease are new and exciting avenues of research. This book, written by the most outstanding scientists in this new filed, is the first presentation of results concerning the implications of apolipoprotein E on the genetics, cell biology, neuropathology, biochemistry, and therapeutic management of Alzheimer's disease.

Download or read book Role of Genomic Copy Number Variation in Alzheimer s Disease and Mild Cognitive Impairment written by Shanker Swaminathan and published by . This book was released on 2012 with total page 274 pages. Available in PDF, EPUB and Kindle. Book excerpt: Alzheimer's disease (AD) is the most common form of dementia defined by loss in memory and cognitive abilities severe enough to interfere significantly with daily life activities. Amnestic mild cognitive impairment (MCI) is a clinical condition in which an individual has memory deficits not normal for the individual's age, but not severe enough to interfere significantly with daily functioning. Every year, approximately 10-15% of individuals with MCI will progress to dementia. Currently, there is no treatment to slow or halt AD progression, but research studies are being conducted to identify causes that can lead to its earlier diagnosis and treatment. Genetic variation plays a key role in the development of AD, but not all genetic factors associated with the disease have been identified. Copy number variants (CNVs), a form of genetic variation, are DNA regions that have added genetic material (duplications) or loss of genetic material (deletions). The regions may overlap one or more genes possibly affecting their function. CNVs have been shown to play a role in certain diseases. At the start of this work, only one published study had examined CNVs in late-onset AD and none had examined MCI. In order to determine the possible involvement of CNVs in AD and MCI susceptibility, genome-wide CNV analyses were performed in participants from three cohorts: the ADNI cohort, the NIA-LOAD/NCRAD Family Study cohort, and a unique cohort of clinically characterized and neuropathologically verified individuals. Only participants with DNA samples extracted from blood/brain tissue were included in the analyses. CNV calls were generated using genome-wide array data available on these samples. After detailed quality review, case (AD and/or MCI)/control association analyses including candidate gene and genome-wide approaches were performed. Although no excess CNV burden was observed in cases compared to controls in the three cohorts, gene-based association analyses identified a number of genes including the AD candidate genes CHRFAM7A, RELN and DOPEY2. Thus, the present work highlights the possible role of CNVs in AD and MCI susceptibility warranting further investigation. Future work will include replication of the findings in independent samples and confirmation by molecular validation experiments.

Download or read book Assessing Multivariate Analysis of GWAS for Identification of Genetic Variants in Alzheimer s Disease written by Priya Bhatt and published by . This book was released on 2012 with total page 168 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Biological and Medical Data Analysis written by José Luis Oliveira and published by Springer. This book was released on 2005-10-24 with total page 413 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book History of Human Genetics written by Heike I. Petermann and published by Springer. This book was released on 2017-05-10 with total page 562 pages. Available in PDF, EPUB and Kindle. Book excerpt: Written by 30 authors from all over the world, this book provides a unique overview of exciting discoveries and surprising developments in human genetics over the last 50 years. The individual contributions, based on seven international workshops on the history of human genetics, cover a diverse range of topics, including the early years of the discipline, gene mapping and diagnostics. Further, they discuss the status quo of human genetics in different countries and highlight the value of genetic counseling as an important subfield of medical genetics.