Table 2 - uploaded by Anna Sillén
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The two highest multipoint and single-point nonparametric LOD scores in the complete family material, the APOE e4 positive and APOE e4 negative families, respectively, are listed with the global significance values estimated by simulation
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Alzheimer's disease (AD) is an age-related disease, which affects approximately 40% of the population at an age above 90 years. The heritability is estimated to be greater than 60% and there are rare autosomal dominant forms indicating a significant genetic influence on the disease process. Despite the successes in the early 1990s when four genes w...
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Context 1
... have used the threshold levels suggested by Lander and Kruglyak 32 to define significant and suggestive linkage in this study. As shown in Table 2, the highest LOD score on chromosome 19q13 reached a significant global P- value for the total material as well as the APOE e4 positive families. The second highest LOD score (2.40) located in 5q35.2 is suggestive of linkage. ...
Context 2
... the whole set of families was analysed, a significant LOD score of 4.84 (pointwise P = 1.1 Â 10 À6 , simulated global P-value 0.01) was found close to marker D19S902 in the region of the APOE gene in 19q13.33, Table 2. This was the only LOD score that reached a global significant linkage value according to Lander and Kruglyak's criteria. ...
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... However, increasing evidence points to a different interpretation. For example, a genome-wide linkage study of 71 Swedish late onset AD families found that the strongest signal in a multipoint linkage analysis of APOE ε4-negative families still resided in the APOE region [5]. Furthermore, multiple studies have shown that individuals who carry an African ε4 haplotype of APOE have less risk of developing AD when compared to those with a Caucasian ε4 haplotype [6][7][8]. ...
Increasing evidence suggests that the Translocase of Outer Mitochondria Membrane 40 (TOMM40) gene may contribute to the risk of Alzheimer’s disease (AD). Currently, there is no consensus as to whether TOMM40 expression is up- or down-regulated in AD brains, hindering a clear interpretation of TOMM40’s role in this disease. The aim of this study was to determine if TOMM40 RNA levels differ between AD and control brains. We applied RT-qPCR to study TOMM40 transcription in human postmortem brain (PMB) and assessed associations of these RNA levels with genetic variants in APOE and TOMM40. We also compared TOMM40 RNA levels with mitochondrial functions in human cell lines. Initially, we found that the human genome carries multiple TOMM40 pseudogenes capable of producing highly homologous RNAs that can obscure precise TOMM40 RNA measurements. To circumvent this obstacle, we developed a novel RNA expression assay targeting the primary transcript of TOMM40. Using this assay, we showed that TOMM40 RNA was upregulated in AD PMB. Additionally, elevated TOMM40 RNA levels were associated with decreases in mitochondrial DNA copy number and mitochondrial membrane potential in oxidative stress-challenged cells. Overall, differential transcription of TOMM40 RNA in the brain is associated with AD and could be an indicator of mitochondrial dysfunction.
... A family-wide WGL research study, including EOAD and LOAD patients, is an example presented by the Swedish series. The unique WGL study conducted in different autosomal dominant families uncovered a probable linkage at chromosomal location 5q35 [111]. However, the WGL study did not validate the chromosomal location 5q35 locus even after the inclusion of more families [112], while the study conducted on a few specific families demonstrated a suggestive linkage of AD at chromosomal location 8q24 [113]. ...
Alzheimer’s disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic components. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood with three genes variants such as APP, PSEN1, and PSEN2 leading to disease. On the other hand, some common alleles including APOE are effectively associated with LOAD identified but the genetics of LOAD is not clear to date. It has been accounted that about 5% to 10% of EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented the severity of EOAD risk in carriers, and APOE ε4 allele was considered as a hallmark of EOAD. A great number of EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease- triggering genes yet. Although several genes have been identified through using the technology of next-generation sequencing in EOAD families including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants were identified through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers live into their 90s that propose the presence of other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics of EOAD and LOAD etiology to discover new potential genetics facets which will assist to understand the pathological mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article based on current knowledge represents the overview of the susceptible genes of EOAD, and LOAD. Next, we represent the probable molecular mechanism which might elucidate the genetic etiology of AD and highlight the role of massively parallel sequencing technologies for novel gene discoveries.
... Other genes APP and PSEN1/2 genes together account for less than 5% of all AD cases [66,83]. Hence, GWAS have also revealed AD-associated genes on chromosomes 6,9,10,11,12,14,18,19 [34,172]. The gene on chromosome 12 [145] was mapped to 12q13, a region which encompasses the vitamin D receptor (VDR) gene [193]. ...
Early reviews identified over 20 risk factors associated with Alzheimer's disease (AD) including age, familial inheritance, exposure to aluminium, traumatic brain injury (TBI), and associated co-morbidities such as vascular disease and infection. In the light of recent evidence, this review reconsiders these risk factors, identifies those currently regarded as important, and discusses various hypotheses to explain how they may cause AD. Rare forms of early-onset familial AD (EO-FAD) are strongly linked to causal gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (LO-SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) and many other genes, vascular disease, TBI and risk factors associated with diet, the immune system, mitochondrial function, metal exposure, and infection are all implicated. These risk factors may act collectively to cause AD pathology: 1) by promoting the liberation of oxygen free radicals with age, 2) via environmental stress acting on regulatory genes early and later in life ('dual hit' hypothesis), or 3) by increasing the cumulative 'allostatic load' on the body over a lifetime. As a consequence, life-style changes which reduce the impact of these factors may be necessary to lower the risk of AD.
... 15 Potential involvement of genes on chromosomes 6,9,10,11,12,14,18,19, and X in LOAD has been demonstrated. 16,17 It has been In the present study, our aim was to test the hypothesis of association of the three polymorphisms, rs983392, rs75932628, and rs3865444 of MS4A6A, TREM2, and CD33 genes, respectively, in LOAD patients in an Iranian population in the north west of Iran. ...
Introduction:
Alzheimer's disease (AD), which is a progressive neurodegenerative disorder, causes structural and functional brain disruption. MS4A6A, TREM2, and CD33 gene polymorphisms loci have been found to be associated with the pathobiology of late-onset AD (LOAD). In the present study, we tested the hypothesis of association of LOAD with rs983392, rs75932628, and rs3865444 polymorphisms in MS4A6A, TREM2, CD33 genes, respectively.
Methods:
In the present study, 113 LOAD patients and 100 healthy unrelated age- and gender-matched controls were selected. DNA was extracted from blood samples by the salting-out method and the genotyping was performed by RFLP-PCR. Electrophoresis was carried out on agarose gel. Sequencing was thereafter utilized for the confirmation of the results.
Results:
Only CD33 rs3865444 polymorphism revealed a significant difference in the genotypic frequencies of GG (P = 0.001) and GT (P = 0.001), and allelic frequencies of G (P = 0.033) and T (P = 0.03) between LOAD patients and controls.
Conclusion:
The evidence from the present study suggests that T allele of CD33 rs3865444 polymorphism is associated with LOAD in the studied Iranian population.
... Results from several genome-wide studies of AD have consistently demonstrated linkage to chromosome 19q13, a region including the APOE locus (Blacker et al., 2003;Sillen et al., 2006). In addition to variants in APOE, several other SNPs on chromosome 19q13 also exhibited significant association with LOAD, that is, rs6859 in PVRL2 , rs4420638 in APOC1 (Li et al., 2008), rs59007384 and rs10524523 (poly-T polymorphism) in TOMM40 (Cervantes et al., 2011;Roses et al., 2010). ...
Although multiple susceptibility loci for late-onset Alzheimer’s disease (LOAD) have been identified; a large portion of the genetic risk for this disease remains unexplained. LOAD risk may be associated with single nucleotide polymorphisms responsible for changes in gene expression (eSNPs). To detect eSNPs associated with LOAD, we integrated data from LOAD genome-wide association studies and expression quantitative trait loci using Sherlock (a Bayesian statistical method). We identified a cis-regulatory eSNP (rs2927438) located on chromosome 19q13.32, for which subsequent analyses confirmed the association with both LOAD risk and the expression level of several nearby genes. Importantly, rs2927438 may represent an APOE-independent LOAD eSNP according to the weak linkage disequilibrium of rs2927438 with the two polymorphisms (rs7412 and rs429358) defining the APOE-ε2, -ε3 and -ε4 alleles. Furthermore, rs2927438 does not influence chromatin interaction events at the APOE locus or cis-regulation of APOE expression. Further exploratory analysis revealed that rs2927438 is significantly associated with tau levels in cerebrospinal fluid. Our findings suggest that rs2927438 may confer APOE-independent risk for LOAD.
... Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the gradual progression of memory loss, impairment of cognitive functions and progressive disability [1][2][3]. The end result of the disease is dementing disorder which mostly happens in the elderly people [4][5][6]. ...
Alzheimer’s disease (AD) is neurodegenerative disorder characterized by the gradual memory loss, impairment of cognitive functions and progressive disability. It is known from previous studies that symptoms of AD are due to synaptic dysfunction and neuronal death in the area of the brain, which performs memory consolidation. Thus, the investigation of deviations in various cellular metabolite linkages is crucial to advance our understanding of early disease mechanism and to identify novel therapeutic targets. This study aims to identify small sets of metabolites that could be potential biomarkers of AD. Liquid chromatography/mass spectrometry-quadrupole time of flight (LC/MS-QTOF)-based metabolomics data were used to determine potential biomarkers. The metabolic profiling detected a total of 100 metabolites for 55 AD patients and 55 healthy control. Random forest (RF), a supervised classification algorithm was used to select the important features that might elucidate biomarkers of AD. Mean decrease accuracy of .05 or higher indicates important variables. Out of 100 metabolites, 10 were significantly modified, namely N-(2-hydroxyethyl) icosanamide which had the highest Gini index followed by X11-12-dihyroxy (arachidic) acid, N-(2-hydroxyethyl) palmitamide, phytosphingosine, dihydrosphingosine, deschlorobenzoyl indomenthacin, XZN-2-hydroxyethyl (icos) 11-enamide, X1-hexadecanoyl (sn) glycerol, trypthophan and dihydroceramide C2.
... Interestingly, in current research, abnormalities were seen in 21 patients and a high degrees of anomalies were seen in chromosomes 10q, 9p, 9q, 14p and 19q. Some chromatid type aberrations (CTAs) have also been observed and it has been already reported in the previous studies by Sillen et al. (2006). The effect of copper has no unusual effect on the chromosomes rather commonly known aberrations were seen. ...
Alzheimer’s disease (AD) is the leading neurodegenerative disorder and the cause of dementia in the elderly people. The current research investigated the relevance of AD individuals challenged with copper exposure and the disease onset through cytogenetic and molecular analysis. The research was performed on 70 AD patients categorized into two groups as the early-onset with age below 65 (n=31) and the late-onset aged above 65 (n=39). The chromosomal aberrations (CAs) were examined in both the groups showing higher CAs in the late-onset and the anomalies were seen in the chromosomes 10q, 9p, 9q, 14p and 19q in 21 patients and the micronucleus (MN) assay was also found to be higher in the late-onset patients. Assessment of ApoE gene showed a definite significant difference between the two groups. In this study, the exposure of copper did not reveal any significant changes in the two groups, conversely, the biochemical parameters serotonin, GABA, dopamine and homocysteine were analyzed and a higher level of homocysteine was seen in the late-onset cases. Consequently, from these findings, it is pertinent to believe that, this is the first report in the Tamil Nadu region where the researchers predicted ApoE to be a molecular marker to diagnose AD.
... An example is provided by the familybased WGL study in the Swedish series, which includes both EOAD and LOAD patients. The original WGL study in multiple autosomal dominant families detected a suggestive linkage at chromosome 5q35 [117]. The inclusion of additional families to the WGL analysis did not confirm the 5q35 locus [118], but the investigation of a selected number of families with autopsy confirmed AD revealed a suggestive locus on chromosome 8q24 [119]. ...
... An example is Q6 provided by the familybased GWL study in the Swedish series, which includes both EOAD and LOAD patients. The original WGL study in multiple autosomal dominant families detected a suggestive linkage at chromosome 5q35 [117]. The inclusion of additional families to the WGL analysis did not confirm the 5q35 locus [118], but the investigation of a selected number of families with autopsy confirmed AD revealed a suggestive locus on chromosome 8q24 [119]. ...
As the discovery of the Alzheimer disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a APOE risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.
... Practical support for this is complex. Some studies have showed evidences for a gene (or genes) in this region (52)(53)(54), while others have not (50,51,58). ...
Background:
Alzheimer's disease (AD) is one of the most common problems for old peoples. Etiology of AD is not clear, but genetic factors play a major role in determining a person's risk to develop AD. Twin and family studies confirm that AD has a genetic basis. AD genetics has been split into two broad categories: early-onset and late-onset. EOAD cases are inherited in an autosomal dominant pattern. In this form, dominant mutations in genes like APP, PSEN-1 and PSEN-2 associated with AD. This study aimed to consider the role of genetic in AD.
Method:
At the first, most of the references in relation with genetic basis of AD searched from the following web-sites: PubMed, Science direct, Wiley & Sons (1995-2014). Then, the most common genes and their affects described briefly.
Results:
Aging is the most obvious risk factor for developing AD. There is a genetic basis for AD, of course this relation is not complete but it is significant.
Conclusion:
More than thousand genes studied in relation with Alzheimer's disease. Against the improvements in understanding different aspects of AD, the accurate genetic foundation of AD remain unclear.
