Genetics Research
rs11754661
Gene: MTHFD1L — Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 1 Like
Chr 6:150885942
6q25.1
Intron Variant
Population Frequencies12
African
G 0.98696A 0.01304GG 0.974072GA/AG 0.025769AA 0.000159pop=50,216
African American
G 0.98649A 0.01351GG 0.973137GA/AG 0.026698AA 0.000165pop=48,394
African Others
G 0.9995A 0.0005GG 0.998902GA/AG 0.001098AA 0pop=1,822
Asian
G 0.96439A 0.03561GG 0.930671GA/AG 0.067445AA 0.001884pop=15,924
East Asian
G 0.96988A 0.03012GG 0.940779GA/AG 0.058208AA 0.001012pop=11,854
European
G 0.933756A 0.066244GG 0.871926GA/AG 0.12366AA 0.004414pop=467,590
Latin American 1
G 0.9596A 0.0404GG 0.92158GA/AG 0.076096AA 0.002324pop=6,886
Latin American 2
G 0.96646A 0.03354GG 0.934367GA/AG 0.06419AA 0.001442pop=11,092
Other
G 0.94638A 0.05362GG 0.896184GA/AG 0.100401AA 0.003415pop=23,426
Other Asian
G 0.9484A 0.0516GG 0.901229GA/AG 0.094349AA 0.004423pop=4,070
South Asian
G 0.9596A 0.0404GG 0.921296GA/AG 0.07662AA 0.002083pop=8,640
Studies73
Unread Studies73 ▼
1
… The rs11754661 polymorphism in MTHFD1L modulates depression risk indirectly through its influence on rumination—a key cognitive phenotype—with the A allele demonstrating …
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Late-onset Alzheimer′s disease (AD) is a complex and heterogeneous neurodegenerative disease with significant genetic components implicated in at least 97 loci from AD genome-…
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As development and ageing are, to some extent, two intertwined processes in the healthy brain, the question of whether neurodevelopmental disorders and neurodegenerative …
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Alzheimer’s disease (AD) is one of the multifaceted neurodegenerative diseases influenced by many genetic and epigenetic factors. Genetic factors are merely not responsible for developing AD in the whole population. The studies of genetic variants can provide significant insights into the molecular basis of Alzheimer’s disease. Our research aimed to show how genetic variants interact with environmental influences in different parts of the world. Methodology We searched PubMed and Google Scholar for articles exploring the relationship between genetic variations and global regions such as America, Europe, and Asia. We aimed to identify common genetic variations susceptible to AD and have no significant heterogeneity. To achieve this, we analyzed 35 single-nucleotide polymorphisms (SNPs) from 17 genes (ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, TOMM40, MS4A6A, ARID5B, SORL1, APOC1, MTHFD1L, BDNF, TFAM, and PICALM) from different regions based on previous genomic studies of AD. It has been reported that rs3865444, CD33, is the most common polymorphism in the American and European populations. From TOMM40 and APOE rs2075650, rs429358, and rs6656401, CR1 is the common investigational polymorphism in the Asian population. Conclusion The results of all the research conducted on AD have consistently shown a correlation between genetic variations and the incidence of AD in the populations of each region. This review is expected to be of immense value in future genetic research and precision medicine on AD, as it provides a comprehensive understanding of the genetic factors contributing to the development of this debilitating disease.
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… association, reported by other authors, between ruminative thinking and the methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L) gene allele A polymorphism (rs11754661), …
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Alzheimer's disease (AD) is on the rise worldwide. Generally, AD is considered neurodegenerative when the production and clearance of amyloid-β (Aβ) are imbalanced. Recent …
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Autism is a complex disease with genetic predisposition factors. Real factors for treatment and early diagnosis are yet to be defined. This study integrated transcriptome and exome …
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It was not until large consortia were established that genome-wide association studies of major depressive disorder (MDD) were able to identify significant variants. However, given the …
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It was not until large consortia were established that genome-wide association studies of major depressive disorder (MDD) were able to identify significant variants. However, given the …
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Despite significant progress in dissecting the genetic architecture of complex diseases by genome-wide association studies (GWAS), the signals identified by association analysis may …
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Metabolic rewiring is essential to enable cancer onset and progression. One important metabolic pathway that is often hijacked by cancer cells is the one-carbon (1C) cycle, in which the …
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La medicina del futuro (el futuro ya es hoy) requiere de la capacidad de procesar rápidamente, integrar y analizar cuidadosamente la enorme cantidad de datos que se generan en el plano de la salud. El cuerpo humano comienza a verse entonces como una fuente de datos, comenzando por el genoma humano. En particular, la genómica está cambiando el paradigma de la medicina en sus tres aspectos fundamentales: la prevención, el diagnóstico y el tratamiento, potenciando la revolución de la medicina de precisión. Una de las cuestiones clave para que la medicina de precisión incremente su adopción en la práctica clínica es contar con una herramienta sólida de manipulación y análisis de los datos genómicos que sirva de apoyo a la toma de decisiones mediante el análisis de los datos y presente los resultados en un formato fácilmente interpretable para los profesionales de la salud.
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Neural tube defects (NTDs) are among the most severe and prevalent human congenital malformations. Their etiology is complex and multifactorial, influenced by dynamically …
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Mild cognitive impairment (MCI) is an intermediate stage between normal cognition and Alzheimer’s disease (AD). Genome-wide association studies (GWAS) have …
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A longevidade humana é influenciada por fatores ambientais e genéticos. O gene MTHFD1L e seus polimorfismos de um único nucleotídeo (SNPs) têm sido associados com doenças crônicas degenerativas e processo de envelhecimento fragilizado. Objetivouse verificar associação do rs11754661 de MTHFD1L com a longevidade numa população de idosos, região metropolitana de Vitória, Espírito Santo, bem como comparar dados sociodemográficos, antropométricos, bioquímicos e clínico entre longevos (≥ 85 anos) e Controles (70-75 anos). Esse estudo, observacional, analítico, na proporção 1: 1, foi realizado com 250 idosos. Os idosos responderam sobre dados socioeconômicos contidos num questionário. Altura, massa corpórea, seguidos do índice de massa corpórea, níveis de glicose, triglicerídeos, colesterol total e frações e pressão arterial foram obtidos. Extraiuse o DNA das amostras e a técnica de Reação em Cadeia da Polimerase em Tempo Real, foi utilizada para estudo do SNP. Para estimar associação dos genótipos e alelos de MTHFD1L (GG, AA e AG) com a longevidade, utilizou-se Odds Ratio e intervalo de confiança 95%. Verificou-se a normalidade das variáveis obtidas no questionário. Testes qui-quadrado, Fisher e Mann-Whitney foram utilizados (p< 0, 05 significativo). Observouse predomínio do sexo feminino, caucasianos, estudo formal de 1-4 anos e renda mensal≤ 1 salário mínimo. Longevos apresentaram maior percentual para desnutrição (20, 8%), menor para sobrepeso/obesidade (4, 0%) e melhores níveis de triglicerídeos. Não foi encontrada associação entre genótipos e alelos de MTHFD1L e longevidade. Dados para agregar aos estudos da longevidade foram gerados e podem contribuir com o desenvolvimento de estratégias para melhorias na qualidade de vida de idosos.
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Rumination, or in other words depressive rumination or ruminative response style, is a trait-like, passive, repetitive and perseverative mode of thinking in response to distress and …
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Human longevity, which exceeds the average life expectancy of the population, is a multifactorial characteristic determined by environmental factors and genetic predisposition. Although several studies investigate the influence of environmental components on longevity, the role of genetic variants in this trait is still unclear. Genes that participate in the metabolism of amino acids and genes that act in inflammatory processes, such as the genes MTHFD1L and SERPINA3, respectively, could influence the variations of the life span of …
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Mitochondrial formate production and its impact on embryonic cranial tissue development in the mouse
Mammalian folate-dependent one-carbon (1C) metabolism provides the building blocks essential during development via amino acid interconversion, universal methyldonor production, regeneration of redox factors, and de novo purine and thymidylate synthesis. Folate supplementation prevents most neural tube defects (NTDs) that occur during the embryonic process of neurulation. The mechanism of how folate functions during neurulation is not well understood, and not all NTDs are preventable by folate supplementation. Mthfd1l is a mitochondrial 1C metabolism enzyme that produces formate, a 1C donor that fuels biosynthesis and the methyl cycle in the cytoplasm. Mthfdll-null (Mthfd1l z/z) mice are embryonic lethal and develop folate-resistant NTDs. These mice also have defects in cranial mesenchyme formation. In this work, the nature of how their mesenchyme is defective is explored. The extracellular matrix (ECM) of Mthfd1l z/z embryos was found to be depleted in glycosaminoglycan (GAG) composition, as well as the basement membrane protein Collagen IV. Imaging mass spectrometry (IMS) was used to construct ion maps of the cranial mesenchyme that identified the spatial distribution and abundance of metabolites in Mthfd1l z/z embryos compared to wild-type (WT). Purine and thymidylate derivatives, as well as amino acids, were diminished in the cranial mesenchyme of Mthfd1l z/z embryos. Loss of Mthfd1l activity in this region also led to abnormal levels of methionine and dysregulated energy metabolism. These alterations in metabolism suggest possible approaches to preventing NTDs in humans. Finally, we created a mouse lacking both Mthfd1l and Aldh1l2, which is another mitochondrial enzyme associated with formate production. These embryos exhibit a more dramatic birth defect phenotype than Mthfd1l z/z embryos. By associating metabolite abundance, gene expression, and tissue development, this study is focused on enhancing our current understanding of how folate-dependent 1C metabolism functions during neurulation.
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Alzheimer Disease (AD) is the most common type of dementia related to aging. It is a serious, chronic and progressive pathology, associated with memory and cognition loss, that leads …
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Cardiovascular diseases including coronary heart disease (CHD) are the leading cause of mortality worldwide and are responsible for approximately one in three deaths across the …
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Alzheimer's disease (AD) represents an enormous global health burden in terms of human suffering and economic cost. AD management requires a shift from the prevailing paradigm targeting pathogenesis to design and develop effective drugs with adequate success in clinical trials. Therefore, it is of interest to report a review on amyloid beta (Aβ) effects and other multi-targets including cholinesterase, NFTs, tau protein and TNF associated with brain cell death to be neuro-protective from AD. It should be noted that these molecules have been generated either by target-based or phenotypic methods. Hence, the use of recent advancements in nanomedicine and other natural compounds screening tools as a feasible alternative for circumventing specific liabilities is realized. We review recent developments in the design and identification of neuro-degenerative compounds against AD generated using current advancements in computational multi-target modeling algorithms reflected by theragnosis (combination of diagnostic tests and therapy) concern.
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The general genetic background is important when studying major common diseases, such as Alzheimer's disease (AD). Determining the underlying genetic factors in populations …
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With advancing age individuals experience a deterioration in cognitive abilities that is characterized by substantial inter-individual variation in the observed trajectories of cognitive …
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A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, namely C677T (rs1801133), results in increased Hcy levels and has been …
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In Eukaryotes, folate-dependent one-carbon (1C) metabolism is a highly compartmentalized process in which mitochondria play a central role. Defects in folate metabolism are associated with diseases such as cancer, Alzheimer's disease, and neural tube defects (NTDs). 1C units are attached to tetrahydrofolate (THF) and carried in various oxidation states between folate-dependent enzymes. There is an exchange of 1C units across the mitochondrial membrane, with 1C donors such as serine and glycine being oxidized to …
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Survival following a diagnosis of multiple myeloma (MM) varies between patients and some of these differences may be a consequence of inherited genetic variation. In this study, to …
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We examined the association of 28 single nucleotide polymorphisms (SNPs), previously associated with dementia or cognitive performance, with tests assessing episodic memory, …
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Characterization of the role of the mitochondrial one-carbon metabolism during embryonic development
Neural tube defects (NTDs) are one of serious structural birth defects resulting from failure of neural tube closure. Folic acid supplementation is the essential factor for prevention of NTDs…
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The role of gender in the effect of folate pathway-related MTHFD1L gene on ruminative response style
Our previous results recently demonstrated that the rs11754661 polymorphism A allele, situated in the folate-related MTHFD1L gene, increases the risk of ruminative response style (depressive rumination, or shortly rumination) in a European white population, and this association completely explains the risk that the A allele confers to depression [1]. Although it has been shown that gender differences in rumination play a considerable part in explaining the gender differences in depressive symptoms [2], data on gender differences in the effect of the MTHFD1L gene on neuropsychiatric [3] or neural [4] outcomes are lacking. Our present aim was to explore the role of gender in the association between rs11754661 and rumination. N= 2120 white European adults (aged 18–60 years) from Budapest and Manchester᐀ lled out the 10-item Ruminative Responses Scale and were genotyped for MTHFD1L rs11754661. We built linear regression models separately in women and men, with population and age as covariates, to test the effect of the A allele of rs11754661 on rumination score. We also ran a
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Alterations in the folate pathway have been related to both major depression and cognitive inflexibility; however, they have not been investigated in the genetic background of ruminative response style, which is a form of perseverative cognition and a risk factor for depression. In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, MTHFR rs1801133 (C677T) and MTHFD1L rs11754661, in a combined European white sample from Budapest, Hungary (n=895) and Manchester, United Kingdom (n=1309). Post hoc analysis investigated whether the association could be replicated in each of the two samples, and the relationship between folate pathway genes, rumination, lifetime depression and Brief Symptom Inventory depression score. Despite its functional effect on folate metabolism, the MTHFR rs1801133 showed no effect on rumination. However, the A allele of MTHFD1L rs11754661 was significantly associated with greater rumination, and this effect was replicated in both the Budapest and Manchester samples. In addition, rumination completely mediated the effects of MTHFD1L rs11754661 on depression phenotypes. These findings suggest that the MTHFD1L gene, and thus the C1-THF synthase enzyme of the folate pathway localized in mitochondria, has an important effect on the pathophysiology of depression through rumination, and maybe via this cognitive intermediate phenotype on other mental and physical disorders. Further research should unravel whether the reversible metabolic effect of MTHFD1L is responsible for increased rumination or other long-term effects on brain development.
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Folic acid is an essential B vitamin, the metabolism of folic acid via one carbon metabolism results in the production of important components for the cell, such as DNA bases and methyl …
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More than 30 independent single-nucleotide polymorphisms (SNPs) have been associated with Alzheimer's disease (AD) risk by genome-wide association studies (GWAS) in European. We aimed to confirm these SNPs in Chinese Han and investigate the utility of these genetic markers. We randomly divided 459 sporadic AD (SAD) patients and 751 cognitively normal controls into two sets (discovery and testing). Thirty-three SAD risk-associated SNPs were firstly tested in the discovery set. Significant SNPs were used to calculate genetic risk score (GRS) in the testing set. Predictive performance of GRS was evaluated using the area under the receiver operating characteristic curve (AUC). In the discovery set, 6 SNPs were confirmed (P = 7.87 × 10−11~0.048), including rs9349407 in CD2AP, rs11218343 in SORL1, rs17125944 in FERMT2, rs6859 in PVRL2, rs157580 and rs2075650 in TOMM40. The first three SNPs were associated with SAD risk independent of APOE genotypes. GRS based on these three SNPs were significantly associated with SAD risk in the independent testing set (P = 0.002). The AUC for discriminating cases from controls was 0.58 for GRS, 0.60 for APOE, and 0.64 for GRS and APOE. Our data demonstrated that GRS based on AD risk-associated SNPs may supplement APOE for better assessing individual risk for AD in Chinese.
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Alzheimer's disease (AD) affects people worldwide, and the prevalence is increasing as the population ages. There is an international effort to understand the biology of AD to develop primary and secondary prevention strategies, and to develop effective therapeutic interventions for individuals who are already symptomatic. One of the critically important pieces of all national plans to address AD is the call for the development of service models to deliver quality, effective care based on the best evidence available. Methods We describe one type of care model developed by the Fundacio ACE, Institut Catala de Neurociencies Aplicades (Fundacio ACE, Barcelona, Spain) that integrates diagnosis, therapy, follow-up care, daycare, and a day hospital, and does so in the context of an active clinical research and educational program. Results There were 13,048 individuals newly evaluated and diagnosed in Fundacio ACE between 1996 and 2011. Of these, 6132 had AD (47.0%), 3871 had mild cognitive impairment (MCI) (29.7%), and 1958 had no cognitive impairment (15.0%). Follow-up information is available on 4735 (47.3%) AD and MCI patients, and these data indicate that MCI develops into dementia at a rate of 222.6/1000 person-years. Apolipoprotein E (APOE) genotyping was available in 22.4% of the patients. The e4 allele occurred in 45.7% of the AD patients, in 37.8% of the MCI subjects, and in 31.6% of those without cognitive impairment. Conclusions Fundacio ACE can serve as a model system that can be adapted to other settings within their specific cultural, governmental, and legal constraints.
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In a recent genome-wide association study, the SLC26A4 gene rs2072064 polymorphism was found to be associated with late-onset Alzheimer's disease in Caucasians. Here, we …
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The MTHFD1L gene encodes the mitochondrial monofunctional enzyme with proven 10-formyltetrahydrofolate synthetase activity. MTHFD1L expression is upregulated in human colon …
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To understand the relation between risk genes for Alzheimer’s disease (AD) and their influence on biomarkers for AD, we examined the association of AD in the Finnish …
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… A SNP (rs11754661) in the MTHFD1L gene was associated with verbal learning and memory (P= 0.02) and rs561655 in PICALM was associated with working memory (P= 0.004). No …
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… A SNP (rs11754661) in the MTHFD1L gene was associated with verbal learning and memory (P = 0.02) and rs561655 in PICALM was associated with working memory (P = 0.004). No …
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Alzheimer's disease (AD) is the most common neurodegenerative disorder with a complex genetic background. Recent genome‐wide association studies (GWAS) have placed …
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The FVB/NJ mouse strain has its origins in a colony of outbred Swiss mice established in 1935 at the National Institutes of Health. Mice derived from this source were …
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… A SNP (rs11754661) in the MTHFD1L gene was associated with verbal learning and memory (P = 0.02) and rs561655 in PICALM was associated with working memory (P = 0.004). No …
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Single Nucleotide Polymorphisms (SNPs) are the most common DNA sequence variations where only a single nucleotide (A, T, C, G) in the human genome differs between individuals. …
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… The MTHFD1L gene rs11754661 marker is associated with susceptibility to Alzheimer's disease in the Chinese Han population. J Neurol Sci, 2011, 308(1-2): 32-34 [83] Shi J, Qian W, …
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We conducted a replication study of the 2 genetic variants, rs11754661 and rs2073067, in MTHFD1L that have been recently reported to be associated with late-onset Alzheimer's disease (LOAD) in a genome-wide study in Caucasians. The associations were evaluated in a case-control sample comprising 1,189 Northern Han-Chinese individuals. The rs11754661 polymorphism is associated with LOAD (OR = 1.727; p = 0.016). For rs2073067, LOAD association was found only in APOEε4 carriers (OR = 0.400; p < 0.001). Haplotype analysis revealed the “AC” haplotype increased the risk of developing LOAD (OR = 1.730; p = 0.015). Our findings support a role of MTHFD1L gene in LOAD.
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Recent large-scale genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (AD) have confirmed the involvement of ten susceptibility genes beyond APOE. We examined the association between variants in these genes and longitudinal cognitive performance.
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We conducted a replication study of the 2 genetic variants, rs11754661 and rs2073067, in MTHFD1L that have been recently reported to be associated with late-onset Alzheimer's disease (LOAD) in a genome-wide study in Caucasians. The associations were evaluated in a case-control sample comprising 1,189 Northern Han-Chinese individuals. The rs11754661 polymorphism is associated with LOAD (OR = 1.727; p = 0.016). For rs2073067, LOAD association was found only in APOEε4 carriers (OR = 0.400; p < 0.001). Haplotype analysis revealed the “AC” haplotype increased the risk of developing LOAD (OR = 1.730; p = 0.015). Our findings support a role of MTHFD1L gene in LOAD.
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known “AD genes’” regions, AD subjects have greater rate and total length of duplications than controls. We did not find evidence for common CNV association to AD using logistic regression with numerous covariates. In chr15q11 20.2M-22.6Mwe found large (>1⁄4500 kbp) duplications are overrepresented by AD cases (47 cases, 4 controls, OR1⁄43.4). This 15q11 region is upstream of the region where deletions are associated with either PraderWilli or Angelman syndromes. The presence of abundant segmental duplications in this region makes it a hot spot for Non Allelic Homologous Recombinations (NAHRs). We were able to identify potential pairs of segmental duplications that might have facilitated some of the recurrent duplications. Conclusions: Duplications in the chr15q11 region are associated with increased risk of late onset AD in the Caucasian population.
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… Nine common SNPs showed medium-to-high LD with rs11754661, of which two localized … rs11754661. Conclusions: Re-sequencing of the MTHFD1L LD block containing rs11754661 …
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We identified and replicated the association of MTHFD1L intronic SNP rs11754661 with Late-onset Alzheimer's disease (LOAD) with genome-wide statistical significance in …
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… Nine common SNPs showed medium-to-high LD with rs11754661, of which two localized … rs11754661. Conclusions: Re-sequencing of the MTHFD1L LD block containing rs11754661 …
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The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery …
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Alzheimer's disease (AD) is the most common form of dementia and the most common neurodegenerative disease, with a complex genetic background. Genome-wide association …
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… We identified and replicated the association of MTHFD1L intronic SNP rs11754661 with Late-onset Alzheimer’s disease (LOAD) with genome-wide statistical significance …
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Leading medical genetics scholar Moyra Smith reviews current and recent work in genetics and genomics to assess progress in understanding human variation and the pathogenesis of …
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This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (eg PhD, MPhil, DClinPsychol) at th Page 1 This thesis has been submitted in fulfilment of the …
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We identified and replicated the association of MTHFD1L intronic SNP rs11754661 with Late-onset Alzheimer's disease (LOAD) with genome-wide statistical significance in a previous genome-wide association study (P= 1.90 ×10− 10 in combined datasets). MTHFD1L is involved in the folate pathway and represents an interesting biological LOAD candidate since it may influence homocysteine levels, a significant risk factor for LOAD. rs11754661 is located in a region of high linkage disequilibrium (LD) extending for 32.6 kb of the gene's 360.7 kb length. We resequenced this LD block to identify and characterize rare and potentially functional variants which may contribute to the observed association.
57
The impact of genetic susceptibility information about Alzheimer's disease (AD) on exercise and mental activities is unclear. The Risk Evaluation and Education for Alzheimer's Disease (REVEAL) Study is a series of multi-site randomized controlled clinical trials examining the impact of Apolipoprotein E (APOE) genetic risk disclosure for AD. We hypothesized that APOE e4 carriers are more likely than non-carriers to report changes to their exercise and mental activities after disclosure.
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Our objective is to evaluate the relationship between the rs11754661 polymorphism of the MTHFD1L gene and Alzheimer's disease (AD) in the ethnic Chinese Han. We conducted a case-control study (n=380, age>50) to determine the prevalence of one common single-nucleotide polymorphism (SNP) of MTHFD1L (rs11754661) in patients with AD in Chinese population of Mainland China, and clarified whether this polymorphism is a risk factor for AD. The prevalence of the minor allele (A) in the rs11754661 polymorphism was significantly different in AD patients and control subjects (P<0.01). The rs11754661 polymorphism was associated with AD in the ethnic Chinese Han (OR=1.829, 95% CI: 1.277–2.619, P=0.001), and the results were influenced by APOE status. Our data revealed that the allele (A) of the rs11754661 polymorphism within MTHFD1L gene may contribute to AD risk in the Chinese Han population.
59
Enlarged early endosomes have been observed in neurons and fibroblasts in Down syndrome (DS). These endosome abnormalities have been implicated in the early development of Alzheimer's disease (AD) pathology in these subjects. Here, we show the presence of enlarged endosomes in blood mononuclear cells and lymphoblastoid cell lines (LCLs) from individuals with DS using immunofluorescence and confocal microscopy. Genotype–phenotype correlations in LCLs carrying partial trisomies 21 revealed that triplication of a 2.56 Mb locus in 21q22.11 is associated with the endosomal abnormalities. This locus contains the gene encoding the phosphoinositide phosphatase synaptojanin 1 (SYNJ1), a key regulator of the signalling phospholipid phosphatidylinositol-4,5-biphosphate that has been shown to regulate clathrin-mediated endocytosis. We found that SYNJ1 transcripts are increased in LCLs from individuals with DS and that overexpression of SYNJ1 in a neuroblastoma cell line as well as in transgenic mice leads to enlarged endosomes. Moreover, the proportion of enlarged endosomes in fibroblasts from an individual with DS was reduced after silencing SYNJ1 expression with RNA interference. In LCLs carrying amyloid precursor protein (APP) microduplications causing autosomal dominant early-onset AD, enlarged endosomes were absent, suggesting that APP overexpression alone is not involved in the modification of early endosomes in this cell type. These findings provide new insights into the contribution of SYNJ1 overexpression to the endosomal changes observed in DS and suggest an attractive new target for rescuing endocytic dysfunction and lipid metabolism in DS and in AD.
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The MTHFD1L gene SNP variant rs11754661 was found to increase the risk of Alzheimer's disease in a recent Whole Genome Association Study [1]. We have carried out an independent study of this genetic variant in 2467 individuals from Spain. We found no evidence of association between the MTHFD1L marker and susceptibility to Alzheimer's disease in our sample.
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Three decades of genetic research in Alzheimer disease (AD) have substantially broadened our understanding of the pathogenetic mechanisms leading to neurodegeneration and …
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The primary focus toward identification of Alzheimer disease (AD) risk genes over the past five years has been testing the common disease common variant (CDCV) …
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Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to …
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Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to strengthen power to identify novel genetic association signals. Associations exceeding the experiment-wide significance threshold (alpha=1.03x10(-7)) were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, P=1.9x10(-36)). Additionally, the SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L (which encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein) was significantly associated with LOAD (P=4.70x10(-8); Bonferroni-corrected P=0.022). Subsequent genotyping of SNPs in high linkage disequilibrium (r2>0.8) with rs11754661 identified statistically significant associations in multiple SNPs (rs803424, P=0.016; rs2073067, P=0.03; rs2072064, P=0.035), reducing the likelihood of association due to genotyping error. In the replication case-control set, we observed an association of rs11754661 in the same direction as the previous association at P=0.002 (P=1.90x10(-10) in combined analysis of discovery and replication sets), with associations of similar statistical significance at several adjacent SNPs (rs17349743, P=0.005; rs803422, P=0.004). In summary, we observed and replicated a novel statistically significant association in MTHFD1L, a gene involved in the tetrahydrofolate synthesis pathway. This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development.
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Cerebral amyloid angiopathy (CAA) is an age-associated condition that is pathologically characterized by deposition of β-amyloid peptide (Aβ) in small and medium sized …
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Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease
Only Apolipoprotein E polymorphisms have been consistently associated with the risk of late-onset Alzheimer disease (LOAD), but they represent only a minority of the underlying …
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APOE is the only confirmed genetic risk factor for Late-onset Alzheimer disease (LOAD), accounting for 50% of the total AD genetic effect. Variants at other loci have …
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It has been proposed that Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) represent separate ends of the same clinicopathological …
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Accumulation of the amyloid β (Aβ) peptide derived from the proteolytic processing of amyloid precursor protein (APP) is the defining pathological hallmark of Alzheimer's …
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... assessed at UBCH-CARD, five of whom have been assessed longitudinally up to 10 years. Clinical information was also available on Page 1 assessed at UBCH-CARD, five of whom …
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Genetic variants associated with Alzheimer’s disease and biomarkers in a Finnish cohort Supporting information for the study: Genetic loci associated with Alzheimer’s disease and …
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Genetic variants included in the study. All were tested for biomarker analyses. SNPs tested in previous studies for genetic association with AD were not included in the present …
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In this survey, we analyzed the specific effects of a 5 months long physical-activity program on weight, leptin, insulin and glucose-lipid metabolism and regulation. Considering the increasing trends of obesity throughout the world, a better understanding of the underlying mechanisms between exercise, endocrine hormones and their regulation may lead to novel approaches to prevent and treat of obesity related metabolic diseases or metabolic disorders.
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