Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia

Sillén, Anna; Brohede, Jesper; Lilius, Lena; Forsell, Charlotte; Andrade, Jorge; Odeberg, Jacob; Ebise, Hayao; Winblad, Bengt; Graff, Caroline

doi:10.1038/jhg.2010.79

Cited by 8 publications

(7 citation statements)

References 88 publications

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“…ANGPT4 (angiopoietin 4) encodes a protein involved in angiogenesis and has been associated with cases of mixed AD/vascular dementia in family-based studies [45]. Meta-analysis results summarizing prior studies has indicated that past diagnosis of depression confers heightened risk for AD later in life [46].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Gene- and Pathway-Based Analysis of Depressive Symptoms in Older Adults

Nho

Ramanan

Horgusluoglu

et al. 2015

JAD

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Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we PERFORMED genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome-wide significant associations (ANGPT4 and FAM110A, q-value = 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling,GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer’s disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Gene- and Pathway-Based Analysis of Depressive Symptoms in Older Adults

Nho

Ramanan

Horgusluoglu

et al. 2015

JAD

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“…The discovery of genetic loci that modify vessel growth has been an area of increasing interest in clinical and preclinical research. [22][23][24][25][26][27] Whereas the genes behind these loci are potentially powerful tools for risk assessment and therapeutic intervention, angiogenesis is intimately associated with tissue development and survival, limiting our ability to identify genetic factors regulating vessel growth by use of genetargeting approaches. 28 However, the use of model systems by us and others 19,20 in various tissue-specific assays, by use of vessel growth as a complex trait, is beginning to find novel genes that also control vessel growth.…”

Section: Discussionmentioning

confidence: 99%

Angiogenesis QTL on Mouse Chromosome 8 Colocalizes with Differential β-Defensin Expression

Smith

Liu

Beyer³

et al. 2015

J Biomol Tech

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Identification of genetic factors that modify complex traits is often complicated by gene-environment interactions that contribute to the observed phenotype. In model systems, the phenotypic outcomes quantified are typically traits that maximize observed variance, which in turn, should maximize the detection of quantitative trait loci (QTL) in subsequent mapping studies. However, when the observed trait is dependent on multiple interacting factors, it can complicate genetic analysis, reducing the likelihood that the modifying mutation will ultimately be found. Alternatively, by focusing on intermediate phenotypes of a larger condition, we can reduce a model's complexity, which will, in turn, limit the number of QTL that contribute to variance. We used a novel method to follow angiogenesis in mice that reduces environmental variance by measuring endothelial cell growth from culture of isolated skin biopsies that varies depending on the genetic source of the tissue. This method, in combination with a backcross breeding strategy, is intended to reduce genetic complexity and limit the phenotypic effects to fewer modifier loci. We determined that our approach was an efficient means to generate recombinant progeny and used this cohort to map a novel s.c. angiogenesis QTL to proximal mouse chromosome (Chr.) 8 with suggestive QTL on Chr. 2 and 7. Global mRNA expression analysis of samples from parental reference strains revealed β-defensins as potential candidate genes for future study.

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“…However, THBS1 and SERPINE1 have been identified as anti-angiogenic [11] – [13] . Angiopoietin ANGPT4 is a protein that promotes angiogenesis [14] . Fractalkine (FKN)-induced activation of CX3CR1 in EC leads to in vivo angiogenesis through the induction of HIF-1alpha and VEGF-A gene expression by CX3CR1 activation and subsequent VEGF-A/KDR-induced angiogenesis [15] .…”

Section: Methodsmentioning

confidence: 99%

Angiogenesis Interactome and Time Course Microarray Data Reveal the Distinct Activation Patterns in Endothelial Cells

et al. 2014

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Angiogenesis involves stimulation of endothelial cells (EC) by various cytokines and growth factors, but the signaling mechanisms are not completely understood. Combining dynamic gene expression time-course data for stimulated EC with protein-protein interactions associated with angiogenesis (the “angiome”) could reveal how different stimuli result in different patterns of network activation and could implicate signaling intermediates as points for control or intervention. We constructed the protein-protein interaction networks of positive and negative regulation of angiogenesis comprising 367 and 245 proteins, respectively. We used five published gene expression datasets derived from in vitro assays using different types of blood endothelial cells stimulated by VEGFA (vascular endothelial growth factor A). We used the Short Time-series Expression Miner (STEM) to identify significant temporal gene expression profiles. The statistically significant patterns between 2D fibronectin and 3D type I collagen substrates for telomerase-immortalized EC (TIME) show that different substrates could influence the temporal gene activation patterns in the same cell line. We investigated the different activation patterns among 18 transmembrane tyrosine kinase receptors, and experimentally measured the protein level of the tyrosine-kinase receptors VEGFR1, VEGFR2 and VEGFR3 in human umbilical vein EC (HUVEC) and human microvascular EC (MEC). The results show that VEGFR1–VEGFR2 levels are more closely coupled than VEGFR1–VEGFR3 or VEGFR2–VEGFR3 in HUVEC and MEC. This computational methodology can be extended to investigate other molecules or biological processes such as cell cycle.

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Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia

Cited by 8 publications

References 88 publications

Comprehensive Gene- and Pathway-Based Analysis of Depressive Symptoms in Older Adults

Comprehensive Gene- and Pathway-Based Analysis of Depressive Symptoms in Older Adults

Angiogenesis QTL on Mouse Chromosome 8 Colocalizes with Differential β-Defensin Expression

Angiogenesis Interactome and Time Course Microarray Data Reveal the Distinct Activation Patterns in Endothelial Cells

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