Genomic Copy Number Variants: Evidence for Association with Antibody Response to Anthrax Vaccine Adsorbed

Falola, Michael; Wiener, Howard W.; Cutter, Gary; Kimberly, Robert P.; Edberg, Jeffrey C.; Arnett, Donna K.; Kaslow, Richard A.; Tang, Jianming; Shrestha, Sadeep

doi:10.1371/journal.pone.0064813

Cited by 8 publications

(7 citation statements)

References 45 publications

(57 reference statements)

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“…The association between LRRC37A/2 variants and any disease or phenotype has therefore never been tested, and it is likely that additional variation within LRRC37A/2 itself is contributing to its altered expression and function that may also impact PD risk. Little is known about the function of LRRC37A/2, although it has been associated with an increased immune and inflammatory response [43], as well as with cellular migration and synapse formation [41]. Despite conducting our RNA-seq analysis of LRRC37A/2 overexpression in HEK293T cells, we observe enrichment of pathways consistent with these data; we found that increased LRRC37A/2 expression upregulated cellular migration and chemotaxis pathways, which are both essential mechanisms involved in wound healing and inflammation.…”

Section: Discussionsupporting

confidence: 70%

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Bowles

Pugh²,

Liu³

et al. 2022

Mol Neurodegeneration

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Background Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. Methods To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. Results We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. Conclusion These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

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Section: Discussionsupporting

confidence: 70%

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Bowles

Pugh²,

Liu³

et al. 2022

Mol Neurodegeneration

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“…Very little is known about the function of LRRC37A/2, other than increased copy number has been associated with an increased antibody response to an Anthrax vaccine 54 , and overexpression in HeLa cells appeared to promote the formation of filopodia 46 , suggesting that LRRC37A/2 may be involved in the immune and inflammatory response, as well as with cellular migration and synapse formation. Our RNA-seq and biochemical analyses of LRRC37A/2 expression support these assertions; we find that LRRC37A is a membrane-bound protein that is likely to play a role in cellular migration and chemotaxis, and is expressed in both neurons and astrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Little is known about the function of LRRC37A/2 , although increased copy number has been associated with an increased antibody response to an Anthrax vaccine 35 , and overexpression in HeLa cells appeared to promote the formation of filopodia 33 , indicating that LRRC37A/2 may be involved in the immune and inflammatory response, as well as with cellular migration and synapse formation. Furthermore, assessment of the GWAS atlas (https://atlas.ctglab.nl/) reveals that several immune phenotypes are significantly associated with H1/H2 haplotypes across the 17q21.31 locus, thus indicating this region is important for the regulation of immunological function.…”

Section: Discussionmentioning

confidence: 99%

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Bowles

Pugh

Liu

et al. 2019

Preprint

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Parkinson's disease (PD) and progressive supranuclear palsy (PSP) are clinically similar neurodegenerative movement disorders that display unique neuropathological features (i.e. Lewy body pathology and Tau pathology, respectively). While each disorder has distinct clinical and genetic risk factors, both are associated with the MAPT 17q.21.31 locus H1 haplotype. This suggests a pleiotropic effect of this genomic region. To better understand the genetic contribution of this region to these diseases, we fine-mapped the apparent pleiotropy of this locus. Our study indicates that PD and PSP are associated with different sub-haplotypes of the H1 clade. PDassociated sub-haplotypes were associated with altered LRRC37A copy number and expression, which, like other PD risk-associated genes, we hypothesize to be most relevant to astroglial function. In contrast, PSP was associated with grossly altered LD structure across the 17q21.31 locus, and risk-associated variants were found to impact chromatin structure in both neurons and microglia. We conclude that the contribution of the 17q21.31 locus to multiple disorders is a result of its structural and haplotypic complexity, which in turn impacts the regulation of multiple genes and neural cell types. This raises the possibility of novel disease-specific pathogenic mechanisms driven by 17q21.31 structural variation and altered epigenetic regulation that appear to converge on glial function and gene expression. By fine-mapping the association of H1 with PD and PSP, we have begun to untangle the apparent pleiotropy of this locus, and gain better insight into the mechanism of each disease, which will guide future functional analyses and disease models for PD and PSP.

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“…The CNV spanning the NSF gene was previously associated with elevated peak antibody response to the AVA-Biothrax vaccine, suggesting that this CNV has an effect on the expression of the genes in this region ( NSF , ARL17 and LRRC37A ) 50 . We have shown that a CNV spanning the NSF gene produces changes in the expression levels of some NSF transcripts, which could have an effect on the availability of neurotransmitter vesicles (loaded with e.g.…”

Section: Discussionmentioning

confidence: 96%

A Highly Polymorphic Copy Number Variant in the NSF Gene is Associated with Cocaine Dependence

Cabana‐Domínguez¹,

Roncero²,

Grau-López³

et al. 2016

Sci Rep

Self Cite

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Cocaine dependence is a complex psychiatric disorder involving both genetic and environmental factors. Several neurotransmitter systems mediate cocaine’s effects, dependence and relapse, being the components of the neurotransmitter release machinery good candidates for the disorder. Previously, we identified a risk haplotype for cocaine dependence in the NSF gene, encoding the protein N-Ethylmaleimide-Sensitive Factor essential for synaptic vesicle turnover. Here we examined the possible contribution to cocaine dependence of a large copy number variant (CNV) that encompasses part of the NSF gene. We performed a case-control association study in a discovery sample (359 cases and 356 controls) and identified an association between cocaine dependence and the CNV (P = 0.013), that was confirmed in the replication sample (508 cases and 569 controls, P = 7.1e-03) and in a pooled analysis (P = 1.8e-04), with an over-representation of low number of copies in cases. Subsequently, we studied the functional impact of the CNV on gene expression and found that the levels of two NSF transcripts were significantly increased in peripheral blood mononuclear cells (PBMC) along with the number of copies of the CNV. These results, together with a previous study from our group, support the role of NSF in the susceptibility to cocaine dependence.

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Genomic Copy Number Variants: Evidence for Association with Antibody Response to Anthrax Vaccine Adsorbed

Cited by 8 publications

References 45 publications

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

A Highly Polymorphic Copy Number Variant in the NSF Gene is Associated with Cocaine Dependence

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