scholarly journals Genome-wide dysregulation of histone acetylation in the Parkinson’s disease brain

2019 ◽  
Author(s):  
Lilah Toker ◽  
Gia T Tran ◽  
Janani Sundaresan ◽  
Ole-Bjørn Tysnes ◽  
Guido Alves ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Chromatin Immunoprecipitation ◽  
Genetic Risk ◽  
Neurodegenerative Disorder ◽  
Unknown Etiology ◽  
Transcriptomic Data ◽  
Genome Wide ◽  
A Genome ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Epigenetic Signatures

AbstractParkinson disease (PD) is a complex neurodegenerative disorder of largely unknown etiology. While several genetic risk factors have been identified, the involvement of epigenetics in the pathophysiology of PD is mostly unaccounted for. We conducted a histone acetylome-wide association study in PD, using brain tissue from two independent cohorts of cases and controls. Immunoblotting revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. Chromatin immunoprecipitation sequencing (ChIP-seq) further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon, with a strong predilection for genes implicated in the disease, including SNCA, PARK7, PRKN and MAPT. Integration of the ChIP-seq with transcriptomic data revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Our findings strongly suggest that dysregulation of histone acetylation plays an important role in the pathophysiology of PD and identify novel epigenetic signatures associated with the disease.

scholarly journals Genome-Wide Association Study and Subsequent Exclusion of ATCAY as a Candidate Gene Involved in Equine Neuroaxonal Dystrophy Using Two Animal Models

Genes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 82 ◽  
Author(s):  
Erin N Hales ◽  
Christina Esparza ◽  
Sichong Peng ◽  
Anna R Dahlgren ◽  
Janel M Peterson ◽  
...  
Keyword(s):  
Association Study ◽  
Candidate Gene ◽  
Genome Wide Association Study ◽  
Neurodegenerative Disorder ◽  
Genome Wide Association ◽  
Neuroaxonal Dystrophy ◽  
Tocopheryl Acetate ◽  
Unknown Etiology ◽  
Genome Wide ◽  
A Genome

Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder of unknown etiology. Clinical signs of neurological deficits develop within the first year of life in vitamin E (vitE) deficient horses. A genome-wide association study (GWAS) was carried out using 670,000 SNP markers in 27 case and 42 control Quarter Horses. Two markers, encompassing a 2.5 Mb region on ECA7, were associated with the phenotype (p = 2.05 × 10-7 and 4.72 × 10-6). Within this region, caytaxin (ATCAY) was identified as a candidate gene due to its known role in Cayman Ataxia and ataxic/dystonic phenotypes in mouse models. Whole-genome sequence data in four eNAD/EDM and five unaffected horses identified 199 associated variants within the ECA7 region. MassARRAY® genotyping was performed on these variants within the GWAS population. The three variants within ATCAY were not concordant with the disease phenotype. No difference in expression or alternative splicing was identified using qRT-PCR in brainstem across the ATCAY transcript. Atcayji-hes mice were then used to conduct functional analysis in a second animal model. Histologic lesions were not identified in the central nervous system of Atcayji-hes mice. Additionally, supplementation of homozygous Atcayji-hes mice with 600 IU/day of dl-α-tocopheryl acetate (vitE) during gestation, lactation, and adulthood did not improve the phenotype. ATCAY has therefore been excluded as a candidate gene for eNAD/EDM.

scholarly journals Learning a genome-wide score of human–mouse conservation at the functional genomics level

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Soo Bin Kwon ◽  
Jason Ernst
Keyword(s):  
Mouse Model ◽  
Functional Genomics ◽  
Functional Genomic ◽  
Transcriptomic Data ◽  
Model Studies ◽  
Genome Wide ◽  
A Genome ◽  
Important Challenge ◽  
Genomic Regions ◽  
Human And Mouse

AbstractIdentifying genomic regions with functional genomic properties that are conserved between human and mouse is an important challenge in the context of mouse model studies. To address this, we develop a method to learn a score of evidence of conservation at the functional genomics level by integrating information from a compendium of epigenomic, transcription factor binding, and transcriptomic data from human and mouse. The method, Learning Evidence of Conservation from Integrated Functional genomic annotations (LECIF), trains neural networks to generate this score for the human and mouse genomes. The resulting LECIF score highlights human and mouse regions with shared functional genomic properties and captures correspondence of biologically similar human and mouse annotations. Analysis with independent datasets shows the score also highlights loci associated with similar phenotypes in both species. LECIF will be a resource for mouse model studies by identifying loci whose functional genomic properties are likely conserved.

scholarly journals Common genetic risk variants identified in the SPARK cohort implicate DDHD2 as a novel autism risk gene

2020 ◽  
Author(s):  
Nana Matoba ◽  
Dan Liang ◽  
Huaigu Sun ◽  
Nil Aygün ◽  
Jessica C. McAfee ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Association Study ◽  
Genetic Risk ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Risk Variants ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
Gene Regulatory

AbstractBackgroundAutism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder. Large genetically informative cohorts of individuals with ASD have led to the identification of three common genome-wide significant (GWS) risk loci to date. However, many more common genetic variants are expected to contribute to ASD risk given the high heritability. Here, we performed a genome-wide association study (GWAS) using the Simons Foundation Powering Autism Research for Knowledge (SPARK) dataset to identify additional common genetic risk factors and molecular mechanisms underlying risk for ASD.MethodsWe performed an association study on 6,222 case-pseudocontrol pairs from SPARK and meta-analyzed with a previous GWAS. We integrated gene regulatory annotations to map non-coding risk variants to their regulated genes. Further, we performed a massively parallel reporter assay (MPRA) to identify causal variant(s) within a novel risk locus.ResultsWe identified one novel GWS locus from the SPARK GWAS. The meta-analysis identified four significant loci, including an additional novel locus. We observed significant enrichment of ASD heritability within regulatory regions of the developing cortex, indicating that disruption of gene regulation during neurodevelopment is critical for ASD risk. The MPRA identified one variant at the novel locus with strong impacts on gene regulation (rs7001340), and expression quantitative trait loci data demonstrated an association between the risk allele and decreased expression of DDHD2 (DDHD domain containing 2) in both adult and pre-natal brains.ConclusionsBy integrating genetic association data with multi-omic gene regulatory annotations and experimental validation, we fine-mapped a causal risk variant and demonstrated that DDHD2 is a novel gene associated with ASD risk.

scholarly journals Meta-analysis of transcriptomic data reveals clusters of consistently deregulated gene and disease ontologies in Down syndrome

2021 ◽  
Vol 17 (9) ◽  
pp. e1009317
Author(s):  
Ilario De Toma ◽  
Cesar Sierra ◽  
Mara Dierssen
Keyword(s):  
Down Syndrome ◽  
Differential Expression ◽  
Web Application ◽  
Meta Analysis ◽  
Chromosome 21 ◽  
Complex Disorders ◽  
Transcriptomic Data ◽  
Genome Wide ◽  
A Genome ◽  
The Impact

Trisomy of human chromosome 21 (HSA21) causes Down syndrome (DS). The trisomy does not simply result in the upregulation of HSA21--encoded genes but also leads to a genome-wide transcriptomic deregulation, which affect differently each tissue and cell type as a result of epigenetic mechanisms and protein-protein interactions. We performed a meta-analysis integrating the differential expression (DE) analyses of all publicly available transcriptomic datasets, both in human and mouse, comparing trisomic and euploid transcriptomes from different sources. We integrated all these data in a “DS network”. We found that genome wide deregulation as a consequence of trisomy 21 is not arbitrary, but involves deregulation of specific molecular cascades in which both HSA21 genes and HSA21 interactors are more consistently deregulated compared to other genes. In fact, gene deregulation happens in “clusters”, so that groups from 2 to 13 genes are found consistently deregulated. Most of these events of “co-deregulation” involve genes belonging to the same GO category, and genes associated with the same disease class. The most consistent changes are enriched in interferon related categories and neutrophil activation, reinforcing the concept that DS is an inflammatory disease. Our results also suggest that the impact of the trisomy might diverge in each tissue due to the different gene set deregulation, even though the triplicated genes are the same. Our original method to integrate transcriptomic data confirmed not only the importance of known genes, such as SOD1, but also detected new ones that could be extremely useful for generating or confirming hypotheses and supporting new putative therapeutic candidates. We created “metaDEA” an R package that uses our method to integrate every kind of transcriptomic data and therefore could be used with other complex disorders, such as cancer. We also created a user-friendly web application to query Ensembl gene IDs and retrieve all the information of their differential expression across the datasets.

scholarly journals Identification of loci affecting sexually dimorphic patterns for height and recurrent laryngeal neuropathy risk in American Belgian Draft Horses

2018 ◽  
Vol 50 (12) ◽  
pp. 1051-1058 ◽  
Author(s):  
Samantha A. Brooks ◽  
John Stick ◽  
Ashley Braman ◽  
Katelyn Palermo ◽  
N. Edward Robinson ◽  
...  
Keyword(s):  
Adult Height ◽  
Growth Traits ◽  
Treatment Strategies ◽  
Unknown Etiology ◽  
Specific Gene ◽  
Sexually Dimorphic ◽  
Haplotype Association ◽  
Genome Wide ◽  
A Genome ◽  
Specific Locus

Equine recurrent laryngeal neuropathy (RLN) is a bilateral mononeuropathy with an unknown etiology. In Thoroughbreds (TB), we previously demonstrated that the haplotype association for height (LCORL/NCAPG locus on ECA3, which affects body size) and RLN was coincident. In the present study, we performed a genome-wide association scan (GWAS) for RLN in 458 American Belgian Draft Horses, a breed fixed for the LCORL/NCAPG risk alelle. In this breed, RLN risk is associated with sexually dimorphic differences in height, and we identified a novel locus contributing to height in a sex-specific manner: MYPN (ECA1). Yet this specific locus contributes little to RLN risk, suggesting that other growth traits correlated to height may underlie the correlation to this disease. Controlling for height, we identified a locus on ECA15 contributing to RLN risk specifically in males. These results suggest that loci with sex-specific gene expression play an important role in altering growth traits impacting RLN etiology, but not necessarily adult height. These newly identified genes are promising targets for novel preventative and treatment strategies.

What genomic research has told us about the obesity and its possible gene therapy targets.

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Genetic Risk ◽  
Genomic Research ◽  
Activity Measurement ◽  
Unhealthy Lifestyle ◽  
Sweetened Beverages ◽  
Therapy Targets ◽  
New Information ◽  
Genome Wide ◽  
A Genome ◽  
Primary Advantage

The discovery of a genome-wide correlation with obesity-related genes hasrevealed new information about the genetics of obesity. Given the lowproportion of obesity heritability explained by available SNPs, it's not shockingthat these SNPs aren't scientifically effective as methods for assessing whowould acquire obesity. The roles of the majority of loci, the majority of whichmap to non-coding sequences, will take thorough analysis to determine theresponsible gene at each locus, which may not be the closest gene. Thismechanistic information, as well as the resulting elucidation of thepathophysiology of obesity, will allow the creation of new therapies, whichcould be the primary advantage of these genetic discoveries.Fortunately, a lack of mechanistic information hasn't stopped researchers fromusing SNPs and genetic risk ratings to shed light on how obesity biologyinteracts with environmental and lifestyle influences. These findings suggestthat an unhealthy lifestyle may amplify the genetic risk of obesity, despite thefact that environmental studies of obesity genes may be distorted byinaccuracies in diet and physical activity measurement. More research isrequired to confirm this theory and to identify the specific dietary components(such as sugar-sweetened beverages) that interfere with genetic variants. Thisstudy could contribute to personalized obesity prevention and care measures inthe future (pending confirmation in clinical trials of genetic-risk-guidedinterventions). Obesity genetics has offered researchers the opportunity toexamine causal interactions between obesity and its various possiblecomplications. However, since the majority of the studies discussed above wereconducted on people of European ethnicity, more research is required inminority ethnic groups with a high risk of obesity to understand the role ofbiology, climate, and relationships among these factors in explaining theirincreased risk.

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