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.

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 Genetic risk factors for variant Creutzfeldt–Jakob disease: a genome-wide association study

2009 ◽  
Vol 8 (1) ◽  
pp. 57-66 ◽  
Author(s):  
Simon Mead ◽  
Mark Poulter ◽  
James Uphill ◽  
John Beck ◽  
Jerome Whitfield ◽  
...  
Keyword(s):  
Risk Factors ◽  
Association Study ◽  
Genetic Risk ◽  
Genome Wide Association Study ◽  
Genetic Risk Factors ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Jakob Disease

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 Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications

2016 ◽  
Vol 76 (5) ◽  
pp. 906-913 ◽  
Author(s):  
Michael J Ombrello ◽  
Victoria L Arthur ◽  
Elaine F Remmers ◽  
Anne Hinks ◽  
Ioanna Tachmazidou ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Genetic Risk ◽  
Genetic Architecture ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Disease Process ◽  
Chromosome 1 ◽  
Childhood Arthritis ◽  
Genome Wide ◽  
A Genome ◽  
Shared Genetic

ObjectivesJuvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA.MethodsWe performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes.ResultsThe major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes.ConclusionsThe lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.

scholarly journals Shared genetic risk between migraine and coronary artery disease: A genome-wide analysis of common variants

PLoS ONE ◽  
2017 ◽  
Vol 12 (9) ◽  
pp. e0185663 ◽  
Author(s):  
Bendik S. Winsvold ◽  
Francesco Bettella ◽  
Aree Witoelar ◽  
Verneri Anttila ◽  
Padhraig Gormley ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genetic Risk ◽  
Common Variants ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Artery Disease ◽  
Shared Genetic

scholarly journals Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

2021 ◽  
Vol 11 (11) ◽  
pp. 1233
Author(s):  
Zulfan Zazuli ◽  
Corine de de Jong ◽  
Wei Xu ◽  
Susanne J. H. Vijverberg ◽  
Rosalinde Masereeuw ◽  
...  
Keyword(s):  
Candidate Gene ◽  
Genetic Risk ◽  
Validation Cohort ◽  
Genotype Imputation ◽  
Candidate Gene Approach ◽  
Genetic Associations ◽  
Discovery Cohort ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10−8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10−7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

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