scholarly journals LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity

2020 ◽  
Author(s):  
Nellie Y. Loh ◽  
Senthil K. Vasan ◽  
Manu Verma ◽  
Agata Wesolowska-Andersen ◽  
Matt J. Neville ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Fat Mass ◽  
Genome Wide Association Study ◽  
Missense Variant ◽  
Mineral Density ◽  
High Bone Mass ◽  
Genome Wide ◽  
A Genome

ABSTRACTWNT signalling is a developmental pathway which plays an important role in post-natal bone accrual. We have previously shown, that in addition to exhibiting extreme high bone mass, subjects with rare gain-of-function (GoF) mutations in the WNT co-receptor LRP5 also display increased lower-body fat mass. Here, we demonstrate using human physiological studies in GoF LRP5 mutation carriers and glucose uptake assays in LRP5 knockdown (KD) adipocytes that LRP5 promotes adipocyte insulin sensitivity. We also show that a low frequency missense variant in LRP5 shown to be associated with low heel bone mineral density in a genome wide association study meta-analysis, is associated with reduced leg fat mass. Finally, using genome wide transcriptomic analyses and in vitro functional studies in LRP5-KD adipose progenitors (APs) we demonstrate that LRP5 plays an essential role in maintaining AP fitness i.e. functional characteristics. Pharmacological activation of LRP5 signalling in adipose tissue provides a promising strategy to prevent the redistribution of adipose tissue and metabolic sequela associated with obesity and ageing.

scholarly journals A genome-wide meta-analysis identifies 53 sequence variants associating with carpal tunnel syndrome

2022 ◽  
Author(s):  
Astros Skuladottir ◽  
Gyda Bjornsdottir ◽  
Egil Ferkingstad ◽  
Gudmundur Einarsson ◽  
Lilja Stefansdottir ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Carpal Tunnel Syndrome ◽  
Carpal Tunnel ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Missense Variant ◽  
Sequence Variants ◽  
Genome Wide ◽  
A Genome ◽  
Tunnel Syndrome

Abstract Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (Ncases = 48,843, Ncontrols = 1,190,837), we found 53 sequence variants at 50 loci that associate with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10−24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in recurrent/persistent cases than nonrecurrent/nonresistant cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.

scholarly journals The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

2020 ◽  
Vol 6 (43) ◽  
pp. eabb3063
Author(s):  
Wei Xu ◽  
Si-Da Han ◽  
Can Zhang ◽  
Jie-Qiong Li ◽  
Yan-Jiang Wang ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Genome Wide Association Study ◽  
In Vitro Study ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Pathophysiological Role ◽  
Independent Cohort

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10−12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

scholarly journals Genome-Wide Association Study of Metabolic Syndrome Reveals Primary Genetic Variants at CETP Locus in Indians

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 321 ◽  
Author(s):  
Gauri Prasad ◽  
Khushdeep Bandesh ◽  
Anil Giri ◽  
Yasmeen Kauser ◽  
Prakriti Chanda ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Rapid Urbanization ◽  
Significance Level ◽  
Genome Wide ◽  
A Genome ◽  
Replication Phase

Indians, a rapidly growing population, constitute vast genetic heterogeneity to that of Western population; however they have become a sedentary population in past decades due to rapid urbanization ensuing in the amplified prevalence of metabolic syndrome (MetS). We performed a genome-wide association study (GWAS) of MetS in 10,093 Indian individuals (6617 MetS and 3476 controls) of Indo-European origin, that belong to our previous biorepository of The Indian Diabetes Consortium (INDICO). The study was conducted in two stages—discovery phase (N = 2158) and replication phase (N = 7935). We discovered two variants within/near the CETP gene—rs1800775 and rs3816117—associated with MetS at genome-wide significance level during replication phase in Indians. Additional CETP loci rs7205804, rs1532624, rs3764261, rs247617, and rs173539 also cropped up as modest signals in Indians. Haplotype association analysis revealed GCCCAGC as the strongest haplotype within the CETP locus constituting all seven CETP signals. In combined analysis, we perceived a novel and functionally relevant sub-GWAS significant locus—rs16890462 in the vicinity of SFRP1 gene. Overlaying gene regulatory data from ENCODE database revealed that single nucleotide polymorphism (SNP) rs16890462 resides in repressive chromatin in human subcutaneous adipose tissue as characterized by the enrichment of H3K27me3 and CTCF marks (repressive gene marks) and diminished H3K36me3 marks (activation gene marks). The variant displayed active DNA methylation marks in adipose tissue, suggesting its likely regulatory activity. Further, the variant also disrupts a potential binding site of a key transcription factor, NRF2, which is known for involvement in obesity and metabolic syndrome.

scholarly journals Genomic variation across a clinical Cryptococcus population linked to disease outcome

2021 ◽  
Author(s):  
Poppy Channa Sakti Sephton-Clark ◽  
Jennifer Tenor ◽  
Dena Toffaletti ◽  
Nancy Meyers ◽  
Charles Giamberardino ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Sugar Transport ◽  
Genomic Variation ◽  
Clinical Isolates ◽  
Genome Wide ◽  
A Genome ◽  
Gwas Approach

Cryptococcus neoformans is the causative agent of cryptococcosis, a disease with poor patient outcomes, accounting for approximately 180,000 deaths each year. Patient outcomes may be impacted by the underlying genetics of the infecting isolate, however, our current understanding of how genetic diversity contributes to clinical outcomes is limited. Here, we leverage clinical, in vitro growth and genomic data for 284 C. neoformans isolates to identify clinically relevant pathogen variants within a population of clinical isolates from patients with HIV-associated cryptococcosis in Malawi. Through a genome-wide association study (GWAS) approach, we identify variants associated with fungal burden and growth rate. We also find both small and large-scale variation, including aneuploidy, associated with alternate growth phenotypes, which may impact the course of infection. Genes impacted by these variants are involved in transcriptional regulation, signal transduction, glycolysis, sugar transport, and glycosylation. When combined with clinical data, we show that growth within the CNS is reliant upon glycolysis in an animal model, and likely impacts patient mortality, as CNS burden modulates patient outcome. Additionally, we find genes with roles in sugar transport are under selection in the majority of these clinical isolates. Further, we demonstrate that two hypothetical proteins identified by GWAS impact virulence in animal models. Our approach illustrates links between genetic variation and clinically relevant phenotypes, shedding light on survival mechanisms within the CNS and pathways involved in this persistence.

scholarly journals A Genome-wide Association Study to Identify Candidate Genes for Metabolic Disorders in Offspring by in Vitro Fertilization

2022 ◽  
Author(s):  
Lihong Liu ◽  
Siyao HA ◽  
MingQing Li ◽  
Zhiling Li
Keyword(s):  
Lipid Metabolism ◽  
Health Risks ◽  
Genome Wide Association Study ◽  
Vitro Fertilization ◽  
Genome Wide ◽  
A Genome ◽  
Offspring Health

Abstract BackgroundIn vitro fertilization (IVF) processes increase offspring's short-term and long-term health risks, but their mechanisms remain unclear. MethodsWe conducted a bibliometric analysis to determine the landscape of IVF offspring health. Subsequently, a bioinformatics method was utilized to identify the co-genes properties and biological function mechanisms of IVF and type 2 diabetes mellitus (T2DM). Finally, we predicted compounds against key targets and performed multiple validations of the mechanisms underlying IVF offspring health risks. ResultsWe identified 15 genes associated with T2DM, and their biological functions are primarily associated with lipid metabolism. We also identified the properties of co-genes, modified characteristics, identified 3 SNPs sites, and determined the three core genes, APOA1, APOB, and APOE, which were mainly correlated with metabolic and cardiovascular diseases. In addition, we predicted drugs that may improve metabolic abnormalities in IVF offspring. ConclusionsThe impact of aberrant lipid metabolism in offspring after IVF therapy warrants additional investigation, particularly in terms of long-term health consequences and possible mechanisms.

scholarly journals Mouse Genome-Wide Association and Systems Genetics Identifies Lhfp as a Regulator of Bone Mass

2018 ◽  
Author(s):  
Larry D. Mesner ◽  
Gina Calabrese ◽  
Basel Al-Barghouthi ◽  
Daniel M. Gatti ◽  
John P. Sundberg ◽  
...  
Keyword(s):  
Bone Mass ◽  
Genome Wide Association Study ◽  
Strong Predictor ◽  
Genome Wide Association ◽  
Systems Genetics ◽  
Fusion Partner ◽  
Mineral Density ◽  
Osteoblast Activity ◽  
Genome Wide ◽  
A Genome

ABSTRACTBone mineral density (BMD) is a strong predictor of osteoporotic fracture. It is also one of the most heritable disease-associated quantitative traits. As a result, there has been considerable effort focused on dissecting its genetic basis. Here, we performed a genome-wide association study (GWAS) in a panel of inbred strains to identify associations influencing BMD. This analysis identified a significant (P=3.1 x 10−12) BMD locus on Chromosome [email protected] Mbp that replicated in two seperate inbred strain panels and overlapped a BMD quantitative trait locus (QTL) previously identified in a F2 intercross. The association mapped to a 300 Kbp region containing four genes; Gm2447, Gm20750, Cog6, and Lhfp. Further analysis found that Lipoma HMGIC Fusion Partner (Lhfp) was highly expressed in bone and osteoblasts and its expression was regulated by local expression QTL (eQTL) in multiple tissues. A co-expression network analysis revealed that Lhfp was strongly connected to genes involved in osteoblast differentiation. To directly evaluate its role in bone, Lhfp deficient mice (Lhfp−/−) were created using CRISPR/Cas9. Consistent with genetic and network predictions, bone marrow stromal cells (BMSCs) from Lhfp−/− displayed increased osteogenic differentiation. Lfhp−/− mice also had elevated BMD due to increased cortical bone mass. In conclusion, we used GWAS and systems genetics in mice to identify Lhfp as a regulator of osteoblast activity and bone mass.

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