scholarly journals Mono- and bi-allelic effects of coding variants on disease in 176,899 Finns

2021 ◽  
Author(s):  
Henrike O. Heyne ◽  
Juha Karjalainen ◽  
Konrad Karczewski ◽  
Susanna Lemmela ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Disease Risk ◽  
Retinal Dystrophy ◽  
Compound Heterozygous ◽  
Recessive Inheritance ◽  
Sequencing Data ◽  
Disease Associations ◽  
Founder Populations ◽  
Definition Of ◽  
Coding Variants ◽  
The Impact

Identifying Mendelian diseases with recessive inheritance is challenging as the majority of cases are caused by compound heterozygous genotypes which require sequencing data in families to definitively identify. Bottleneck events, such as in the Finnish population, enrich specific homozygous variants to higher frequencies and thus facilitate identification of disease associations through easily recognized homozygous genotypes. Here, we study homozygous and heterozygous effects of 82,516 coding variants on 2,444 disease endpoints using nationwide electronic health record (EHR) data of 176,899 Finns. We find known and novel associations to homozygous genotypes across a broad spectrum of phenotypes such as retinal dystrophy, adult-onset cataract and female infertility (13/20 of which would have been missed by the traditional additive GWAS model). With these results, and supporting simulations, we demonstrate the added benefit of homozygous scans in GWAS. We further use these results to explore inheritance patterns of known Mendelian variants. We find many Mendelian variants whose inheritance cannot be adequately described with the traditional definition of dominant or recessive. In particular, we find disease risk in heterozygous carriers of variants known to cause disease with recessive inheritance, as well as for variants labeled benign in ClinVar. Our results demonstrate how biobank efforts, particularly in founder populations, can broaden our understanding of the impact of genetic variants.

scholarly journals The impact of rare variation on gene expression across tissues

Nature ◽  
2017 ◽  
Vol 550 (7675) ◽  
pp. 239-243 ◽  
Author(s):  
Xin Li ◽  
◽  
Yungil Kim ◽  
Emily K. Tsang ◽  
Joe R. Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Rare Variants ◽  
Disease Risk ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Sequencing Data ◽  
Common Genetic Variants ◽  
Coding Variants ◽  
The Impact

Abstract Rare genetic variants are abundant in humans and are expected to contribute to individual disease risk1,2,3,4. While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants1,5. Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles1,6,7, but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues8,9,10,11, but their effects across tissues are unknown. Here we identify gene expression outliers, or individuals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release12. We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in individual genomes.

scholarly journals Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

2017 ◽  
Author(s):  
Andrea Ganna ◽  
Kyle F. Satterstrom ◽  
Seyedeh M Zekavat ◽  
Indraniel Das ◽  
Mitja I. Kurki ◽  
...  
Keyword(s):  
Complex Traits ◽  
Sequencing Data ◽  
Multiple Phenotypes ◽  
Gene Sets ◽  
Whole Exome ◽  
Increased Risk ◽  
Whole Exome Sequencing Data ◽  
Lower Education ◽  
Coding Variants ◽  
The Impact

AbstractThere is a limited understanding about the impact of rare protein truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization and reduced age. Gene sets implicated from GWAS did not show a significant protein truncating variants-burden beyond what captured by established Mendelian genes. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.Main abbreviationsPTV= Protein Truncating VariantsPI= Protein Truncating IntolerantPI-PTV= Protein Truncating Variant in genes that are Intolerant to Protein Truncating Variants

scholarly journals The impact of rare variation on gene expression across tissues

2016 ◽  
Author(s):  
Xin Li ◽  
Yungil Kim ◽  
Emily K. Tsang ◽  
Joe R. Davis ◽  
Farhan N. Damani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rare Variants ◽  
Disease Risk ◽  
Whole Genome Sequencing Data ◽  
Personal Genome ◽  
Sequencing Data ◽  
Potential Health ◽  
Rare Variation ◽  
Functional Variants ◽  
The Impact

AbstractRare genetic variants are abundant in humans yet their functional effects are often unknown and challenging to predict. The Genotype-Tissue Expression (GTEx) project provides a unique opportunity to identify the functional impact of rare variants through combined analyses of whole genomes and multi-tissue RNA-sequencing data. Here, we identify gene expression outliers, or individuals with extreme expression levels, across 44 human tissues, and characterize the contribution of rare variation to these large changes in expression. We find 58% of underexpression and 28% of overexpression outliers have underlying rare variants compared with 9% of non-outliers. Large expression effects are enriched for proximal loss-of-function, splicing, and structural variants, particularly variants near the TSS and at evolutionarily conserved sites. Known disease genes have expression outliers, underscoring that rare variants can contribute to genetic disease risk. To prioritize functional rare regulatory variants, we develop RIVER, a Bayesian approach that integrates RNA and whole genome sequencing data from the same individual. RIVER predicts functional variants significantly better than models using genomic annotations alone, and is an extensible tool for personal genome interpretation. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues with potential health consequences, and provide an integrative method for interpreting rare variants in individual genomes.

PERTANGGUNGJAWABAN KERUGIAN NEGARA DALAM PENGELOLAAN KEUANGAN DAERAH

EDUKASI ◽  
2018 ◽  
Vol 16 (1) ◽  
Author(s):  
Hendra Karianga
Keyword(s):  
Financial Management ◽  
Criminal Liability ◽  
The State ◽  
Legal Proceedings ◽  
Regional Finance ◽  
Regional Budget ◽  
State Finance ◽  
Budget Policy ◽  
Definition Of ◽  
The Impact

Sources of revenue and expenditure of APBD (regional budget) can be allocated to finance the compulsory affairs and optional affairs in the form of programs and activities related to the improvement of public services, job creation, poverty alleviation, improvement of environmental quality, and regional economic growth. The implications of these policies is the need for funds to finance the implementation of the functions, that have become regional authority, is also increasing. In practice, regional financial management still poses a complicated issue because the regional head are reluctant to release pro-people regional budget policy, even implication of regional autonomy is likely to give birth to little kings in region causing losses to state finance and most end up in legal proceedings. This paper discusses the loss of state finance and forms of liability for losses to the state finance. The result of the study can be concluded firstly,  there are still many differences in giving meaning and definition of the loss of state finace and no standard definition of state losses, can cause difficulties. The difficulty there is in an effort to determine the amount of the state finance losses. The calculation of state/regions losses that occur today is simply assessing the suitability of the size of the budget and expenditure without considering profits earned by the community and the impact of the use of budget to the community. Secondly, the liability for losses to the state finance is the fulfillment of the consequences for a person to give or to do something in the regional financial management by giving birth to three forms of liability, namely the Criminal liability, Civil liability, and Administrative liability.Keywords: state finance losses, liability, regional finance.

Empowering Women Entrepreneurs Through Microfinance - A Case of Rural Bangladesh

2017 ◽  
Vol 3 (2) ◽  
pp. 7
Author(s):  
Saida Parvin
Keyword(s):  
Women's Empowerment ◽  
Assessment Tools ◽  
Women’S Empowerment ◽  
Case Study Method ◽  
Policy Makers ◽  
Theoretical Contribution ◽  
Donor Agencies ◽  
Definition Of ◽  
The Impact

Women’s empowerment has been at the centre of research focus for many decades. Extant literature examined the process, outcome and various challenges. Some claimed substantial success, while others contradicted with evidence of failure. But the success remains a matter of debate due to lack of empirical evidence of actual empowerment of women around the world. The current study aimed to address this gap by taking a case study method. The study critically evaluates 20 cases carefully sampled to include representatives from the entire country of Bangladesh. The study demonstrates popular beliefs about microfinance often misguide even the borrowers and they start living in a fabricated feeling of empowerment, facing real challenges to achieve true empowerment in their lives. The impact of this finding is twofold; firstly there is a theoretical contribution, where the definition of women’s empowerment is proposed to be revisited considering findings from these cases. And lastly, the policy makers at governmental and non-governmental organisations, and multinational donor agencies need to revise their assessment tools for funding.

scholarly journals Quantitative disease risk scores from EHR with applications to clinical risk stratification and genetic studies

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Danqing Xu ◽  
Chen Wang ◽  
Atlas Khan ◽  
Ning Shang ◽  
Zihuai He ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Disease Risk ◽  
Association Studies ◽  
Large Datasets ◽  
Risk Scores ◽  
Sequencing Data ◽  
Case Definitions ◽  
Phenotypic Data ◽  
Clinical Risk ◽  
Phenotypic Features

AbstractLabeling clinical data from electronic health records (EHR) in health systems requires extensive knowledge of human expert, and painstaking review by clinicians. Furthermore, existing phenotyping algorithms are not uniformly applied across large datasets and can suffer from inconsistencies in case definitions across different algorithms. We describe here quantitative disease risk scores based on almost unsupervised methods that require minimal input from clinicians, can be applied to large datasets, and alleviate some of the main weaknesses of existing phenotyping algorithms. We show applications to phenotypic data on approximately 100,000 individuals in eMERGE, and focus on several complex diseases, including Chronic Kidney Disease, Coronary Artery Disease, Type 2 Diabetes, Heart Failure, and a few others. We demonstrate that relative to existing approaches, the proposed methods have higher prediction accuracy, can better identify phenotypic features relevant to the disease under consideration, can perform better at clinical risk stratification, and can identify undiagnosed cases based on phenotypic features available in the EHR. Using genetic data from the eMERGE-seq panel that includes sequencing data for 109 genes on 21,363 individuals from multiple ethnicities, we also show how the new quantitative disease risk scores help improve the power of genetic association studies relative to the standard use of disease phenotypes. The results demonstrate the effectiveness of quantitative disease risk scores derived from rich phenotypic EHR databases to provide a more meaningful characterization of clinical risk for diseases of interest beyond the prevalent binary (case-control) classification.

Defining Preterm Birth and Stillbirth in the Western Pacific: A Systematic Review

2021 ◽  
pp. 101053952110260
Author(s):  
Mairead Connolly ◽  
Laura Phung ◽  
Elise Farrington ◽  
Michelle J. L. Scoullar ◽  
Alyce N. Wilson ◽  
...  
Keyword(s):  
Preterm Birth ◽  
National Level ◽  
Health Indicators ◽  
Western Pacific ◽  
World Health ◽  
Middle Income ◽  
Middle Income Countries ◽  
Definition Of ◽  
Health Organization ◽  
The Impact

Preterm birth and stillbirth are important global perinatal health indicators. Definitions of these indicators can differ between countries, affecting comparability of preterm birth and stillbirth rates across countries. This study aimed to document national-level adherence to World Health Organization (WHO) definitions of preterm birth and stillbirth in the WHO Western Pacific region. A systematic search of government health websites and 4 electronic databases was conducted. Any official report or published study describing the national definition of preterm birth or stillbirth published between 2000 and 2020 was eligible for inclusion. A total of 58 data sources from 21 countries were identified. There was considerable variation in how preterm birth and stillbirth was defined across the region. The most frequently used lower gestational age threshold for viability of preterm birth was 28 weeks gestation (range 20-28 weeks), and stillbirth was most frequently classified from 20 weeks gestation (range 12-28 weeks). High-income countries more frequently used earlier gestational ages for preterm birth and stillbirth compared with low- to middle-income countries. The findings highlight the importance of clear, standardized, internationally comparable definitions for perinatal indicators. Further research is needed to determine the impact on regional preterm birth and stillbirth rates.

Value assessment of antimicrobials and the implications for development, access, and funding of effective treatments: Australian stakeholder perspective

2020 ◽  
pp. 1-7
Author(s):  
Nadine T. Hillock ◽  
Tracy L. Merlin ◽  
Jonathan Karnon ◽  
John Turnidge ◽  
Jaklin Eliott
Keyword(s):  
Cost Effectiveness ◽  
Healthcare Resource ◽  
Economic Evaluations ◽  
Value Assessment ◽  
Antimicrobial Drugs ◽  
Policy Makers ◽  
Stakeholder Perspective ◽  
Definition Of ◽  
The Impact ◽  
Potential Use

Abstract Background The frameworks used by Health Technology Assessment (HTA) agencies for value assessment of medicines aim to optimize healthcare resource allocation. However, they may not be effective at capturing the value of antimicrobial drugs. Objectives To analyze stakeholder perceptions regarding how antimicrobials are assessed for value for reimbursement purposes and how the Australian HTA framework accommodates the unique attributes of antimicrobials in cost-effectiveness evaluation. Methods Eighteen individuals representing the pharmaceutical industry or policy-makers were interviewed. Interviews were transcribed verbatim, coded, and thematically analyzed. Results Key emergent themes were that reimbursement decision-making should consider the antibiotic spectrum when assessing value, risk of shortages, the impact of procurement processes on low-priced comparators, and the need for methodological transparency when antimicrobials are incorporated into the economic evaluation of other treatments. Conclusions Participants agreed that the current HTA framework for antimicrobial value assessment is inadequate to properly inform funding decisions, as the contemporary definition of cost-effectiveness fails to explicitly incorporate the risk of future resistance. Policy-makers were uncertain about how to incorporate future resistance into economic evaluations without a systematic method to capture costs avoided due to good stewardship. Lacking financial reward for the benefits of narrower-spectrum antimicrobials, companies will likely focus on developing broad-spectrum agents with wider potential use. The perceived risks of shortages have influenced the funding of generic antimicrobials in Australia, with policy-makers suggesting a willingness to pay more for assured supply. Although antibiotics often underpin the effectiveness of other medicines, it is unclear how this is incorporated into economic models.

scholarly journals miR-208b Reduces the Expression of Kcnj5 in a Cardiomyocyte Cell Line

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 719
Author(s):  
Julia Hupfeld ◽  
Maximilian Ernst ◽  
Maria Knyrim ◽  
Stephanie Binas ◽  
Udo Kloeckner ◽  
...  
Keyword(s):  
Untranslated Region ◽  
Electrical Remodeling ◽  
Sequencing Data ◽  
Western Blots ◽  
Cardiovascular Pathology ◽  
Hypertrophic Response ◽  
Channel Dependent ◽  
Cardiac Excitation ◽  
The Impact ◽  
Generation Sequencing

MicroRNAs (miRs) contribute to different aspects of cardiovascular pathology, among them cardiac hypertrophy and atrial fibrillation. Cardiac miR expression was analyzed in a mouse model with structural and electrical remodeling. Next-generation sequencing revealed that miR-208b-3p was ~25-fold upregulated. Therefore, the aim of our study was to evaluate the impact of miR-208b on cardiac protein expression. First, an undirected approach comparing whole RNA sequencing data to miR-walk 2.0 miR-208b 3′-UTR targets revealed 58 potential targets of miR-208b being regulated. We were able to show that miR-208b mimics bind to the 3′ untranslated region (UTR) of voltage-gated calcium channel subunit alpha1 C and Kcnj5, two predicted targets of miR-208b. Additionally, we demonstrated that miR-208b mimics reduce GIRK1/4 channel-dependent thallium ion flux in HL-1 cells. In a second undirected approach we performed mass spectrometry to identify the potential targets of miR-208b. We identified 40 potential targets by comparison to miR-walk 2.0 3′-UTR, 5′-UTR and CDS targets. Among those targets, Rock2 and Ran were upregulated in Western blots of HL-1 cells by miR-208b mimics. In summary, miR-208b targets the mRNAs of proteins involved in the generation of cardiac excitation and propagation, as well as of proteins involved in RNA translocation (Ran) and cardiac hypertrophic response (Rock2).

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