scholarly journals Genomic editing of metformin efficacy-associated genetic variants in SLC47A1 does not alter SLC47A1 expression

2021 ◽  
Author(s):  
Sebastian Kalamajski ◽  
Mi Huang ◽  
Jonathan Dalla-Riva ◽  
Maria Keller ◽  
Adem Y Dawed ◽  
...  
Keyword(s):  
Genetic Variants ◽  
In Silico ◽  
Meta Analysis ◽  
Metformin Treatment ◽  
Common Variants ◽  
Common Genetic Variants ◽  
The Common ◽  
Genomic Editing ◽  
In Silico Analyses ◽  
Hba1c Levels

Abstract Several pharmacogenetics studies have identified an association between a greater metformin-dependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy.

scholarly journals Cell Type-Specific Annotation and Fine Mapping of Variants Associated With Brain Disorders

2020 ◽  
Vol 11 ◽  
Author(s):  
Abolfazl Doostparast Torshizi ◽  
Iuliana Ionita-Laza ◽  
Kai Wang
Keyword(s):  
Genetic Variants ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Brain Disorders ◽  
Common Variants ◽  
Cell Type ◽  
Tissue Specific ◽  
Common Genetic Variants ◽  
Functional Consequences ◽  
Context Free

Common genetic variants confer susceptibility to a large number of complex brain disorders. Given that such variants predominantly localize in non-coding regions of the human genome, there is a significant challenge to predict and characterize their functional consequences. More importantly, most available computational methods, generally defined as context-free methods, output prediction scores regarding the functionality of genetic variants irrespective of the context, i.e., the tissue or cell-type affected by a disease, limiting the ability to predict the functional consequences of common variants on brain disorders. In this study, we introduce a comparative multi-step pipeline to investigate the relative effectiveness of context-specific and context-free approaches to prioritize disease causal variants. As an experimental case, we focused on schizophrenia (SCZ), a debilitating neuropsychiatric disease for which a large number of susceptibility variants is identified from genome-wide association studies. We tested over two dozen available methods and examined potential associations between the cell/tissue-specific mapping scores and open chromatin accessibility, and provided a prioritized map of SCZ risk loci for in vitro or in-vivo functional analysis. We found extensive differences between context-free and tissue-specific approaches and showed how they may play complementary roles. As a proof of concept, we found a few sets of genes, through a consensus mapping of both categories, including FURIN to be among the top hits. We showed that the genetic variants in this gene and related genes collectively dysregulate gene expression patterns in stem cell-derived neurons and characterize SCZ phenotypic manifestations, while genes which were not shared among highly prioritized candidates in both approaches did not demonstrate such characteristics. In conclusion, by combining context-free and tissue-specific predictions, our pipeline enables prioritization of the most likely disease-causal common variants in complex brain disorders.

scholarly journals Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ekaterina Yonova-Doing ◽  
Wanting Zhao ◽  
Robert P. Igo ◽  
Chaolong Wang ◽  
Periasamy Sundaresan ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Association Studies ◽  
Meta Analysis ◽  
Crystalline Lens ◽  
Genome Wide Association Studies ◽  
Nuclear Cataract ◽  
Common Variants ◽  
Age Related ◽  
Genome Wide ◽  
Common Genetic Variants

AbstractNuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10−19), TMPRSS5 (rs4936279, P = 2.5 × 10−10), LINC01412 (rs16823886, P = 1.3 × 10−9), GLTSCR1 (rs1005911, P = 9.8 × 10−9), and COMMD1 (rs62149908, P = 1.2 × 10−8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.

scholarly journals A comprehensive meta-analysis of common genetic variants in autism spectrum conditions

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Varun Warrier ◽  
Vivienne Chee ◽  
Paula Smith ◽  
Bhismadev Chakrabarti ◽  
Simon Baron-Cohen
Keyword(s):  
Genetic Variants ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Autism Spectrum Conditions ◽  
Common Genetic Variants

A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E

2009 ◽  
Vol 127 (3) ◽  
pp. 303-314 ◽  
Author(s):  
Manit Nuinoon ◽  
Wattanan Makarasara ◽  
Taisei Mushiroda ◽  
Iswari Setianingsih ◽  
Pustika Amalia Wahidiyat ◽  
...  
Keyword(s):  
Disease Severity ◽  
Genetic Variants ◽  
Genome Wide Association ◽  
Hemoglobin E ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
The Common

scholarly journals Common variants contribute to intrinsic human brain functional networks

2020 ◽  
Author(s):  
Bingxin Zhao ◽  
Tengfei Li ◽  
Stephen M. Smith ◽  
Di Xiong ◽  
Xifeng Wang ◽  
...  
Keyword(s):  
Human Brain ◽  
Genetic Variants ◽  
Brain Function ◽  
Brain Activity ◽  
Well Being ◽  
Central Executive ◽  
Common Variants ◽  
Default Mode ◽  
Common Genetic Variants ◽  
Intrinsic Brain Activity

AbstractThe human brain remains active in the absence of explicit tasks and forms networks of correlated activity. Resting-state functional magnetic resonance imaging (rsfMRI) measures brain activity at rest, which has been linked with both cognitive and clinical outcomes. The genetic variants influencing human brain function are largely unknown. Here we utilized rsfMRI from 44,190 individuals of multiple ancestries (37,339 in the UK Biobank) to discover and validate the common genetic variants influencing intrinsic brain activity. We identified hundreds of novel genetic loci associated with intrinsic functional signatures (P < 2.8 × 10−11), including associations to the central executive, default mode, and salience networks involved in the triple network model of psychopathology. A number of intrinsic brain activity associated loci colocalized with brain disorder GWAS (e.g., Alzheimer’s disease, Parkinson’s disease, schizophrenia) and cognition, such as 19q13.32, 17q21.31, and 2p16.1. Particularly, we detected a colocalization between one (rs429358) of the two variants in the APOE ε4 locus and function of the default mode, central executive, attention, and visual networks. Genetic correlation analysis demonstrated shared genetic influences between brain function and brain structure in the same regions. We also detected significant genetic correlations with 26 other complex traits, such as ADHD, major depressive disorder, schizophrenia, intelligence, education, sleep, subjective well-being, and neuroticism. Common variants associated with intrinsic brain activity were enriched within regulatory element in brain tissues.

scholarly journals Consortium genome-wide meta-analysis for childhood dental caries traits

2017 ◽  
Author(s):  
Simon Haworth ◽  
Dmitry Shungin ◽  
Justin T van der Tas ◽  
Strahinja Vucic ◽  
Carolina Medina Gomez ◽  
...  
Keyword(s):  
Dental Caries ◽  
Genetic Variants ◽  
Primary Teeth ◽  
Meta Analysis ◽  
Genetic Effects ◽  
Permanent Dentition ◽  
Permanent Teeth ◽  
Common Disease ◽  
Genome Wide ◽  
Common Genetic Variants

AbstractPrior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from 9 contributing centers. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage (imputed to Haplotype Reference Consortium or 1000 Genomes phase 1 version 3 panels) accounting for population stratification. Fixed–effects meta-analysis was performed weighted by inverse standard error. Analysis included up to 19,003 individuals (7,530 affected) for primary teeth and 13,353 individuals (5,875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth (intronic within ALLC, Odds Ratio (OR) 0.85, Effect Allele Frequency (EAF) 0.60, p 4.13e-8) and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, p 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low (h2 of 1% [95% CI: 0%:7%] and 6% [95% CI 0%:13%] for primary and permanent dentitions, respectively) compared to corresponding within-study estimates (h2 of 28%, [95% CI: 9%:48%] and 17% [95% CI:2%:31%]) or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.Author summaryDental caries (tooth decay) is a common disease in children. Previous studies suggest genetic factors alter caries risk, but to date there is a gap of knowledge in identifying which specific genetic variants are responsible. We undertook analysis in a consortium including around 19,000 children and investigated whether any of 8 million common genetic variants were associated with risk of caries in primary (milk) or permanent teeth. If identified, these variants are used as ‘tags’ to highlight genes which may be involved in a disease. We identified variants in two loci associated with caries status; in the primary (rs1594318) and permanent dentition (rs7738851). The former is intronic in ALLC, a gene with poorly understood function. The latter is an intronic variant within NEDD9, a gene which has several known functions including a role in development of craniofacial structures. To gain a more comprehensive understanding of genetic effects which influence caries larger studies and a better understanding of environmental modifiers or interactions with genetic effects are required.

scholarly journals Common Variants in 22 Genes Regulate Response to Metformin Intervention in Children with Obesity: A Pharmacogenetic Study of a Randomized Controlled Trial

2019 ◽  
Vol 8 (9) ◽  
pp. 1471 ◽  
Author(s):  
Augusto Anguita-Ruiz ◽  
Belén Pastor-Villaescusa ◽  
Rosaura Leis ◽  
Gloria Bueno ◽  
Raúl Hoyos ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Genetic Variants ◽  
Controlled Trial ◽  
Common Variants ◽  
Oral Antidiabetic Agent ◽  
Double Blind ◽  
Pharmacogenetic Study ◽  
Randomized Controlled ◽  
Common Genetic Variants ◽  
Wide Range

Metformin is a first-line oral antidiabetic agent that has shown additional effects in treating obesity and metabolic syndrome. Inter-individual variability in metformin response could be partially explained by the genetic component. Here, we aimed to test whether common genetic variants can predict the response to metformin intervention in obese children. The study was a multicenter and double-blind randomized controlled trial that was stratified according to sex and pubertal status in 160 children with obesity. Children were randomly assigned to receive either metformin (1g/d) or placebo for six months after meeting the defined inclusion criteria. We conducted a post hoc genotyping study in 124 individuals (59 placebo, 65 treated) comprising finally 231 genetic variants in candidate genes. We provide evidence for 28 common variants as promising pharmacogenetics regulators of metformin response in terms of a wide range of anthropometric and biochemical outcomes, including body mass index (BMI) Z-score, and glucose, lipid, and inflammatory traits. Although no association remained statistically significant after multiple-test correction, our findings support previously reported variants in metformin transporters or targets as well as identify novel and promising loci, such as the ADYC3 and the BDNF genes, with plausible biological relation to the metformin’s action mechanism. Trial Registration: Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011 (URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023061-21/ES).

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