scholarly journals P825 The impact of a SNP-dose–response effect on course of inflammatory bowel disease: a numerical analysis of SNP distribution within the Swiss IBD Cohort Study

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S640-S641
Author(s):  
L Biedermann ◽  
L Denoth ◽  
J B Rossel ◽  
M Butter ◽  
S Vavricka ◽  
...  
Keyword(s):  
Cohort Study ◽  
Risk Score ◽  
Association Studies ◽  
Large Population ◽  
Median Number ◽  
Clinical Disease ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Individual Snps ◽  
The Impact

Abstract Background Several large genome wide association studies have identified an increasing number of IBD risk loci with currently more than 240 established loci and generated robust data on disease association. However, knowledge remains limited on distinctive associations to specific clinical characteristics. The Swiss IBD Cohort Study (SIBDCS) represents a large prospective cohort study with clinically and phenotypically sound data collection since 2006 including genotyping. In this study, we aimed to determine individual associations of known risk loci with clinical features of patients in the SIBDCS, as well as their combined effect on clinical outcomes. Methods Based on 158 analysed SNPs, we investigated the numerical distribution of risk alleles and determined an individual SNP risk score (defined as percentage of risk alleles; i.e. number of risk alleles divided by twice the number of given SNPs multiplied with 100). We then performed linear regression modelling to investigate, whether relevant clinical disease characteristics associate with this SNP risk score. Further, for each given clinical outcome, a model was run with all SNPs as potential predictors, and the number of significant associations per SNP counted. Results In a total of 2304 genotyped patients, we observed a median number of risk alleles of 167, 168 and 167 for IBD overall, CD and UC/IC, respectively with a narrow inter quartile range [11 (q25 = 162, q75 = 173) for IBD and CD; 12 (q25 = 161, q75 = 173) for UC/IC]. A higher SNP risk score was significantly associated with any complications (defined as a composite of any or more of colorectal cancer, colon dysplasia, intestinal lymphoma, osteopenia/-porosis, anaemia, deep venous thrombosis, pulmonary embolism, nephro- or cholelithiasis, malabsorption syndrome, massive haemorrhage, perforation/peritonitis, pouchitis), stenosis in CD patients; pancolitis, conversion to CD, female sex in UC patients; higher clinical disease activity in both CD & UC. Regarding individual SNPs, we identified substantial differences in terms of the frequency of associations to disease-related outcomes with up to 11 for rs4899554 in CD and 7 for rs9557195 in UC, respectively. Conclusion In our large population of IBD patients there is high per patient frequency of hetero- and homozygous SNP risk alleles. The association of higher SNP risk score with several disease-related outcomes indicates a potential interplay of per patient given SNP risk alleles.

scholarly journals The impact of schizophrenia and mood disorder risk alleles on emotional problems: investigating change from childhood to middle age

2017 ◽  
Vol 48 (13) ◽  
pp. 2153-2158 ◽  
Author(s):  
Lucy Riglin ◽  
Stephan Collishaw ◽  
Alexander Richards ◽  
Ajay K. Thapar ◽  
Frances Rice ◽  
...  
Keyword(s):  
Mood Disorder ◽  
Genetic Risk ◽  
Association Studies ◽  
Adult Life ◽  
Emotional Problems ◽  
Genome Wide Association Studies ◽  
Risk Alleles ◽  
Different Ages ◽  
The Impact ◽  
Disorder Risk

AbstractBackgroundPrevious studies find that both schizophrenia and mood disorder risk alleles contribute to adult depression and anxiety. Emotional problems (depression or anxiety) begin in childhood and show strong continuities into adult life; this suggests that symptoms are the manifestation of the same underlying liability across different ages. However, other findings suggest that there are developmental differences in the etiology of emotional problems at different ages. To our knowledge, no study has prospectively examined the impact of psychiatric risk alleles on emotional problems at different ages in the same individuals.MethodsData were analyzed using regression-based analyses in a prospective, population-based UK cohort (the National Child Development Study). Schizophrenia and major depressive disorder (MDD) polygenic risk scores (PRS) were derived from published Psychiatric Genomics Consortium genome-wide association studies. Emotional problems were assessed prospectively at six time points from age 7 to 42 years.ResultsSchizophrenia PRS were associated with emotional problems from childhood [age 7, OR 1.09 (1.03–1.15), p = 0.003] to mid-life [age 42, OR 1.10 (1.05–1.17), p < 0.001], while MDD PRS were associated with emotional problems only in adulthood [age 42, OR 1.06 (1.00–1.11), p = 0.034; age 7, OR 1.03 (0.98–1.09), p = 0.228].ConclusionsOur prospective investigation suggests that early (childhood) emotional problems in the general population share genetic risk with schizophrenia, while later (adult) emotional problems also share genetic risk with MDD. The results suggest that the genetic architecture of depression/anxiety is not static across development.

A Polygenic Risk Score Suggests Shared Genetic Architecture of Voice Break With Early Markers of Pubertal Onset in Boys

2020 ◽  
Vol 105 (3) ◽  
pp. e349-e357 ◽  
Author(s):  
María C Lardone ◽  
Alexander S Busch ◽  
José L Santos ◽  
Patricio Miranda ◽  
Susana Eyheramendy ◽  
...  
Keyword(s):  
Risk Score ◽  
Genetic Architecture ◽  
Pubertal Timing ◽  
Association Studies ◽  
Pubic Hair ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Polygenic Risk ◽  
Risk Alleles

Abstract Context Voice break, as a landmark of advanced male puberty in genome-wide association studies (GWAS), has revealed that pubertal timing is a highly polygenic trait. Although voice break is easily recorded in large cohorts, it holds quite low precision as a marker of puberty. In contrast, gonadarche and pubarche are early and clinically well-defined measures of puberty onset. Objective To determine whether a polygenic risk score (PRS) of alleles that confer risk for voice break associates with age at gonadarche (AAG) and age at pubarche (AAP) in Chilean boys. Experimental Design Longitudinal study. Subjects and Methods 401 boys from the Growth and Obesity Chilean Cohort Study (n = 1194; 49.2% boys). Main Outcome Measures Biannual clinical pubertal staging including orchidometry. AAG and AAP were estimated by censoring methods. Genotyping was performed using the Multi-Ethnic Global Array (Illumina). Using GWAS summary statistics from the UK-Biobank, 29 significant and independent single nucleotide polymorphisms associated with age at voice break were extracted. Individual PRS were computed as the sum of risk alleles weighted by the effect size. Results The PRS was associated with AAG (β=0.01, P = 0.04) and AAP (β=0.185, P = 0.0004). In addition, boys within the 20% highest PRS experienced gonadarche and pubarche 0.55 and 0.67 years later than those in the lowest 20%, respectively (P = 0.013 and P = 0.007). Conclusions Genetic variants identified in large GWAS on age at VB significantly associate with age at testicular growth and pubic hair development, suggesting that these events share a genetic architecture across ethnically distinct populations.

scholarly journals TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 513
Author(s):  
Grace H. Yang ◽  
Danielle A. Fontaine ◽  
Sukanya Lodh ◽  
Joseph T. Blumer ◽  
Avtar Roopra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Association Studies ◽  
Cell Cycle Gene ◽  
Genome Wide Association Studies ◽  
Β Cell ◽  
Nucleotide Incorporation ◽  
Damage Response ◽  
The Impact

Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.

scholarly journals Pharmacogenetic Polygenic Risk Score for Bronchodilator Response in Children and Adolescents with Asthma: Proof-of-Concept

2021 ◽  
Vol 11 (4) ◽  
pp. 319
Author(s):  
Joanne E. Sordillo ◽  
Sharon M. Lutz ◽  
Michael J. McGeachie ◽  
Jessica Lasky-Su ◽  
Scott T. Weiss ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Risk Score ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Linear Regression Models ◽  
Standard Deviation Increase ◽  
Polygenic Risk ◽  
Bronchodilator Response ◽  
Children With Asthma

Genome-wide association studies (GWAS) of response to asthma medications have primarily focused on Caucasian populations, with findings that may not be generalizable to minority populations. We derived a polygenic risk score (PRS) for response to albuterol as measured by bronchodilator response (BDR), and examined the PRS in a cohort of Hispanic school-aged children with asthma. We leveraged a published GWAS of BDR to identify relevant genetic variants, and ranked the top variants according to their Combined Annotation Dependent Depletion (CADD) scores. Variants with CADD scores greater than 10 were used to compute the PRS. Once we derived the PRS, we determined the association of the PRS with BDR in a cohort of Hispanic children with asthma (the Genetics of Asthma in Costa Rica Study (GACRS)) in adjusted linear regression models. Mean BDR in GACRS participants was5.6% with a standard deviation of 10.2%. We observed a 0.63% decrease in BDR in response to albuterol for a standard deviation increase in the PRS (p = 0.05). We also observed decreased odds of a BDR response at or above the 12% threshold for a one standard deviation increase in the PRS (OR = 0.80 (95% CI 0.67 to 0.95)). Our findings show that combining variants from a pharmacogenetic GWAS into a PRS may be useful for predicting medication response in asthma.

scholarly journals Children’s Greenness Exposure and IQ-Associated DNA Methylation: A Prospective Cohort Study

2021 ◽  
Vol 18 (14) ◽  
pp. 7429
Author(s):  
Kyung-Shin Lee ◽  
Yoon-Jung Choi ◽  
Jin-Woo Cho ◽  
Sung-Ji Moon ◽  
Youn-Hee Lim ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cohort Study ◽  
Literature Review ◽  
Cognitive Ability ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Association Studies ◽  
The Body ◽  
Genome Wide Association Studies ◽  
Regulatory Pathways

Epigenetics is known to be involved in regulatory pathways through which greenness exposure influences child development and health. We aimed to investigate the associations between residential surrounding greenness and DNA methylation changes in children, and further assessed the association between DNA methylation and children’s intelligence quotient (IQ) in a prospective cohort study. We identified cytosine-guanine dinucleotide sites (CpGs) associated with cognitive abilities from epigenome- and genome-wide association studies through a systematic literature review for candidate gene analysis. We estimated the residential surrounding greenness at age 2 using a geographic information system. DNA methylation was analyzed from whole blood using the HumanMethylationEPIC array in 59 children at age 2. We analyzed the association between greenness exposure and DNA methylation at age 2 at the selected CpGs using multivariable linear regression. We further investigated the relationship between DNA methylation and children’s IQ. We identified 8743 CpGs associated with cognitive ability based on the literature review. Among these CpGs, we found that 25 CpGs were significantly associated with greenness exposure at age 2, including cg26269038 (Bonferroni-corrected p ≤ 0.05) located in the body of SLC6A3, which encodes a dopamine transporter. DNA methylation at cg26269038 at age 2 was significantly associated with children’s performance IQ at age 6. Exposure to surrounding greenness was associated with cognitive ability-related DNA methylation changes, which was also associated with children’s IQ. Further studies are warranted to clarify the epigenetic pathways linking greenness exposure and neurocognitive function.

Abstract 13798: Ablation of the Hypertension Candidate Gene ATP2B1 Results in Increased Blood Pressure and Cardiac Hypertrophic Remodeling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sally K Hammad ◽  
Min Zi ◽  
Sukhpal Prehar ◽  
Robert Little ◽  
Ludwig Neyses ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Diastolic Pressure ◽  
Association Studies ◽  
Weight Ratio ◽  
Blood Pressure Regulation ◽  
Heart Weight ◽  
Genome Wide Association Studies ◽  
Pressure Regulation ◽  
The Impact

Introduction: Hypertension is a major risk factor for cardiac hypertrophy and heart failure. Genome wide association studies have recently identified single nucleotide polymorphisms in ATP2B1 , the gene encoding the calcium extrusion pump, plasma membrane calcium ATPase (PMCA1), as having a strong association with hypertension risk. Hypothesis: PMCA1 plays an important role in regulation of blood pressure and protection against hypertension and cardiac hypertrophy. Aims: We aim to examine whether there is a functional link between PMCA1 and blood pressure regulation, and the development of hypertension. And to determine the impact this link may have on cardiac structure and function. Methods and Results: To study the role of PMCA1 we generated a global PMCA1 heterozygous knockout mouse (PMCA1 Ht ). PMCA1 Ht mice had 46% to 52% reduction in PMCA1 protein expression compared to the WT, in aorta, heart, kidney and brain. To study the mice under hypertensive stress conditions, 3 month old PMCA1 Ht and wild type (WT) mice were infused via minipump with angiotensin II (1mg/Kg/daily) or water as a control. Upon angiotensin treatment, PMCA1 Ht mice showed a significantly greater increase in systolic (62.24±3.05 mmHg) and diastolic pressure (52.68±4.67 mmHg), in comparison to the WT (33.37±2.91 mmHg and 23.94±4.56 mmHg, respectively), P<0.001, n=12. Moreover, PMCA1 Ht mice showed a significantly greater hypertrophic response as indicated by a greater heart weight to tibia length ratio, cardiomyocyte cell size (410±18.7 μm 2 ), compared to WT mice (340.4±9.8 μm 2 ), and increased expression of B-type natriuretic peptide (BNP), 2.36 ± 0.25 fold change, n =5-6, P< 0.01. Echocardiography showed no significant changes between PMCA1 Ht and WT mice, in heart rate, and in cardiac function, as indicated by fractional shortening and ejection fraction. In addition, PMCA1 Ht mice showed no sign of lung congestion as indicated by lung weight to body weight ratio. Conclusion: ATP2B1 deletion leads to increased blood pressure and cardiac hypertrophy. This provides functional evidence that PMCA1 is involved in blood pressure regulation and protects against the development of hypertension and cardiac hypertrophy.

A Variant Noncoding Region Regulates Prrx1 and Predisposes to Atrial Arrhythmias

2021 ◽  
Author(s):  
Fernanda M Bosada ◽  
Mathilde R Rivaud ◽  
Jae-Sun Uhm ◽  
Sander Verheule ◽  
Karel van Duijvenboden ◽  
...  
Keyword(s):  
Sodium Current ◽  
Association Studies ◽  
Noncoding Region ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Enhancer Activity ◽  
Atrial Cardiomyocytes ◽  
The Impact ◽  
Lineage Specific Gene

Rationale: Atrial Fibrillation (AF) is the most common cardiac arrhythmia diagnosed in clinical practice. Genome-wide association studies have identified AF-associated common variants across 100+ genomic loci, but the mechanism underlying the impact of these variant loci on AF susceptibility in vivo has remained largely undefined. One such variant region, highly associated with AF, is found at 1q24, close to PRRX1, encoding the Paired Related Homeobox 1 transcription factor. Objective: To identify the mechanistic link between the variant region at 1q24 and AF predisposition. Methods and Results: The mouse orthologue of the noncoding variant genomic region (R1A) at 1q24 was deleted using CRISPR genome editing. Among the genes sharing the topologically associated domain with the deleted R1A region (Kifap3, Prrx1, Fmo2, Prrc2c), only the broadly expressed gene Prrx1 was downregulated in mutants, and only in cardiomyocytes. Expression and epigenetic profiling revealed that a cardiomyocyte lineage-specific gene program (Mhrt, Myh6, Rbm20, Tnnt2, Ttn, Ckm) was upregulated in R1A-/- atrial cardiomyocytes, and that Mef2 binding motifs were significantly enriched at differentially accessible chromatin sites. Consistently, Prrx1 suppressed Mef2-activated enhancer activity in HL-1 cells. Mice heterozygous or homozygous for the R1A deletion were susceptible to atrial arrhythmia induction, had atrial conduction slowing and more irregular RR intervals. Isolated R1A-/- mouse left atrial cardiomyocytes showed lower action potential upstroke velocities and sodium current, as well as increased systolic and diastolic calcium concentrations compared to controls. Conclusions: The noncoding AF variant region at 1q24 modulates Prrx1 expression in cardiomyocytes. Cardiomyocyte-specific reduction of Prrx1 expression upon deletion of the noncoding region leads to a profound induction of a cardiac lineage-specific gene program and to propensity for AF. These data indicate that AF-associated variants in humans may exert AF predisposition through reduced PRRX1 expression in cardiomyocytes.

Genetic addiction risk score analysis: hypodopaminergic polymorphic risk alleles in polydrug addicted males and meso-limbic dopaminergic agonistic activation by neuroadaptagen amino-acid therapy

2011 ◽  
Vol 26 (S2) ◽  
pp. 803-803
Author(s):  
K. Blum ◽  
E. Stice ◽  
Y. Liu ◽  
J. Giordano ◽  
S. Morse ◽  
...  
Keyword(s):  
Amino Acid ◽  
Risk Score ◽  
D2 Receptor ◽  
Controlled Study ◽  
Double Blind ◽  
Heroin Addicts ◽  
Acid Therapy ◽  
Risk Alleles ◽  
Addiction Risk ◽  
The Impact

IntroductionThere is a need to classify patients at genetic risk for drug seeking behavior prior to or upon entry to chemical dependency programs.MethodsThe prevalence of seven risk alleles (DRD2 = A1; SLC6A3 (DAT) = 10R; DRD4 = 3R or 7R; 5HTTLPR = L or LA; MAO = 3R; COMT = G) and corresponding severity risk score (Low (LS) = 1–36%, moderate (MS) = 37–50%, and high (HS) = 51–100%) were calculated. Group 1 consisted of 16 Caucasian male psycho-stimulant addicts, and Group 2 consisted of 10 Chinese male heroin addicts (9 were genotyped). qEEG and fMRI visualized the impact of Neuroadaptagen Amino-Acid Therapy complex on mesolimbic system activation.Results[Findings by Group]74% of the combined groups had a moderate to high genetic addiction risk score (GARS). One acute dose of KB220-IV variant in heroin addicts having brain abnormalities was found to normalize qEEG. Additionally, a randomized double-blind placebo controlled study involving oral KB220-Z variant established qEEG normalization of reward circuitry in abstinent psycho-stimulant abusers (P < 0.03).ConclusionsWe cautiously suggest that long-term activation of dopaminergic receptors will lead to D2 receptor proliferation and enhanced “dopamine sensitivity,” thus reducing aberrant craving behavior especially in carriers of the DRD2 A1 allele. Although supported by 20 clinical trials, KB220-Z awaits PET scanning to determine its chronic effects on D2 receptor numbers.

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