scholarly journals A genome-wide association study of childhood adiposity and blood lipids

2021 ◽  
Vol 6 ◽  
pp. 303
Author(s):  
Katie O'Nunain ◽  
Eleanor Sanderson ◽  
Michael Holmes ◽  
George Davey Smith ◽  
Tom Richardson
Keyword(s):  
Blood Pressure ◽  
Genetic Correlations ◽  
Later Life ◽  
Functional Enrichment ◽  
Genome Wide Association ◽  
Health Concern ◽  
Genome Wide Association Studies ◽  
Childhood Adiposity ◽  
Genome Wide ◽  
A Genome

Background: The rising prevalence of childhood obesity and dyslipidaemia is a major public health concern due to its association with morbidity and mortality in later life. Methods: In this study, we have conducted genome-wide association studies (GWAS) for eight measures of adiposity and lipids in a cohort of young individuals (mean age 9.9) from the Avon Longitudinal Study of Parents and Children (ALSPAC). These measures were body mass index (BMI), systolic and diastolic blood pressure, high- density and low-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I and apolipoprotein B. We next undertook functional enrichment, pathway analyses and linkage disequilibrium (LD) score regression to evaluate genetic correlations with later-life cardiometabolic diseases. Results: Using GWAS we identified 14 unique loci associated with at least one risk factor in this cohort of age 10 individuals (P<5x10-8), with lipoprotein lipid-associated loci being enriched for liver tissue-derived gene expression and lipid synthesis pathways. LD score regression provided evidence of various genetic correlations, such as childhood systolic blood pressure being genetically correlated with later-life coronary artery disease (rG=0.26, 95% CI=0.07 to 0.46, P=0.009) and hypertension (rG=0.37, 95% CI=0.19 to 0.55, P=6.57x10-5), as well as childhood BMI with type 2 diabetes (rG=0.35, 95% CI=0.18 to 0.51, P=3.28x10-5). Conclusions: Our findings suggest that there are genetic variants inherited at birth which begin to exert their effects on cardiometabolic risk factors as early as age 10 in the life course. However, further research is required to assess whether the genetic correlations we have identified are due to direct or indirect effects of childhood adiposity and lipid traits.

Genome-Wide Association Studies for Immunoglobulins in Colostrum and Serum in Chinese Holstein

2020 ◽  
Author(s):  
Shan Lin ◽  
Cuncun Ke ◽  
Lin Liu ◽  
Yahui Gao ◽  
Lingna Xu ◽  
...  
Keyword(s):  
Immune Response ◽  
Dairy Cattle ◽  
Candidate Genes ◽  
Functional Enrichment ◽  
Genome Wide Association ◽  
Holstein Cows ◽  
Genome Wide Association Studies ◽  
Chinese Holstein ◽  
Genome Wide ◽  
A Genome

Abstract BackgroundImmunoglobulins (Igs) are important components of the innate immune system, and fight pathogens as a part of the first defense line. Newborn dairy calves get maternal antibodies from colostrum. Therefore, contents of immunoglobulins in colostrum and serum of cows are essential traits when estimating potential natural disease resistance of calves. In this study, a genome-wide association study (GWAS) was performed to identify candidate genes that are responsible for the observed genetic variation of immunoglobulins contents in colostrum and blood in Holstein cows.ResultsColostrum, blood and hair follicle samples were collected from the 620 Chinese Holstein cows within 24 hours after calving. The concentration of IgG, IgG1, IgG2, IgA and IgM in both colostrum and serum were detected via ELISA methods, respectively. Using GCTA software, GWASs were performed with 88,934 SNPs genotyped by using Illumina 50K (54,609 SNPs) and GeneSeek 150K (140,668 SNPs) chips in which 50K chip were imputed to 150K SNPs with BEAGLE 3.0.4 software. As a result, 20 and 5 SNPs were detected genome-wide significantly associated with contents of the IgG and IgM in colostrum and serum (P<3.16E–6). In addition, 57, 11 and 10 SNPs were suggestive significantly associated with IgG, IgA and IgM traits (P<6.32E–5). Next, a total of 1,083 functional genes were identified that included or adjacent to these significant SNPs with a distance less than 1 Mb. Functional enrichment analysis showed that these genes were involved in immune related pathways, such as immune response, Fc gamma R-mediated phagocytosis, negative regulation of immunoglobulin secretion, humoral immune response, Fc-epsilon receptor and NF-kappaB signaling pathways. By integrating analysis of the functional enrichment and the known QTL data, we identified 21 candidate genes associated with contents of immunoglobulins in colostrum and serum, including ABR, TIMM22, CRK, MYO1C, RILP, SERPINF2, AKT1, BCL11B, HHIPL1, DYNC1H1, HSP90AA1, TRAF3, KLC1, IL6, PYCARD, ITGAM, TGFB1I1, GUSB, CRCP, RABGEF1 and SBDS.ConclusionsIn this study, we identified 21 candidate genes associated with immunoglobulins level in colostrum and serum in dairy cattle. This founding demonstrated the possibility of increasing immunity through selective breeding and provided an important information for molecular breeding of dairy cattle.

scholarly journals Rapid response to the Alpha-1 Adrenergic Agent Phenylephrine in the Perioperative Period is Impacted by Genomics and Ancestry

2019 ◽  
Author(s):  
Stephane Wenric ◽  
Janina M. Jeff ◽  
Thomas Joseph ◽  
Muh-Ching Yee ◽  
Gillian M. Belbin ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Rapid Response ◽  
Genome Wide Association ◽  
Study Cohort ◽  
Genome Wide Association Studies ◽  
Entire Study ◽  
Entire Cohort ◽  
Genome Wide ◽  
A Genome ◽  
Clinical Covariates

AbstractBackgroundThe emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes that occur during in-patient clinical care. We hypothesized that there is a genetic underpinning to the magnitude of the response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery.MethodsWe quantified the response to phenylephrine by determining the delta between the minimum blood pressure (BP) within five minutes before and the maximum BP within five minutes after bolus administration. We then performed a genome-wide association study (GWAS) adjusted for genetic ancestry, demographics, and relevant clinical covariates to investigate genetic factors underlying individual differences systolic BP response to phenylephrine (ΔSBP), as well as mean arterial pressure (ΔMAP) and diastolic BP (ΔDBP), for both the entire study cohort as well as for each of 3 ancestry sub-cohorts; European American(EA), African American(AA), and Hispanic American(HA).Results4,317 patients met inclusion criteria, of which 3,699 were genotyped. Average ΔBP values over the entire cohort were ΔSBP=17(+-25) mmHg, ΔMAP=14(+-18) mmHg, ΔDBP=11(+-14) mmHg. The largest difference between populations was observed for ΔSBP (ΔSBPEA=20(+-24) mmHg; ΔSBPHA=16(+-25) mmHg; ΔSBPAA=15(+-25) mmHg). The differences remained after adjusting for clinical covariates and ancestry (EA vs. HA: ΔSBP, p<0.032;ΔMAP, p<0.021;ΔDBP,p<0.008);(EA vs. AA:ΔSBP,p<5.13×10-5;ΔMAP,p<2.1×10-4;ΔDBP,p<3.3×10-4). GWAS revealed significant associations between loci and BP response in 5 different genome regions (p<5×10-8) in the entire cohort, and suggestive associations in 2 different regions in EAs (p<6×10-8,p<7×10-8). We observed non-random enrichment in association with SBP drug response in 165 loci previously reported to be associated with systolic blood pressure. Finally, we discovered rare variants, rs188427942 and rs147664194 present at ∼1% in EAs and rs146535276 present at ∼1% in AAs respectively, where patients carrying one copy of these variants show no response to phenylephrine.ConclusionsIt is possible to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from routinely collected perioperative data. There are population differences in rapid response to phenylephrine, large effect alleles and novel genes affecting pharmaceutical response, and phenylephrine non-responders, with implications for personalized treatment during surgery.

scholarly journals A Genome-Wide Association Study for Hypertensive Kidney Disease in Korean Men

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 751
Author(s):  
Hye-Rim Kim ◽  
Hyun-Seok Jin ◽  
Yong-Bin Eom
Keyword(s):  
Blood Pressure ◽  
Kidney Disease ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Integrated Analysis ◽  
Eqtl Analysis ◽  
Strong Linkage Disequilibrium ◽  
Genome Wide ◽  
A Genome

Hypertension is one of the major risk factors for chronic kidney disease (CKD), and the coexistence of hypertension and CKD increases morbidity and mortality. Although many genetic factors have been identified separately for hypertension and kidney disease, studies specifically focused on hypertensive kidney disease (HKD) have been rare. Therefore, this study aimed to identify loci or genes associated with HKD. A genome-wide association study (GWAS) was conducted using two Korean cohorts, the Health Examinee (HEXA) and Korean Association REsource (KARE). Consequently, 19 single nucleotide polymorphisms (SNPs) were found to be significantly associated with HKD in the discovery and replication phases (p < 5 × 10−8, p < 0.05, respectively). We further analyzed HKD-related traits such as the estimated glomerular filtration rate (eGFR), creatinine, blood urea nitrogen (BUN), systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the 14q21.2 locus, which showed a strong linkage disequilibrium (LD). Expression quantitative trait loci (eQTL) analysis was also performed to determine whether HKD-related SNPs affect gene expression changes in glomerular and arterial tissues. The results suggested that the FANCM gene may affect the development of HKD through an integrated analysis of eQTL and GWAS and was the most significantly associated candidate gene. Taken together, this study indicated that the FANCM gene is involved in the pathogenesis of HKD. Additionally, our results will be useful in prioritizing other genes for further experiments.

scholarly journals Genetic components of human pain sensitivity: a protocol for a genome-wide association study of experimental pain in healthy volunteers

BMJ Open ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. e025530 ◽  
Author(s):  
Annina B Schmid ◽  
Kaustubh Adhikari ◽  
Luis Miguel Ramirez-Aristeguieta ◽  
Juan-Camilo Chacón-Duque ◽  
Giovanni Poletti ◽  
...  
Keyword(s):  
Latin American ◽  
Pain Sensitivity ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Healthy Individuals ◽  
Genetic Components ◽  
Genome Wide ◽  
A Genome ◽  
The University ◽  
Genetic Contributions

IntroductionPain constitutes a major component of the global burden of diseases. Recent studies suggest a strong genetic contribution to pain susceptibility and severity. Whereas most of the available evidence relies on candidate gene association or linkage studies, research on the genetic basis of pain sensitivity using genome-wide association studies (GWAS) is still in its infancy. This protocol describes a proposed GWAS on genetic contributions to baseline pain sensitivity and nociceptive sensitisation in a sample of unrelated healthy individuals of mixed Latin American ancestry.Methods and analysisA GWAS on genetic contributions to pain sensitivity in the naïve state and following nociceptive sensitisation will be conducted in unrelated healthy individuals of mixed ancestry. Mechanical and thermal pain sensitivity will be evaluated with a battery of quantitative sensory tests evaluating pain thresholds. In addition, variation in mechanical and thermal sensitisation following topical application of mustard oil to the skin will be evaluated.Ethics and disseminationThis study received ethical approval from the University College London research ethics committee (3352/001) and from the bioethics committee of the Odontology Faculty at the University of Antioquia (CONCEPTO 01–2013). Findings will be disseminated to commissioners, clinicians and service users via papers and presentations at international conferences.

Abstract P359: A Sickle Cell Variant Associates With Urine Albumin Excretion in Genome Wide Association Study of Hispanics: The HCHS/SOL Study

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Nora Franceschini ◽  
Adrienne Stilp ◽  
Christina L Wassel ◽  
Holly J Mattix-Kramer ◽  
Michael F Flessner ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Sickle Cell ◽  
Missense Variant ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Minority Population ◽  
Genome Wide Association Studies ◽  
Urine Albumin ◽  
Genome Wide ◽  
A Genome

Introduction: Genome wide association studies have identified genetic variants in the Cubillin gene ( CUBN ) that explain inter-individual variation in urine albumin-to-creatinine excretion (UACR) in populations. These studies have not included Hispanics/Latinos, the fast growing minority population in the U.S., who has also high prevalence of chronic kidney disease and its risk factors. Hypothesis: By leveraging on population admixture of Hispanics and using a genome wide association approach, we hypothesized that novel loci associated with UACR would be identified. Methods: We used data from 12,212 self-identified Hispanic individuals recruited in a community-based study, aged 18-74 years at screening (2008-2011), and randomly selected from households in four U.S. field centers (Chicago, IL; Miami, FL; Bronx, NY; San Diego, CA). Urine albumin (mg/dl) and creatinine (g/dl) were measured at the baseline exam. UACR was log-transformed for analysis. Individuals were excluded if reporting to have end-stage renal disease. Genotyping was performed using a custom Illumina Omni2.5M array. Imputation of variants was performed using 1000 Genome Project data from cosmopolitan HapMap samples. After quality control of imputed data, we performed mixed linear regression analyses that accounted for the sampling strategy and family relatedness, for variants with minor allele frequency (MAF) > 0.01 and imputation quality > 0.3. We used additive genetic models and adjusted for age, sex, and principal components which were estimated from the data. In a secondary analysis, we also examine the association of significant variants with kidney function using estimated glomerular filtration rate (eGFR) equations. Results: Among 12,212 participants, 41% were men, and mean age was 46 (SD =13). There was little evidence for genome wide inflation (lambda =1.024). We identified significant associations of single nucleotide polymorphisms (SNPs) with UACR at two loci: CUBN and HBB . The CUBN SNP (chr10:16966414, p=2.1x10-8) is an indel variant with MAF of 0.14, which was not in linkage disequilibrium with previously reported SNP rs1801239 (rsq=0.38, p=1.3x10-4) identified in individuals of European ancestry. The HBB SNP is a missense variant which results in an E [Glu] ⇒ A [Ala] substitution in the beta-globin chain of hemoglobin and a cause of the Mendelian disorder sickle cell anemia (rs334, T allele frequency =0.01, beta=0.44, SE=0.06, p=7.6x10-12). rs344 was not associated with eGFR in our data (p>0.05). Conclusion: This study identified a novel association of a sickle cell missense variant with UACR in Hispanics, and provided evidence for allelic heterogeneity at the CUBN locus. Our findings suggest a role for Mendelian gene variants in increased albuminuria in Hispanic populations with admixture.

scholarly journals Prioritization of genes associated with the pathogenesis of leukosis in cattle

2019 ◽  
Vol 22 (8) ◽  
pp. 1063-1069 ◽  
Author(s):  
N. S. Yudin ◽  
N. L. Podkolodnyy ◽  
T. A. Agarkova ◽  
E. V. Ignatieva
Keyword(s):  
Protein Interactions ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Mammalian Species ◽  
Genome Wide Association ◽  
Farm Animals ◽  
Genome Wide Association Studies ◽  
Protein Protein Interactions ◽  
Genome Wide ◽  
A Genome

Selection by means of genetic markers is a promising approach to the eradication of infectious diseases in farm animals, especially in the absence of effective methods of treatment and prevention. Bovine leukemia virus (BLV) is spread throughout the world and represents one of the biggest problems for the livestock production and food security in Russia. However, recent genome-wide association studies have shown that sensitivity/resistance to BLV is polygenic. The aim of this study was to create a catalog of cattle genes and genes of other mammalian species involved in the pathogenesis of BLV-induced infection and to perform gene prioritization using bioinformatics methods. Based on manually collected information from a range of open sources, a total of 446 genes were included in the catalog of cattle genes and genes of other mammals involved in the pathogenesis of BLV-induced infection. The following criteria were used to prioritize 446 genes from the catalog: (1) the gene is associated with leukemia according to a genome-wide association study; (2) the gene is associated with leukemia according to a case-control study; (3) the role of the gene in leukemia development has been studied using knockout mice; (4) protein-protein interactions exist between the gene-encoded protein and either viral particles or individual viral proteins; (5) the gene is annotated with Gene Ontology terms that are overrepresented for a given list of genes; (6) the gene participates in biological pathways from the KEGG or REACTOME databases, which are over-represented for a given list of genes; (7) the protein encoded by the gene has a high number of protein-protein interactions with proteins encoded by other genes from the catalog. Based on each criterion, a rank was assigned to each gene. Then the ranks were summarized and an overall rank was determined. Prioritization of 446 candidate genes allowed us to identify 5 genes of interest (TNF,LTB,BOLA-DQA1,BOLA-DRB3,ATF2), which can affect the sensitivity/resistance of cattle to leukemia.

scholarly journals Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry

2018 ◽  
Vol 28 (1) ◽  
pp. 166-174 ◽  
Author(s):  
Sara L Pulit ◽  
Charli Stoneman ◽  
Andrew P Morris ◽  
Andrew R Wood ◽  
Craig A Glastonbury ◽  
...  
Keyword(s):  
Body Fat ◽  
Association Studies ◽  
Meta Analysis ◽  
Fat Distribution ◽  
Body Fat Distribution ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

scholarly journals Retrospective Association Analysis of Longitudinal Binary Traits Identifies Important Loci and Pathways in Cocaine Use

Genetics ◽  
2019 ◽  
Vol 213 (4) ◽  
pp. 1225-1236 ◽  
Author(s):  
Weimiao Wu ◽  
Zhong Wang ◽  
Ke Xu ◽  
Xinyu Zhang ◽  
Amei Amei ◽  
...  
Keyword(s):  
Association Analysis ◽  
Binary Data ◽  
Association Studies ◽  
Association Test ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Cocaine Use ◽  
Genome Wide ◽  
A Genome ◽  
Time Varying Covariates

Longitudinal phenotypes have been increasingly available in genome-wide association studies (GWAS) and electronic health record-based studies for identification of genetic variants that influence complex traits over time. For longitudinal binary data, there remain significant challenges in gene mapping, including misspecification of the model for phenotype distribution due to ascertainment. Here, we propose L-BRAT (Longitudinal Binary-trait Retrospective Association Test), a retrospective, generalized estimating equation-based method for genetic association analysis of longitudinal binary outcomes. We also develop RGMMAT, a retrospective, generalized linear mixed model-based association test. Both tests are retrospective score approaches in which genotypes are treated as random conditional on phenotype and covariates. They allow both static and time-varying covariates to be included in the analysis. Through simulations, we illustrated that retrospective association tests are robust to ascertainment and other types of phenotype model misspecification, and gain power over previous association methods. We applied L-BRAT and RGMMAT to a genome-wide association analysis of repeated measures of cocaine use in a longitudinal cohort. Pathway analysis implicated association with opioid signaling and axonal guidance signaling pathways. Lastly, we replicated important pathways in an independent cocaine dependence case-control GWAS. Our results illustrate that L-BRAT is able to detect important loci and pathways in a genome scan and to provide insights into genetic architecture of cocaine use.

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