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  • 1
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    Online Resource
    The genomics of heart failure: design and rationale of the HERMES consortium
    Wiley ; 2021
    In:  ESC Heart Failure Vol. 8, No. 6 ( 2021-12), p. 5531-5541
    Details
    In: ESC Heart Failure, Wiley, Vol. 8, No. 6 ( 2021-12), p. 5531-5541
    Abstract: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P   〈  5 × 10 −8 under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
    Type of Medium: Online Resource
    ISSN: 2055-5822 , 2055-5822
    URL: Issue
    URL: Article
    DOI: 10.1002/ehf2.v8.6
    DOI: 10.1002/ehf2.13517
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2814355-3
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  • 2
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    Mutations in folate transporter genes and risk for human myelomeningocele
    Wiley ; 2017
    In:  American Journal of Medical Genetics Part A Vol. 173, No. 11 ( 2017-11), p. 2973-2984
    Details
    In: American Journal of Medical Genetics Part A, Wiley, Vol. 173, No. 11 ( 2017-11), p. 2973-2984
    Abstract: The molecular mechanisms linking folate deficiency and neural tube defect (NTD) risk in offspring remain unclear. Folate transporters (SLC19A1, SLC46A1, SLC25A32, and FOLH1) and folate receptors (FOLR1, FOLR2, and FOLR3) are suggested to play essential roles in transporting folate from maternal intestinal lumen to the developing embryo. Loss of function variants in these genes may affect folate availability and contribute to NTD risk. This study examines whether variants within the folate transporter and receptor genes are associated with an increased risk for myelomeningocele (MM). Exons and their flanking intron sequences of 348 MM subjects were sequenced using the Sanger sequencing method and/or next generation sequencing to identify variants. Frequencies of alleles of single nucleotide polymorphisms (SNPs) in MM subjects were compared to those from ethnically matched reference populations to evaluate alleles’ associated risk for MM. We identified eight novel variants in SLC19A1 and twelve novel variants in FOLR1 , FOLR2 , and FOLR3 . Pathogenic variants include c.1265delG in SLC19A1 resulting in an early stop codon, four large insertion deletion variants in FOLR3 , and a stop_gain variant in FOLR3 . No new variants were identified in SLC46A1 , SLC25A32 , or FOLH1 . In SLC19A1 , c.80A 〉 G (rs1051266) was not associated with our MM cohort; we did observe a variant allele G frequency of 61.7%, higher than previously reported in other NTD populations. In conclusion, we discovered novel loss of function variants in genes involved in folate transport in MM subjects. Our results support the growing evidence of associations between genes involved in folate transport and susceptibility to NTDs.
    Type of Medium: Online Resource
    ISSN: 1552-4825 , 1552-4833
    URL: Issue
    URL: Article
    DOI: 10.1002/ajmg.a.v173.11
    DOI: 10.1002/ajmg.a.38472
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 1493479-6
    SSG: 12
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  • 3
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    Identifying blood pressure loci whose effects are modulated by multiple lifestyle exposures
    Wiley ; 2020
    In:  Genetic Epidemiology Vol. 44, No. 6 ( 2020-09), p. 629-641
    Details
    In: Genetic Epidemiology, Wiley, Vol. 44, No. 6 ( 2020-09), p. 629-641
    Abstract: Although multiple lifestyle exposures simultaneously impact blood pressure (BP) and cardiovascular health, most analysis so far has considered each single lifestyle exposure (e.g., smoking) at a time. Here, we exploit gene–multiple lifestyle exposure interactions to find novel BP loci. For each of 6,254 Framingham Heart Study participants, we computed lifestyle risk score (LRS) value by aggregating the risk of four lifestyle exposures (smoking, alcohol, education, and physical activity) on BP. Using the LRS, we performed genome‐wide gene–environment interaction analysis in systolic and diastolic BP using the joint 2 degree of freedom (DF) and 1 DF interaction tests. We identified one genome‐wide significant ( p   〈  5 × 10 −8 ) and 11 suggestive ( p   〈  1 × 10 −6 ) loci. Gene–environment analysis using single lifestyle exposures identified only one of the 12 loci. Nine of the 12 BP loci detected were novel. Loci detected by the LRS were located within or nearby genes with biologically plausible roles in the pathophysiology of hypertension, including KALRN, VIPR2, SNX1 , and DAPK2 . Our results suggest that simultaneous consideration of multiple lifestyle exposures in gene–environment interaction analysis can identify additional loci missed by single lifestyle approaches.
    Type of Medium: Online Resource
    ISSN: 0741-0395 , 1098-2272
    URL: Issue
    URL: Article
    DOI: 10.1002/gepi.v44.6
    DOI: 10.1002/gepi.22292
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 1492643-X
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  • 4
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    Comprehensive linkage and linkage heterogeneity analysis of 4344 sibling pairs affected with hypertension from the Family Blood Pressure Program
    Wiley ; 2007
    In:  Genetic Epidemiology Vol. 31, No. 3 ( 2007-04), p. 195-210
    Details
    In: Genetic Epidemiology, Wiley, Vol. 31, No. 3 ( 2007-04), p. 195-210
    Type of Medium: Online Resource
    ISSN: 0741-0395 , 1098-2272
    URL: Issue
    URL: Journal
    URL: Article
    DOI: 10.1002/gepi.v31:3
    DOI: 10.1002/(ISSN)1098-2272
    DOI: 10.1002/gepi.20202
    Language: English
    Publisher: Wiley
    Publication Date: 2007
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  • 5
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    Efficient gene–environment interaction tests for large biobank‐scale sequencing studies
    Wiley ; 2020
    In:  Genetic Epidemiology Vol. 44, No. 8 ( 2020-11), p. 908-923
    Details
    In: Genetic Epidemiology, Wiley, Vol. 44, No. 8 ( 2020-11), p. 908-923
    Abstract: Complex human diseases are affected by genetic and environmental risk factors and their interactions. Gene–environment interaction (GEI) tests for aggregate genetic variant sets have been developed in recent years. However, existing statistical methods become rate limiting for large biobank‐scale sequencing studies with correlated samples. We propose efficient Mixed‐model Association tests for GEne–Environment interactions (MAGEE), for testing GEI between an aggregate variant set and environmental exposures on quantitative and binary traits in large‐scale sequencing studies with related individuals. Joint tests for the aggregate genetic main effects and GEI effects are also developed. A null generalized linear mixed model adjusting for covariates but without any genetic effects is fit only once in a whole genome GEI analysis, thereby vastly reducing the overall computational burden. Score tests for variant sets are performed as a combination of genetic burden and variance component tests by accounting for the genetic main effects using matrix projections. The computational complexity is dramatically reduced in a whole genome GEI analysis, which makes MAGEE scalable to hundreds of thousands of individuals. We applied MAGEE to the exome sequencing data of 41,144 related individuals from the UK Biobank, and the analysis of 18,970 protein coding genes finished within 10.4 CPU hours.
    Type of Medium: Online Resource
    ISSN: 0741-0395 , 1098-2272
    URL: Issue
    URL: Article
    DOI: 10.1002/gepi.v44.8
    DOI: 10.1002/gepi.22351
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 6
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    Mining gold dust under the genome wide significance level: a two‐stage approach to analysis of GWAS
    Wiley ; 2011
    In:  Genetic Epidemiology Vol. 35, No. 2 ( 2011-02), p. 111-118
    Details
    In: Genetic Epidemiology, Wiley, Vol. 35, No. 2 ( 2011-02), p. 111-118
    Abstract: We propose a two‐stage approach to analyze genome‐wide association data in order to identify a set of promising single‐nucleotide polymorphisms (SNPs). In stage one, we select a list of top signals from single SNP analyses by controlling false discovery rate. In stage two, we use the least absolute shrinkage and selection operator (LASSO) regression to reduce false positives. The proposed approach was evaluated using simulated quantitative traits based on genome‐wide SNP data on 8,861 Caucasian individuals from the Atherosclerosis Risk in Communities (ARIC) Study. Our first stage, targeted at controlling false negatives, yields better power than using Bonferroni‐corrected significance level. The LASSO regression reduces the number of significant SNPs in stage two: it reduces false‐positive SNPs and it reduces true‐positive SNPs also at simulated causal loci due to linkage disequilibrium. Interestingly, the LASSO regression preserves the power from stage one, i.e., the number of causal loci detected from the LASSO regression in stage two is almost the same as in stage one, while reducing false positives further. Real data on systolic blood pressure in the ARIC study was analyzed using our two‐stage approach which identified two significant SNPs, one of which was reported to be genome‐significant in a meta‐analysis containing a much larger sample size. On the other hand, a single SNP association scan did not yield any significant results. Genet. Epidemiol . 32:111‐118, 2011.© 2010 Wiley‐Liss, Inc.
    Type of Medium: Online Resource
    ISSN: 0741-0395 , 1098-2272
    URL: Issue
    URL: Article
    DOI: 10.1002/gepi.v35.2
    DOI: 10.1002/gepi.20556
    Language: English
    Publisher: Wiley
    Publication Date: 2011
    detail.hit.zdb_id: 1492643-X
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  • 7
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    A polygenic risk score of atrial fibrillation improves prediction of lifetime risk for heart failure
    Wiley ; 2024
    In:  ESC Heart Failure
    Details
    In: ESC Heart Failure, Wiley
    Abstract: Heart failure (HF) has shared genetic architecture with its risk factors: atrial fibrillation (AF), body mass index (BMI), coronary heart disease (CHD), systolic blood pressure (SBP), and type 2 diabetes (T2D). We aim to assess the association and risk prediction performance of risk‐factor polygenic risk scores (PRSs) for incident HF and its subtypes in bi‐racial populations. Methods and results Five PRSs were constructed for AF, BMI, CHD, SBP, and T2D in White participants of the Atherosclerosis Risk in Communities (ARIC) study. The associations between PRSs and incident HF and its subtypes were assessed using Cox models, and the risk prediction performance of PRSs was assessed using C statistics. Replication was performed in the ARIC study Black and Cardiovascular Health Study (CHS) White participants. In 8624 ARIC study Whites, 1922 (31% cumulative incidence) HF cases developed over 30 years of follow‐up. PRSs of AF, BMI, and CHD were associated with incident HF ( P   〈  0.001), where PRS AF showed the strongest association [hazard ratio (HR): 1.47, 95% confidence interval (CI): 1.41–1.53]. Only the addition of PRS AF to the ARIC study HF risk equation improved C statistics for 10 year risk prediction from 0.812 to 0.829 (∆ C : 0.017, 95% CI: 0.009–0.026). The PRS AF was associated with both incident HF with reduced ejection fraction (HR: 1.43, 95% CI: 1.27–1.60) and incident HF with preserved ejection fraction (HR: 1.46, 95% CI: 1.33–1.62). The associations between PRS AF and incident HF and its subtypes, as well as the improved risk prediction, were replicated in the ARIC study Blacks and the CHS Whites ( P   〈  0.050). Protein analyses revealed that N‐terminal pro‐brain natriuretic peptide and other 98 proteins were associated with PRS AF . Conclusions The PRS AF was associated with incident HF and its subtypes and had significant incremental value over an established HF risk prediction equation.
    Type of Medium: Online Resource
    ISSN: 2055-5822 , 2055-5822
    URL: Article
    DOI: 10.1002/ehf2.14665
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 2814355-3
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  • 8
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    An Empirical Comparison of Joint and Stratified Frameworks for Studying G × E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene‐Lifestyle Interactions Working Group
    Wiley ; 2016
    In:  Genetic Epidemiology Vol. 40, No. 5 ( 2016-07), p. 404-415
    Details
    In: Genetic Epidemiology, Wiley, Vol. 40, No. 5 ( 2016-07), p. 404-415
    Abstract: Studying gene‐environment (G × E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G × E interactions uses a single regression model that includes both the genetic main and G × E interaction effects (the “joint” framework). The alternative “stratified” framework combines results from genetic main‐effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome‐wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family‐based and population‐based samples. In cohort‐specific analyses, the two frameworks provided similar inference for population‐based cohorts. The agreement was reduced for family‐based cohorts. In meta‐analyses, agreement between the two frameworks was less than that observed in cohort‐specific analyses, despite the increased sample size. In meta‐analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family‐based cohorts in meta‐analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population‐based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low‐frequency variants and/or family‐based cohorts.
    Type of Medium: Online Resource
    ISSN: 0741-0395 , 1098-2272
    URL: Issue
    URL: Article
    DOI: 10.1002/gepi.2016.40.issue-5
    DOI: 10.1002/gepi.21978
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 1492643-X
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  • 9
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    Characteristics of a spina bifida population including North American Caucasian and Hispanic individuals
    Wiley ; 2008
    In:  Birth Defects Research Part A: Clinical and Molecular Teratology Vol. 82, No. 10 ( 2008-10), p. 692-700
    Details
    In: Birth Defects Research Part A: Clinical and Molecular Teratology, Wiley, Vol. 82, No. 10 ( 2008-10), p. 692-700
    Abstract: Meningomyelocele (MM) is a common human birth defect. MM is a disorder of neural development caused by contributions from genes and environmental factors that result in the NTD and lead to a spectrum of physical and neurocognitive phenotypes. METHODS: A multidisciplinary approach has been taken to develop a comprehensive understanding of MM through collaborative efforts from investigators specializing in genetics, development, brain imaging, and neurocognitive outcome. Patients have been recruited from five different sites: Houston and the Texas‐Mexico border area; Toronto, Canada; Los Angeles, California; and Lexington, Kentucky. Genetic risk factors for MM have been assessed by genotyping and association testing using the transmission disequilibrium test. RESULTS: A total of 509 affected child/parent trios and 309 affected child/parent duos have been enrolled to date for genetic association studies. Subsets of the patients have also been enrolled for studies assessing development, brain imaging, and neurocognitive outcomes. The study recruited two major ethnic groups, with 45.9% Hispanics of Mexican descent and 36.2% North American Caucasians of European descent. The remaining patients are African‐American, South and Central American, Native American, and Asian. Studies of this group of patients have already discovered distinct corpus callosum morphology and neurocognitive deficits that associate with MM. We have identified maternal MTHFR 667T allele as a risk factor for MM. In addition, we also found that several genes for glucose transport and metabolism are potential risk factors for MM. CONCLUSIONS: The enrolled patient population provides a valuable resource for elucidating the disease characteristics and mechanisms for MM development. Birth Defects Research (Part A) 82:692–700, 2008. © 2008 Wiley‐Liss, Inc.
    Type of Medium: Online Resource
    ISSN: 1542-0752 , 1542-0760
    URL: Issue
    URL: Article
    DOI: 10.1002/bdra.v82:10
    DOI: 10.1002/bdra.20499
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 2108606-0
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  • 10
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    Association of folate receptor ( folr1 , folr2 , folr3 ) and reduced folate carrier ( slc19a1 ) genes with meningomyelocele
    Wiley ; 2010
    In:  Birth Defects Research Part A: Clinical and Molecular Teratology Vol. 88, No. 8 ( 2010-08), p. 689-694
    Details
    In: Birth Defects Research Part A: Clinical and Molecular Teratology, Wiley, Vol. 88, No. 8 ( 2010-08), p. 689-694
    Abstract: Meningomyelocele (MM) results from lack of closure of the neural tube during embryologic development. Periconceptional folic acid supplementation is a modifier of MM risk in humans, leading toan interest in the folate transport genes as potential candidates for association to MM. METHODS This study used the SNPlex Genotyping (ABI, Foster City, CA) platform to genotype 20 single polymorphic variants across the folate receptor genes ( FOLR1 , FOLR2 , FOLR3 ) and the folate carrier gene ( SLC19A1 ) to assess their association to MM. The study population included 329 trio and 281 duo families. Only cases with MM were included. Genetic association was assessed using the transmission disequilibrium test in PLINK. RESULTS A variant in the FOLR2 gene (rs13908), three linked variants in the FOLR3 gene (rs7925545, rs7926875, rs7926987), and two variants in the SLC19A1 gene (rs1888530 and rs3788200) were statistically significant for association to MM in our population. CONCLUSION This study involved the analyses of selected single nucleotide polymorphisms across the folate receptor genes and the folate carrier gene in a large population sample. It provided evidence that the rare alleles of specific single nucleotide polymorphisms within these genes appear to be statistically significant for association to MM in the patient population that was tested. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.
    Type of Medium: Online Resource
    ISSN: 1542-0752 , 1542-0760
    URL: Issue
    URL: Article
    DOI: 10.1002/bdra.v88:8
    DOI: 10.1002/bdra.20706
    Language: English
    Publisher: Wiley
    Publication Date: 2010
    detail.hit.zdb_id: 2108606-0
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