Publications by authors named "Mariza de Andrade"

253 Publications

Associations of Genetically Predicted Lipoprotein (a) Levels with Cardiovascular Traits in Individuals of European and African Ancestry.

Circ Genom Precis Med 2021 Jul 20. Epub 2021 Jul 20.

Department of Cardiovascular Medicine & Gonda Vascular Center, Mayo Clinic, Rochester, MN.

- Lipoprotein (a) [Lp(a)] levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with 1) atherosclerotic cardiovascular disease (ASCVD) subtypes: coronary heart disease (CHD), cerebrovascular disease (CVD), peripheral artery disease (PAD), and abdominal aortic aneurysm (AAA); and 2) non-ASCVD phenotypes, stratified by ancestry. - We performed 1) Mendelian randomization (MR) analyses for previously reported cardiovascular associations, and 2) phenome-wide MR (MR-PheWAS) analyses for novel associations. Analyses were stratified by ancestry in electronic MEdical Records and GEnomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804,507 EA and 103,580 AA participants. - In MR analyses using the combined cohort, a 1-standard deviation (SD) genetic increase in Lp(a) level was associated with ASCVD subtypes in EA - odds ratio and 95% confidence interval for CHD 1.28(1.16-1.41); CVD 1.14(1.07-1.21); PAD 1.22(1.11-1.34); AAA 1.28(1.17-1.40); in AA the effect estimate was lower than in EA and nonsignificant for CHD 1.11(0.99-1.24) and CVD 1.06(0.99-1.14) but similar for PAD 1.16(1.01-1.33) and AAA 1.34(1.11-1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34(1.10-1.62), mitral valve disorders 1.18(1.09-1.27), congestive heart failure 1.12(1.05-1.19), and chronic kidney disease 1.07(1.01-1.14). In AA no significant associations were noted for aortic valve disorders 1.08(0.94-1.25), mitral valve disorders 1.02(0.89-1.16), congestive heart failure 1.02(0.95-1.10), or chronic kidney disease 1.05(0.99-1.12). MR-PheWAS identified novel associations in EA with arterial thromboembolic disease, non-aortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension. - Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with ASCVD in four major arterial beds in EA but only with PAD and AAA in AA. Additional, novel cardiovascular associations were detected in EA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003354DOI Listing
July 2021

Outcomes of COVID-19 in Patients With Cancer: A Closer Look at Pre-Emptive Routine Screening Strategies.

JCO Oncol Pract 2021 Jun 14:OP2100177. Epub 2021 Jun 14.

Division of Medical Oncology, Mayo Clinic, Rochester, MN.

Purpose: The benefit of routine pre-emptive screening for severe acute respiratory syndrome coronavirus 2 infections in patients with cancer before cancer-directed therapies is unclear. Herein, we characterize the outcomes of a cohort of patients with cancer who were diagnosed with COVID-19 by routine screening (RS) in comparison with those diagnosed on the basis of clinical suspicion or exposure history (nonroutine screening [NRS]).

Methods: A multisite prospective observational study was conducted at three major and five satellite campuses of the Mayo Clinic Cancer Center between March 18 and July 31, 2020. The primary outcome was COVID-19-related hospital admission. Secondary outcomes included intensive care unit admissions and all-cause mortality.

Results: Five thousand four hundred fifty-two patients underwent RS in the outpatient setting only, and 44 (0.81%) were diagnosed with COVID-19. RS detected 19 additional patients from the scheduled inpatient admissions for surgical or interventional procedures or inpatient chemotherapy. One hundred sixty-one patients were diagnosed with COVID-19 on the basis of NRS. COVID-19-related hospitalization rate (17.5% 26.7%; = .14), intensive care unit admission (1.6% 5.6%; = .19), and mortality (4.8% 3.7%; = .72) were not significantly different between the RS and NRS groups. In the multivariable analysis, age ≥ 60 years (odds ratio, 4.4; = .023) and an absolute lymphocyte count ≤ 1.4 × 10/L (odds ratio, 9.2; = .002) were independent predictors of COVID-19-related hospital admission.

Conclusion: The COVID-19 positivity rate was low on the basis of RS. Comparing the hospital admission and mortality outcomes with the NRS cohort, there were no significant differences. The value of routine pre-emptive screening of asymptomatic patients with cancer for COVID-19 remains low.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/OP.21.00177DOI Listing
June 2021

An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs.

J Hepatol 2021 May 23. Epub 2021 May 23.

Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.

Backgrounds & Aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening.

Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts.

Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57 genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (T)1 and T17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders.

Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders.

Lay Summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2021.04.055DOI Listing
May 2021

A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.

Am J Epidemiol 2021 Apr 16. Epub 2021 Apr 16.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/aje/kwab115DOI Listing
April 2021

Genetic Variation and Recurrent Haplotypes on Chromosome 6q23-25 Risk Locus in Familial Lung Cancer.

Cancer Res 2021 Jun 14;81(12):3162-3173. Epub 2021 Apr 14.

Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland.

Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: at 6q25.3, at 6q26, and (6q24.1) and (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work. SIGNIFICANCE: This study identifies four genes associated with lung cancer risk, which could help guide future lung cancer prevention and treatment approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-3196DOI Listing
June 2021

Robust, flexible, and scalable tests for Hardy-Weinberg equilibrium across diverse ancestries.

Genetics 2021 May;218(1)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Traditional Hardy-Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/genetics/iyab044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128395PMC
May 2021

Rare deleterious germline variants and risk of lung cancer.

NPJ Precis Oncol 2021 Feb 16;5(1):12. Epub 2021 Feb 16.

Mayo Clinic College of Medicine, Scottsdale, AZ, USA.

Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04-75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71-8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3' UTR (OR 4.33, 95%CI 2.03-9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73-11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33-5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41698-021-00146-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887261PMC
February 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection.

JAMA Cardiol 2020 Aug;5(8):929-938

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.

Importance: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death.

Objective: To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility.

Design, Setting, And Participants: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019.

Main Outcomes And Measures: Genetic loci and positional candidate genes associated with SCAD.

Results: This study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1).

Conclusions And Relevance: This study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2020.0872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203673PMC
August 2020

Bivariate traits association analysis using generalized estimating equations in family data.

Stat Appl Genet Mol Biol 2020 05 5;19(2). Epub 2020 May 5.

Departamento de Matemáticas, Universidad Nacional de Colombia, Manizales, Caldas, 170001, Colombia.

Genome wide association study (GWAS) is becoming fundamental in the arduous task of deciphering the etiology of complex diseases. The majority of the statistical models used to address the genes-disease association consider a single response variable. However, it is common for certain diseases to have correlated phenotypes such as in cardiovascular diseases. Usually, GWAS typically sample unrelated individuals from a population and the shared familial risk factors are not investigated. In this paper, we propose to apply a bivariate model using family data that associates two phenotypes with a genetic region. Using generalized estimation equations (GEE), we model two phenotypes, either discrete, continuous or a mixture of them, as a function of genetic variables and other important covariates. We incorporate the kinship relationships into the working matrix extended to a bivariate analysis. The estimation method and the joint gene-set effect in both phenotypes are developed in this work. We also evaluate the proposed methodology with a simulation study and an application to real data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/sagmb-2019-0030DOI Listing
May 2020

A Digital Health Weight Loss Program in 250,000 Individuals.

J Obes 2020 26;2020:9497164. Epub 2020 Mar 26.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

Importance: Obesity is a worsening epidemic worldwide. Effective and accessible weight loss programs to combat obesity on a large scale are warranted, but a need for frequent face-to-face care might impose a limitation.

Objective: To evaluate whether individuals following a weight loss program based on a mobile application, wireless scale, and nutritional program but no face-to-face care can achieve clinically significant weight loss in a large cohort.

Design: Retrospective observational analysis. . China from October 2016 to December 2017. . Mobile application users with a minimum of 2 weights (baseline and ≥35 days). . A commercial (Weijian Technologies) weight loss program consisting of a dietary replacement, self-monitoring using a wireless home scale, and frequent guidance via mobile application. . Mean weight change around 42, 60, 90, and 120 days after program initiation with subgroup analysis by gender, age, and frequency of use.

Results: 251,718 individuals, with a mean age of 37.3 years (SD: 9.86) (79% female), were included with a mean weight loss of 4.3 kg (CI: ±0.02) and a mean follow-up of 120 days (SD: 76.8 days). Mean weight loss at 42, 60, 90, and 120 d was 4.1 kg (CI: ±0.02), 4.9 kg (CI: ±0.02), 5.6 kg (CI: ±0.03), and 5.4 kg (CI: ±0.04), respectively. At 120 d, 62.7% of participants had lost at least 5% of their initial weight. Both genders and all usage frequency tertiles showed statistically significant weight loss from baseline at each interval ( < 0.001), and this loss was greater in men than in women (120 d: 6.5 vs. 5.2 kg; < 0.001). The frequency of recording (categorized as high-, medium-, or low-frequency users) was associated with greater weight loss when comparing high, medium, and low tertile use groups at all time intervals investigated (e.g., 120 d: -8.6, -5.6, and -2.2 kg, respectively; < 0.001).

Conclusions: People following a commercially available hybrid weight loss program using a mobile application, wireless scale, and nutritional program without face-to-face interaction on average achieved clinically significant short- and midterm weight loss. These results support the implementation of comparable technologies for weight control in a large population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/9497164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136816PMC
May 2021

A digital health weight-loss intervention in severe obesity.

Digit Health 2020 Jan-Dec;6:2055207620910279. Epub 2020 Mar 4.

Department of Cardiovascular Medicine, Mayo Clinic, USA.

Introduction: Severe obesity is a growing epidemic that causes significant morbidity and mortality, and is particularly difficult to reverse. Efficacious and cost-effective interventions are needed to combat this epidemic. This study hypothesized that obese people (body mass index (BMI) ≥35 kg/m) using a remote weight-loss program combining a mobile application, wireless scales, and low-calorie meal replacement would experience clinically significant weight loss.

Methods: This study was a retrospective observational analysis of 8275 individuals with a baseline BMI ≥35 kg/m who used a remote weight-loss program combining mobile applications, frequent self-weighing, and calorie restriction via meal replacement for a minimum of 35 days. Weight changes were evaluated at multiple intervals (42, 60, 90, and 120 days), and weight loss was evaluated for all and for pre-specified subgroups based on demographic features and frequency of self-weighing.

Results: Mean weight loss at 42 days ( = 6781) was 8.1 kg (margin of error (MOE) = 0.126 kg) with 73.6% of users experiencing >5% total body weight loss. Both men (9.1 kg; MOE = 0.172 kg; 7.9% from baseline) and women (7.1 kg; MOE = 0.179 kg; 7.2% from baseline) experienced significant weight loss. At the 120-day interval ( = 2914), mean weight loss was 14 kg (MOE = 0.340 kg), 13% total body weight loss from baseline, and 82.3% of participants had lost >5% of their initial body weight. The decrease in body-fat percent correlated well with weight loss ( = 0.92;  < 0.001).

Conclusions: In a large cohort of individuals with class II or III obesity, a remote weight-loss program combining mobile applications, daily self-weighing, and calorie restriction via meal replacement resulted in dramatic weight loss among subjects who were active users when evaluated through a retrospective observational analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2055207620910279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059223PMC
March 2020

Whole Exome Sequencing of Highly Aggregated Lung Cancer Families Reveals Linked Loci for Increased Cancer Risk on Chromosomes 12q, 7p, and 4q.

Cancer Epidemiol Biomarkers Prev 2020 02 11;29(2):434-442. Epub 2019 Dec 11.

Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland.

Background: Lung cancer kills more people than any other cancer in the United States. In addition to environmental factors, lung cancer has genetic risk factors as well, though the genetic etiology is still not well understood. We have performed whole exome sequencing on 262 individuals from 28 extended families with a family history of lung cancer.

Methods: Parametric genetic linkage analysis was performed on these samples using two distinct analyses-the lung cancer only (LCO) analysis, where only patients with lung cancer were coded as affected, and the all aggregated cancers (AAC) analysis, where other cancers seen in the pedigree were coded as affected.

Results: The AAC analysis yielded a genome-wide significant result at rs61943670 in at 12q23.3. has been implicated somatically in lung cancer, but this germline finding is novel and is a significant expression quantitative trait locus in lung tissue. Interesting genome-wide suggestive haplotypes were also found within individual families, particularly near at 7p36.1 in one family and a large linked haplotype spanning 4q21.3-28.3 in a different family. The 4q haplotype contains potential causal rare variants in at 4q22.1 and at 4q21.3.

Conclusions: Regions on 12q, 7p, and 4q are linked to increased cancer risk in highly aggregated lung cancer families, 12q across families and 7p and 4q within a single family. , and are currently the best candidate genes.

Impact: Functional work on these genes is planned for future studies and if confirmed would lead to potential biomarkers for risk in cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-19-0887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007362PMC
February 2020

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

BMC Cardiovasc Disord 2019 10 29;19(1):240. Epub 2019 Oct 29.

Department Primary Care & Population Health, University College London, London, UK.

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.

Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.

Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.

Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12872-019-1187-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820948PMC
October 2019

Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.

Blood 2019 11;134(19):1645-1657

Boston VA Healthcare System, Boston, MA.

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019000435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871304PMC
November 2019

Immune Cell Infiltration May Be a Key Determinant of Long-Term Survival in Small Cell Lung Cancer.

J Thorac Oncol 2019 07 9;14(7):1286-1295. Epub 2019 May 9.

Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address:

Introduction: Although most patients with SCLC die within a few months of diagnosis, a subgroup of patients survive for many years. Factors determining long-term survivorship remain largely unknown. We present the first comprehensive comparative genomic and tumor microenvironment analyses of SCLC between patients with long-term survivorship and patients with the expected survivorship.

Methods: We compared surgically resected tumors of 23 long-term SCLC survivors (survival >4 years) and 18 SCLC survivors with the expected survival time (survival ≤2 years). There were no significant differences in clinical variables, including TNM staging and curative- versus non-curative-intent surgery between the groups. Gene expression profiling was performed by using microarrays, and tumor microenvironment analyses were performed by immunohistochemistry of prominent immune-related markers.

Results: Immune-related genes and pathways represented the majority of the differentially overexpressed genes in long-term survivorship compared with in expected survivorship. The differences in the immunological tumor microenvironment were confirmed by quantitative immunostaining. Increased numbers of tumor-infiltrating and associated lymphocytes were present throughout tumors of long-term survivors of SCLC. Several differentiating patterns of enhanced antitumor immunity were identified. Although some areas of the tumors of long-term survivors of SCLC also harbored higher numbers of suppressive immune cells (monocytes, regulatory lymphocytes, and macrophages), the ratios of these suppressive cells to CD3-positive lymphocytes were generally lower in the tumors of long-term survivors of SCLC, indicating a less tumor-suppressive microenvironment.

Conclusions: Our data demonstrate that long-term survivorship of patients with SCLC is strongly influenced by the presence of the immune cells in the tumor microenvironment. Characterization of the antitumor immune responses may identify opportunities for individualized immunotherapies for SCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2019.03.028DOI Listing
July 2019

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 515.33 TERT-CLPTM1Ll Region.

J Thorac Oncol 2019 08 19;14(8):1360-1369. Epub 2019 Apr 19.

National Institute of Occupational Health (STAMI), Oslo, Norway.

Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer.

Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer.

Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate.

Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2019.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833942PMC
August 2019

Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel.

Genet Med 2019 09 20;21(9):2135-2144. Epub 2019 Mar 20.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

Purpose: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs.

Methods: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap).

Results: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA).

Conclusion: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0475-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752313PMC
September 2019

A phenome-wide association study to discover pleiotropic effects of , , and .

NPJ Genom Med 2019 11;4. Epub 2019 Feb 11.

20Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI 54449 USA.

We conducted an electronic health record (EHR)-based phenome-wide association study (PheWAS) to discover pleiotropic effects of variants in three lipoprotein metabolism genes , , and . Using high-density genotype data, we tested the associations of variants in the three genes with 1232 EHR-derived binary phecodes in 51,700 European-ancestry (EA) individuals and 585 phecodes in 10,276 African-ancestry (AA) individuals; 457 , 730 , and 720 variants were filtered by imputation quality (  > 0.4), minor allele frequency (>1%), linkage disequilibrium (  < 0.3), and association with LDL-C levels, yielding a set of two , three , and five variants in EA but no variants in AA. Cases and controls were defined for each phecode using the PheWAS package in R. Logistic regression assuming an additive genetic model was used with adjustment for age, sex, and the first two principal components. Significant associations were tested in additional cohorts from Vanderbilt University ( = 29,713), the Marshfield Clinic Personalized Medicine Research Project ( = 9562), and UK Biobank ( = 408,455). We identified one , two , and two variants significantly associated with an examined phecode. Only one of the variants was associated with a non-lipid disease phecode, ("myopia") but this association was not significant in the replication cohorts. In this large-scale PheWAS we did not find LDL-C-related variants in , , and to be associated with non-lipid-related phenotypes including diabetes, neurocognitive disorders, or cataracts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-019-0078-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370860PMC
February 2019

Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection.

J Am Coll Cardiol 2019 01;73(1):58-66

Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Kensington, New South Wales, Australia.

Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.

Objectives: This study sought to test the association between the rs9349379 genotype and SCAD.

Methods: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.

Results: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.

Conclusions: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2018.09.085DOI Listing
January 2019

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits.

Am J Hum Genet 2019 01 27;104(1):112-138. Epub 2018 Dec 27.

School of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323610PMC
January 2019

Age-related DNA methylation and hemostatic factors.

Blood 2018 10;132(17):1736

Mayo Clinic.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-08-867028DOI Listing
October 2018

Long-term risk of depressive and anxiety symptoms after early bilateral oophorectomy.

Menopause 2018 11;25(11):1275-1285

Divisions of Epidemiology.

Objective: We studied the long-term risk of depressive and anxiety symptoms in women who underwent bilateral oophorectomy before menopause.

Design: We conducted a cohort study among all women residing in Olmsted County, MN, who underwent bilateral oophorectomy before the onset of menopause for a noncancer indication from 1950 through 1987. Each member of the bilateral oophorectomy cohort was matched by age with a referent woman from the same population who had not undergone an oophorectomy. In total, we studied 666 women with bilateral oophorectomy and 673 referent women. Women were followed for a median of 24 years, and depressive and anxiety symptoms were assessed using a structured questionnaire via a direct or proxy telephone interview performed from 2001 through 2006.

Results: Women who underwent bilateral oophorectomy before the onset of menopause had an increased risk of depressive symptoms diagnosed by a physician (hazard ratio = 1.54, 95% CI: 1.04-2.26, adjusted for age, education, and type of interview) and of anxiety symptoms (adjusted hazard ratio = 2.29, 95% CI: 1.33-3.95) compared with referent women. The findings remained consistent after excluding depressive or anxiety symptoms that first occurred within 10 years after oophorectomy. The associations were greater with younger age at oophorectomy but did not vary across indications for the oophorectomy. In addition, treatment with estrogen to age 50 years in women who underwent bilateral oophorectomy at younger ages did not modify the risk.

Conclusions: Bilateral oophorectomy performed before the onset of menopause is associated with an increased long-term risk of depressive and anxiety symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/GME.0000000000001229DOI Listing
November 2018

The eMERGE genotype set of 83,717 subjects imputed to ~40 million variants genome wide and association with the herpes zoster medical record phenotype.

Genet Epidemiol 2019 02 8;43(1):63-81. Epub 2018 Oct 8.

Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

The Electronic Medical Records and Genomics (eMERGE) network is a network of medical centers with electronic medical records linked to existing biorepository samples for genomic discovery and genomic medicine research. The network sought to unify the genetic results from 78 Illumina and Affymetrix genotype array batches from 12 contributing medical centers for joint association analysis of 83,717 human participants. In this report, we describe the imputation of eMERGE results and methods to create the unified imputed merged set of genome-wide variant genotype data. We imputed the data using the Michigan Imputation Server, which provides a missing single-nucleotide variant genotype imputation service using the minimac3 imputation algorithm with the Haplotype Reference Consortium genotype reference set. We describe the quality control and filtering steps used in the generation of this data set and suggest generalizable quality thresholds for imputation and phenotype association studies. To test the merged imputed genotype set, we replicated a previously reported chromosome 6 HLA-B herpes zoster (shingles) association and discovered a novel zoster-associated loci in an epigenetic binding site near the terminus of chromosome 3 (3p29).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gepi.22167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375696PMC
February 2019

GAW20: methods and strategies for the new frontiers of epigenetics and pharmacogenomics.

BMC Proc 2018 17;12(Suppl 9):26. Epub 2018 Sep 17.

12Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104 USA.

GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families ( = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates. The contributions from individual research groups were extensively discussed prior, during, and after the Workshop in groups based on discussion themes, before being submitted for publication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12919-018-0113-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156831PMC
September 2018

The challenge of detecting genotype-by-methylation interaction: GAW20.

BMC Genet 2018 09 17;19(Suppl 1):81. Epub 2018 Sep 17.

Department of Statistics, Columbia University, 1255 Amsterdam Avenue, New York, NY, 10027, USA.

Background: GAW20 working group 5 brought together researchers who contributed 7 papers with the aim of evaluating methods to detect genetic by epigenetic interactions. GAW20 distributed real data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, including single-nucleotide polymorphism (SNP) markers, methylation (cytosine-phosphate-guanine [CpG]) markers, and phenotype information on up to 995 individuals. In addition, a simulated data set based on the real data was provided.

Results: The 7 contributed papers analyzed these data sets with a number of different statistical methods, including generalized linear mixed models, mediation analysis, machine learning, W-test, and sparsity-inducing regularized regression. These methods generally appeared to perform well. Several papers confirmed a number of causative SNPs in either the large number of simulation sets or the real data on chromosome 11. Findings were also reported for different SNPs, CpG sites, and SNP-CpG site interaction pairs.

Conclusions: In the simulation (200 replications), power appeared generally good for large interaction effects, but smaller effects will require larger studies or consortium collaboration for realizing a sufficient power.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12863-018-0650-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157121PMC
September 2018

Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.

J Thorac Oncol 2018 10 4;13(10):1483-1495. Epub 2018 Jul 4.

Maria Sklodowska-Curie Institute of Oncology Center, Warsaw, Poland.

Background: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior.

Methods: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls.

Results: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility.

Conclusion: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2018.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366341PMC
October 2018

Genome-wide association study of familial lung cancer.

Carcinogenesis 2018 09;39(9):1135-1140

National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.

To identify genetic variation associated with lung cancer risk, we performed a genome-wide association analysis of 685 lung cancer cases that had a family history of two or more first or second degree relatives compared with 744 controls without lung cancer that were genotyped on an Illumina Human OmniExpressExome-8v1 array. To ensure robust results, we further evaluated these findings using data from six additional studies that were assembled through the Transdisciplinary Research on Cancer of the Lung Consortium comprising 1993 familial cases and 33 690 controls. We performed a meta-analysis after imputation of all variants using the 1000 Genomes Project Phase 1 (version 3 release date September 2013). Analyses were conducted for 9 327 222 SNPs integrating data from the two sources. A novel variant on chromosome 4p15.31 near the LCORL gene and an imputed rare variant intergenic between CDKN2A and IFNA8 on chromosome 9p21.3 were identified at a genome-wide level of significance for squamous cell carcinomas. Additionally, associations of CHRNA3 and CHRNA5 on chromosome 15q25.1 in sporadic lung cancer were confirmed at a genome-wide level of significance in familial lung cancer. Previously identified variants in or near CHRNA2, BRCA2, CYP2A6 for overall lung cancer, TERT, SECISPB2L and RTEL1 for adenocarcinoma and RAD52 and MHC for squamous carcinoma were significantly associated with lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgy080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148967PMC
September 2018
-->