scholarly journals A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1008802
Author(s):  
Catherine Tcheandjieu ◽  
Matthew Aguirre ◽  
Stefan Gustafsson ◽  
Priyanka Saha ◽  
Praneetha Potiny ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Genetic Testing ◽  
General Population ◽  
Association Study ◽  
Target Genes ◽  
Rare Variants ◽  
Body Height ◽  
Genetic Syndrome ◽  
Human Phenotype ◽  
Increased Risk

The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, NOTCH2 FBN1, PTPN1 and RAS-opathy genes, and genes in the 22q11.2 locus) and performed a gene burden test. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.

scholarly journals A phenome-wide association study of four syndromic genes reveals pleiotropic effects of common and rare variants in the general population

2019 ◽  
Author(s):  
Catherine Tcheandjieu ◽  
Matthew Aguirre ◽  
Stefan Gustafsson ◽  
Priyanka Saha ◽  
Praneetha Potiny ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Genetic Testing ◽  
General Population ◽  
Body Fat ◽  
Rare Variants ◽  
Body Fat Percentage ◽  
Fat Percentage ◽  
Reduced Body ◽  
Multiple Phenotype ◽  
Rare Alleles

AbstractThe clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a few phenotypes of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore pleiotropy of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population.Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, TBX1, FBN1, PTPN11, NOTCH2, and MAP2K1) and performed a gene burden testing.Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome.Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.Author SummaryStandard medical evaluation of genetic syndromes relies upon recognizing a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. This may lead to missing diagnoses in patients with silent or a low expressed form of the syndrome. Here we take advantage of a rich electronic health record, various phenotypic measurements, and genetic information in 337,198 unrelated white British from the UKBB, to study the relation between single syndromic disease phenotypes and genes related to syndromic disease. We show multiple phenotype-genotypes associations in concordance with phenotypes variations found in syndromic diseases. For example, we show that mutation in FBN1 was associated with high standing/sitting height ratio and reduced body fat percentage as observed in individuals with Marfan syndrome. Our findings suggest that common and rare alleles in SD genes are causative of individual component phenotypes present in a general population; further research is needed to characterize the pleiotropic effect of alleles in syndromic genes in persons without the syndromic disease.

scholarly journals First French study relative to preconception genetic testing: 1500 general population participants’ opinion

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Valérie Bonneau ◽  
Mathilde Nizon ◽  
Xenia Latypova ◽  
Aurélie Gaultier ◽  
Eugénie Hoarau ◽  
...  
Keyword(s):  
Genetic Testing ◽  
General Population ◽  
Social Security ◽  
Genetic Disease ◽  
Ethical Issues ◽  
Family Doctor ◽  
Screening Strategy ◽  
Medical Prescription ◽  
Medical Progress ◽  
Increased Risk

Abstract Background Until very recently, preconception genetic testing was only conducted in particular communities, ethnic groups or families for which an increased risk of genetic disease was identified. To detect in general population a risk for a couple to have a child affected by a rare, recessive or X-linked, genetic disease, carrier screening is proposed in several countries. We aimed to determine the current public opinion relative to this approach in France, using either a printed or web-based questionnaire. Results Among the 1568 participants, 91% are favorable to preconception genetic tests and 57% declare to be willing to have the screening if the latter is available. A medical prescription by a family doctor or a gynecologist would be the best way to propose the test for 73%, with a reimbursement from the social security insurance. However, 19% declare not to be willing to use the test because of their ethic or moral convictions, and the fear that the outcome would question the pregnancy. Otherwise, most participants consider that the test is a medical progress despite the risk of an increased medicalization of the pregnancy. Conclusion This first study in France highlights a global favorable opinion for the preconception genetic carrier testing under a medical prescription and a reimbursement by social security insurance. Our results emphasize as well the complex concerns underpinned by the use of this screening strategy. Therefore, the ethical issues related to these tests include the risk of eugenic drift mentioned by more than half of the participants.

scholarly journals Hypertension in the United States Fire Service

2021 ◽  
Vol 18 (10) ◽  
pp. 5432
Author(s):  
Saeed U. Khaja ◽  
Kevin C. Mathias ◽  
Emilie D. Bode ◽  
Donald F. Stewart ◽  
Kepra Jack ◽  
...  
Keyword(s):  
Blood Pressure ◽  
General Population ◽  
Age Groups ◽  
Total Sample ◽  
The United States ◽  
Fire Service ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cardiac Events ◽  
Antihypertensive Medications ◽  
Increased Risk

Hypertension is a major risk factor for atherosclerotic cardiovascular disease and cardiac remodeling and is associated with an increased risk of sudden cardiac events, the leading cause of duty-related death in the fire service. We assessed systemic blood pressures and prevalence of hypertension among US firefighters by decade of life. Medical records of career firefighters (5063 males and 274 females) from four geographically diverse occupational health clinics were assessed. Hypertension was defined as systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg, or taking antihypertensive medication. Results from the firefighter sample were compared to the US general population (2015–2016 and 2017–2018 National Health and Nutrition Examination Surveys). Among the total sample, 69% of firefighters met the criteria for hypertension and 17% were taking antihypertensive medications. Percentages of hypertensive male and female firefighters were 45% and 11% among 20–29 years old, respectively, and increased to 78% and 79% among 50–59 years old, respectively. Compared to the general population, male firefighters had a higher prevalence of hypertension (p < 0.05) across all age groups (11–16% higher). In order to improve firefighter health and protect against sudden incapacitation in this public safety occupational group, increased efforts are necessary to screen for and manage high blood pressure.

scholarly journals Rates of Chronic Medical Conditions in 1991 Gulf War Veterans Compared to the General Population

2019 ◽  
Vol 16 (6) ◽  
pp. 949 ◽  
Author(s):  
Clara Zundel ◽  
Maxine Krengel ◽  
Timothy Heeren ◽  
Megan Yee ◽  
Claudia Grasso ◽  
...  
Keyword(s):  
Blood Pressure ◽  
General Population ◽  
High Blood Pressure ◽  
Population Based ◽  
Chronic Medical Conditions ◽  
Medical Conditions ◽  
Gulf War Veterans ◽  
Increased Risk ◽  
Prevalence Estimates ◽  
The Difference

Prevalence of nine chronic medical conditions in the population-based Ft. Devens Cohort (FDC) of GW veterans were compared with the population-based 2013–2014 National Health and Nutrition Examination Survey (NHANES) cohort. Excess prevalence was calculated as the difference in prevalence estimates from the Ft. Devens and NHANES cohorts; and confidence intervals and p-values are based on the standard errors for the two prevalence estimates. FDC males were at increased risk for reporting seven chronic medical conditions compared with NHANES males. FDC females were at decreased risk for high blood pressure and increased risk for diabetes when compared with NHANES females. FDC veterans reporting war-related chemical weapons exposure showed higher risk of high blood pressure; diabetes; arthritis and chronic bronchitis while those reporting taking anti-nerve gas pills had increased risk of heart attack and diabetes. GW veterans are at higher risk of chronic conditions than the general population and these risks are associated with self-reported toxicant exposures.

scholarly journals Sleep disturbance associations with blood pressure and body mass index in school-aged children

2020 ◽  
Vol 60 (6) ◽  
pp. 303-9
Author(s):  
Restu Maharany Arumningtyas ◽  
Agung Triono ◽  
Retno Sutomo
Keyword(s):  
Blood Pressure ◽  
Body Mass Index ◽  
Sleep Disturbance ◽  
Body Mass ◽  
Sleep Disturbances ◽  
Body Height ◽  
Common Type ◽  
Primary School Children ◽  
School Aged Children ◽  
Increased Risk

Background Sleep disturbances can lead to many health problems in school-aged children, including hypertension and obesity. However, a lack of consensus about the etiology of these conditions is due to conflicting reports on the possible effects of sleep disturbances. Objective To assess for possible associations between sleep disturbances and blood pressure as well as body mass index in school-aged children. Methods This cross-sectional study involved primary school children in the 4th-5th grades. Subjects’ blood pressure, body weight, and body height were measured and their parents completed the Sleep Disturbances Scale for Children (SDSC) questionnaire. Results Of the 816 children enrolled, 503 (61.6%) children had sleep disturbances. The most common type of sleep disturbance was initiating and maintaining sleep. Bivariate analysis revealed a significantly increased risk of hypertension among subjects with sleep disturbances (PR 15.06; 95%CI 8.13 to 27.90) and increased risk of obesity (PR 22.65; 95%CI 12.28 to 41.78). Conclusion The most common type of sleep disturbance is initiating and maintaining sleep. Sleep disturbances are significantly associated with hypertension and obesity in children.

P2649Do these data apply to me? Examining the applicability of trials assessing strategies for optimal management of blood pressure to older patients in UK primary care

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J Sheppard ◽  
J Burt ◽  
M Lown ◽  
E Temple ◽  
R Lowe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Primary Care ◽  
General Population ◽  
Older Patients ◽  
Random Effect ◽  
Cross Sectional Study ◽  
Eligibility Criteria ◽  
Cross Sectional ◽  
Increased Risk ◽  
Cardiovascular Medications

Abstract Background There is debate as to what extent older patients (≥80 years) should be treated for high blood pressure. Existing trials show that blood pressure lowering in this population is effective at preventing stroke and heart failure but also results in an increased risk of adverse events. However, it has been suggested that these studies enrolled healthier patients, who are less representative of the general population and more likely to benefit from treatment. Purpose This study aimed to compare the characteristics of patients eligible for three blood pressure management trials and assess the likelihood of eligibility for each trial based on common characteristics of older patients. Methods Cross-sectional study of data extracted from the medical records of 15,376 patients aged ≥80 years, registered to 24 general practices in the south of England. Anonymised patient data relating to the eligibility criteria for two previous medication intensification trials (HYVET, SPRINT) and one medication reduction trial (OPTiMISE) were extracted. Patients eligible for each trial were defined according to criteria specified in each trial protocol. Descriptive statistics were used to define the characteristics of each trial population. A logistic regression model was constructed to estimate predictors of eligibility for each trial, with practice included as a random effect. Results Approximately 268 (1.7%), 5,290 (34.4%) and 3,940 (25.6%) patients were eligible for HYVET, SPRINT and OPTiMISE trials respectively. There was little overlap in eligibility for each trial (1.0% were eligible for HYVET and SPRINT; 0% were eligible for HYVET and OPTiMISE; 10.2% were eligible for SPRINT and OPTiMISE). Patients eligible for OPTiMISE were comparable to the general population in terms of frailty (eFI 0.12 [OPTiMISE] vs 0.11 [general population]), but had more morbidities (4 vs 3) and cardiovascular medications prescribed (4 vs 2). Patients in HYVET and SPRINT were less frail, multi-morbid and prescribed less cardiovascular medications. Overall, increasing frailty and a history of cardiovascular disease reduced the likelihood of being eligible for any trial. Conclusions Patients eligible for OPTiMISE appear to best represent the population aged ≥80 years attending UK primary care. Increasing frailty and/or multi-morbidity reduce the likelihood of eligibility for all three blood pressure trials. Caution should be exercised when applying the results from randomised controlled trials to management of blood pressure in frail and multi-morbid patients. Acknowledgement/Funding This study was funded by the National Institute for Health Research (NIHR) SPCR and Oxford CLAHRC

scholarly journals Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes in over 200,000 adults

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
A De Marvao ◽  
K McGurk ◽  
S Zheng ◽  
M Thanaj ◽  
W Bai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
General Population ◽  
Wall Thickness ◽  
Biomedical Research ◽  
Rare Variants ◽  
Left Ventricular ◽  
Uk Biobank ◽  
Increased Risk ◽  
Encoding Genes

Abstract Background Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population. Purpose To determine the population prevalence of HCM-associated sarcomeric variants, characterise their phenotypic manifestations, estimate penetrance, and identify associations between sarcomeric variants and clinical outcomes, we performed an observational study of 218,813 adults in the UK Biobank (UKBB), of whom 200,584 have whole exome sequencing (WES). Methods We carried out an integrated analysis of WES and cardiac magnetic resonance (CMR) imaging in UK Biobank participants stratified by sarcomere-encoding variant status. Computer vision techniques were used to automatically segment the four chambers of the heart (Figure 1). Cardiac motion analysis was used to derive strain and strain rates. Regional analysis of left ventricular wall thickness was performed using three-dimensional modelling of these segmentations. Results Median age at recruitment was 58 (IQR 50–63 years), and participants were followed up for a median of 10.8 years (IQR 9.9–11.6 years) with a total of 19,507 primary clinical events reported. The prevalence of rare variants (allele frequency &lt;0.ehab724.17314) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), and the prevalence of pathogenic or likely pathogenic variants (SARC-P/LP) was 0.24% (n=474, 1 in 423). SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events (MACE) compared to controls (HR 1.68, 95% CI 1.37–2.06, p&lt;0.001), mainly due to heart failure endpoints (Figure 2: cumulative hazard curves with zoomed plots for lifetime risk of A) death and MACE or B) heart failure, stratified by genotype; genotype negative (SARC-NEG), carriers of indeterminate sarcomeric variants (SARC-IND) or SARC-P/LP; C) Forest plot of comparative lifetime risk of clinical endpoints by genotype). While males had a higher overall risk of adverse outcomes, the incremental genetic risk from SARC-P/LP mutations was greater in females (HR for females: 2.18 CI 1.65–2.89, p&lt;0.001; HR for males: 1.42 CI 1.05–1.9, p=0.02). In 21,322 participants with CMR, SARC-P/LP were associated with asymmetric increase in left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p&lt;0.001) but hypertrophy (≥13mm) was only present in 16% (n=7/43, 95% CI 7–31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5±1.7 vs 9.4±1.6 mm, p=0.002) with no combined excess cardiovascular risk. Conclusions In the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM but are associated with increased risk of adverse cardiovascular outcomes and a sub-clinical cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The study was supported by the Medical Research Council, UK (MC-A651-53301); National Institute for Health Research (NIHR) Imperial College Biomedical Research Centre; NIHR Royal Brompton Cardiovascular Biomedical Research Unit; British Heart Foundation (NH/17/1/32725, RG/19/6/34387, RE/18/4/34215).

Abstract P327: Risk Factors for Prehypertension in the Community

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Lisa Rafalson ◽  
Richard P Donahue ◽  
Saverio Stranges
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
New York ◽  
Weight Gain ◽  
Waist Circumference ◽  
General Population ◽  
Population Based ◽  
Health Study ◽  
Increased Risk

Background: Prehypertension is an increasingly highly prevalent condition in the general population, and is associated with an increased risk for coronary heart disease and stroke. However, evidence from population-based studies of the risk factors for prehypertension is scant. We sought to examine the predictors of progression from normotension to prehypertension in a community-based population from Western New York. Methods: We conducted a longitudinal analysis, over six years of follow-up, among 569 men and women (51.8 years, 96% White, 70% female) who were free of prehypertension, hypertension, cardiovascular disease and type 2 diabetes at the baseline examination, in the Western New York Health Study (WNYHS). Incident prehypertension at follow-up was defined as systolic blood pressure of 120-139 mmHg and/or diastolic blood pressure of 80-89 mmHg. Results: In bivariate analyses, there were several correlates of incident prehypertension, including age, BMI and waist circumference, impaired fasting glucose (IFG), uric acid, and baseline blood pressure levels. After multivariate adjustment, IFG at baseline odds ratio (OR):1.69, 95%CI:1.06-2.67) and weight gain since age 25 (OR: 1.28, 1.11-1.58 per 10 lb. increase) were the strongest significant predictors of prehypertension at follow-up. Neither waist circumference nor current BMI were predictor variables in models when they were substituted for weight gain. Conclusions: Results from this study suggest early dysregulation of glucose metabolism and weight gain over the lifespan are likely to represent important risk factors for prehypertension in the general population.

scholarly journals Genome-wide association study of cardiovascular disease in testicular cancer patients treated with platinum-based chemotherapy

2020 ◽  
Author(s):  
Lars C. Steggink ◽  
Hink Boer ◽  
Coby Meijer ◽  
Joop D. Lefrandt ◽  
Leon W. M. M. Terstappen ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
General Population ◽  
Testicular Cancer ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
Platinum Based Chemotherapy ◽  
Increased Risk

Abstract Genetic variation may mediate the increased risk of cardiovascular disease (CVD) in chemotherapy-treated testicular cancer (TC) patients compared to the general population. Involved single nucleotide polymorphisms (SNPs) might differ from known CVD-associated SNPs in the general population. We performed an explorative genome-wide association study (GWAS) in TC patients. TC patients treated with platinum-based chemotherapy between 1977 and 2011, age ≤55 years at diagnosis, and ≥3 years relapse-free follow-up were genotyped. Association between SNPs and CVD occurrence during treatment or follow-up was analyzed. Data-driven Expression Prioritized Integration for Complex Trait (DEPICT) provided insight into enriched gene sets, i.e., biological themes. During a median follow-up of 11 years (range 3–37), CVD occurred in 53 (14%) of 375 genotyped patients. Based on 179 SNPs associated at p ≤ 0.001, 141 independent genomic loci associated with CVD occurrence. Subsequent, DEPICT found ten biological themes, with the RAC2/RAC3 network (linked to endothelial activation) as the most prominent theme. Biology of this network was illustrated in a TC cohort (n = 60) by increased circulating endothelial cells during chemotherapy. In conclusion, the ten observed biological themes highlight possible pathways involved in CVD in chemotherapy-treated TC patients. Insight in the genetic susceptibility to CVD in TC patients can aid future intervention strategies.

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