Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies.
Ontology highlight
ABSTRACT:
SUBMITTER: Unlu G
PROVIDER: S-EPMC7147997 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies.
Unlu Gokhan G Qi Xinzi X Gamazon Eric R ER Melville David B DB Patel Nisha N Rushing Amy R AR Hashem Mais M Al-Faifi Abdullah A Chen Rui R Li Bingshan B Cox Nancy J NJ Alkuraya Fowzan S FS Knapik Ela W EW
Nature medicine 20200113 1
Discovery of genotype-phenotype relationships remains a major challenge in clinical medicine. Here, we combined three sources of phenotypic data to uncover a new mechanism for rare and common diseases resulting from collagen secretion deficits. Using a zebrafish genetic screen, we identified the ric1 gene as being essential for skeletal biology. Using a gene-based phenome-wide association study (PheWAS) in the EHR-linked BioVU biobank, we show that reduced genetically determined expression of RI ...[more]
Similar Datasets
Project description:Rationale: Red cell distribution width (RDW) is a prognostic factor in many diseases; however, its clinical utility remains limited because the relative value of RDW as a biomarker across disease states has not been established. Objectives: To establish an unbiased RDW disease hierarchy to guide the clinical use of RDW and to assess its relationship to cardiovascular hemodynamic and structural parameters. Methods: We performed phenome-wide association studies for RDW in discovery and replication cohorts derived from a deidentified electronic health record in nonanemic individuals. RDW values obtained within 30 days of echocardiogram or right heart catheterization were tested for association with structural and hemodynamic variables. Results: RDW was associated with 263 phenotypes in both men and women in the discovery cohort (n?=?121,530), 48 of which replicated in an independent cohort (n?=?2,039). The strongest associations were observed with pulmonary arterial hypertension (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.9-2.3), chronic pulmonary heart disease (OR, 2.0; 95% CI, 1.9-2.2), and congestive heart failure (OR, 1.9; 95% CI, 1.8-2.0); P?<?1?×?10-74 for all. By echocardiography, RDW was higher in the setting of right ventricular dysfunction than left ventricular dysfunction (P?<?0.001). Measured invasively, mean pulmonary arterial pressure was associated with RDW (21 vs. 33 mm Hg at 25th vs. 75th percentile RDW; P?<?1?×?10-7) and remained strongly significant even when controlling for mean pulmonary capillary wedge pressure (21 vs. 29 mm Hg at 25th vs. 75th percentile RDW; P?<?1?×?10-7). Conclusions: Among 1,364 coded medical conditions, increased RDW was strongly associated with pulmonary hypertension and heart failure. Hemodynamic and echocardiographic phenotyping confirmed these associations and underscored that the most clinically relevant phenotype associated with RDW was pulmonary hypertension. These hypothesis-generating findings highlight the potential shared pathophysiology of pulmonary hypertension and elevated RDW. Elevated RDW in the absence of anemia should alert clinicians to the potential for underlying cardiopulmonary disease.
| S-EPMC6491061 | biostudies-literature
Project description:Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N?=?10,674) and replication (N?=?11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (?: 0.125 to 0.868, pFDR?<?0.043). Several behavioural traits are also associated with depression-PRS (?: 0.014 to 0.180, pFDR: 0.049 to 1.28?×?10-14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.
| S-EPMC7210889 | biostudies-literature
Project description:BackgroundIron is integral to many physiological processes, and variations in its levels, even within the normal range, can have implications for health. The objective of this study was to explore the broad clinical effects of varying iron status.Methods and findingsGenome-wide association study (GWAS) summary data obtained from 48,972 European individuals (55% female) across 19 cohorts in the Genetics of Iron Status Consortium were used to identify 3 genetic variants (rs1800562 and rs1799945 in the hemochromatosis gene [HFE] and rs855791 in the transmembrane protease serine 6 gene [TMPRSS6]) that associate with increased serum iron, ferritin, and transferrin saturation and decreased transferrin levels, thus serving as instruments for systemic iron status. Phenome-wide association study (PheWAS) of these instruments was performed on 424,439 European individuals (54% female) in the UK Biobank who were aged 40-69 years when recruited from 2006 to 2010, with their genetic data linked to Hospital Episode Statistics (HES) from April, 1995 to March, 2016. Two-sample summary data mendelian randomization (MR) analysis was performed to investigate the effect of varying iron status on outcomes across the human phenome. MR-PheWAS analysis for the 3 iron status genetic instruments was performed separately and then pooled by meta-analysis. Correction was made for testing of multiple correlated phenotypes using a 5% false discovery rate (FDR) threshold. Heterogeneity between MR estimates for different instruments was used to indicate possible bias due to effects of the genetic variants through pathways unrelated to iron status. There were 904 distinct phenotypes included in the MR-PheWAS analyses. After correcting for multiple testing, the 3 genetic instruments for systemic iron status demonstrated consistent evidence of a causal effect of higher iron status on decreasing risk of traits related to anemia (iron deficiency anemia: odds ratio [OR] scaled to a standard deviation [SD] increase in genetically determined serum iron levels 0.72, 95% confidence interval [CI] 0.64-0.81, P = 4 × 10-8) and hypercholesterolemia (hypercholesterolemia: OR 0.88, 95% CI 0.83-0.93, P = 2 × 10-5) and increasing risk of traits related to infection of the skin and related structures (cellulitis and abscess of the leg: OR 1.25, 95% CI 1.10-1.42, P = 6 × 10-4). The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and misclassification of diagnoses in the HES data. Furthermore, this work only investigated participants with European ancestry, and the findings may not be applicable to other ethnic groups.ConclusionsOur findings offer novel, to our knowledge, insight into previously unreported effects of iron status, highlighting a potential protective effect of higher iron status on hypercholesterolemia and a detrimental role on risk of skin and skin structure infections. Given the modifiable and variable nature of iron status, these findings warrant further investigation.
| S-EPMC6586257 | biostudies-literature
Project description:The ability to conduct genome-wide association studies (GWAS) has enabled new exploration of how genetic variations contribute to health and disease etiology. However, historically GWAS have been limited by inadequate sample size due to associated costs for genotyping and phenotyping of study subjects. This has prompted several academic medical centers to form "biobanks" where biospecimens linked to personal health information, typically in electronic health records (EHRs), are collected and stored on a large number of subjects. This provides tremendous opportunities to discover novel genotype-phenotype associations and foster hypotheses generation.In this work, we study how emerging Semantic Web technologies can be applied in conjunction with clinical and genotype data stored at the Mayo Clinic Biobank to mine the phenotype data for genetic associations. In particular, we demonstrate the role of using Resource Description Framework (RDF) for representing EHR diagnoses and procedure data, and enable federated querying via standardized Web protocols to identify subjects genotyped for Type 2 Diabetes and Hypothyroidism to discover gene-disease associations. Our study highlights the potential of Web-scale data federation techniques to execute complex queries.This study demonstrates how Semantic Web technologies can be applied in conjunction with clinical data stored in EHRs to accurately identify subjects with specific diseases and phenotypes, and identify genotype-phenotype associations.
| S-EPMC3554594 | biostudies-literature
Project description:BACKGROUND:Vitamin D deficiency is highly prevalent across the globe. Existing studies suggest that a low vitamin D level is associated with more than 130 outcomes. Exploring the causal role of vitamin D in health outcomes could support or question vitamin D supplementation. METHODS:We carried out a systematic literature review of previous Mendelian-randomization studies on vitamin D. We then implemented a Mendelian Randomization-Phenome Wide Association Study (MR-PheWAS) analysis on data from 339 256 individuals of White British origin from UK Biobank. We first ran a PheWAS analysis to test the associations between a 25(OH)D polygenic risk score and 920 disease outcomes, and then nine phenotypes (i.e. systolic blood pressure, diastolic blood pressure, risk of hypertension, T2D, ischaemic heart disease, body mass index, depression, non-vertebral fracture and all-cause mortality) that met the pre-defined inclusion criteria for further analysis were examined by multiple MR analytical approaches to explore causality. RESULTS:The PheWAS analysis did not identify any health outcome associated with the 25(OH)D polygenic risk score. Although a selection of nine outcomes were reported in previous Mendelian-randomization studies or umbrella reviews to be associated with vitamin D, our MR analysis, with substantial study power (>80% power to detect an association with an odds ratio >1.2 for per standard deviation increase of log-transformed 25[OH]D), was unable to support an interpretation of causal association. CONCLUSIONS:We investigated the putative causal effects of vitamin D on multiple health outcomes in a White population. We did not support a causal effect on any of the disease outcomes tested. However, we cannot exclude small causal effects or effects on outcomes that we did not have enough power to explore due to the small number of cases.
| S-EPMC6857754 | biostudies-literature
Project description:BACKGROUND:The role of urate in cardiovascular diseases (CVDs) has been extensively investigated in observational studies; however, the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance. METHODS AND FINDINGS:A phenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic model (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 unrelated White British individuals (54% female) in the UK Biobank who were aged 40-69 years (mean age, 56.87; SD, 7.99) when recruited from 2006 to 2010. Mendelian randomization (MR) analyses were performed to replicate significant findings using various genome-wide association study (GWAS) consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for urate. PheWAS analysis, examining the association with 1,431 disease outcomes, identified 13 distinct phecodes representing 4 disease groups (inflammatory polyarthropathies, hypertensive disease, circulatory disease, and metabolic disorders) and 9 disease outcomes (gout, gouty arthropathy, pyogenic arthritis, essential hypertension, coronary atherosclerosis, ischemic heart disease, chronic ischemic heart disease, myocardial infarction, and hypercholesterolemia) that were associated with genetically determined serum urate levels after multiple testing correction (p < 3.35 × 10-4). TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases, and blood lipid levels but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with CVDs. The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and possible misclassification of cases for mild disease that did not require hospitalization. CONCLUSION:In this study, high serum urate levels were found to be associated with increased risk of different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a common mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities.
| S-EPMC6799886 | biostudies-literature
Project description:Heritability estimation provides important information about the relative contribution of genetic and environmental factors to phenotypic variation, and provides an upper bound for the utility of genetic risk prediction models. Recent technological and statistical advances have enabled the estimation of additive heritability attributable to common genetic variants (SNP heritability) across a broad phenotypic spectrum. Here, we present a computationally and memory efficient heritability estimation method that can handle large sample sizes, and report the SNP heritability for 551 complex traits derived from the interim data release (152,736 subjects) of the large-scale, population-based UK Biobank, comprising both quantitative phenotypes and disease codes. We demonstrate that common genetic variation contributes to a broad array of quantitative traits and human diseases in the UK population, and identify phenotypes whose heritability is moderated by age (e.g., a majority of physical measures including height and body mass index), sex (e.g., blood pressure related traits) and socioeconomic status (education). Our study represents the first comprehensive phenome-wide heritability analysis in the UK Biobank, and underscores the importance of considering population characteristics in interpreting heritability.
| S-EPMC5400281 | biostudies-literature
Project description:BackgroundWe explored premature stop-gain variants to test the hypothesis that variants, which are likely to have a consequence on protein structure and function, will reveal important insights with respect to the phenotypes associated with them. We performed a phenome-wide association study (PheWAS) exploring the association between a selected list of functional stop-gain genetic variants (variation resulting in truncated proteins or in nonsense-mediated decay) and an extensive group of diagnoses to identify novel associations and uncover potential pleiotropy.ResultsIn this study, we selected 25 stop-gain variants: 5 stop-gain variants with previously reported phenotypic associations, and a set of 20 putative stop-gain variants identified using dbSNP. For the PheWAS, we used data from the electronic MEdical Records and GEnomics (eMERGE) Network across 9 sites with a total of 41,057 unrelated patients. We divided all these samples into two datasets by equal proportion of eMERGE site, sex, race, and genotyping platform. We calculated single effect associations between these 25 stop-gain variants and ICD-9 defined case-control diagnoses. We also performed stratified analyses for samples of European and African ancestry. Associations were adjusted for sex, site, genotyping platform and the first three principal components to account for global ancestry. We identified previously known associations, such as variants in LPL associated with hyperglyceridemia indicating that our approach was robust. We also found a total of three significant associations with p < 0.01 in both datasets, with the most significant replicating result being LPL SNP rs328 and ICD-9 code 272.1 "Disorder of Lipoid metabolism" (pdiscovery = 2.59x10-6, preplicating = 2.7x10-4). The other two significant replicated associations identified by this study are: variant rs1137617 in KCNH2 gene associated with ICD-9 code category 244 "Acquired Hypothyroidism" (pdiscovery = 5.31x103, preplicating = 1.15x10-3) and variant rs12060879 in DPT gene associated with ICD-9 code category 996 "Complications peculiar to certain specified procedures" (pdiscovery = 8.65x103, preplicating = 4.16x10-3).ConclusionIn conclusion, this PheWAS revealed novel associations of stop-gained variants with interesting phenotypes (ICD-9 codes) along with pleiotropic effects.
| S-EPMC4989894 | biostudies-literature
Project description:BackgroundChildhood obesity is reported to be associated with the risk of many diseases in adulthood. However, observational studies cannot fully account for confounding factors. We aimed to systematically assess the causal associations between childhood body mass index (BMI) and various adult traits/diseases using two-sample Mendelian randomization (MR).MethodsAfter data filtering, 263 adult traits genetically correlated with childhood BMI (P < 0.05) were subjected to MR analyses. Inverse-variance weighted, MR-Egger, weighted median, and weighted mode methods were used to estimate the causal effects. Multivariable MR analysis was performed to test whether the effects of childhood BMI on adult traits are independent from adult BMI.ResultsWe identified potential causal effects of childhood obesity on 60 adult traits (27 disease-related traits, 27 lifestyle factors, and 6 other traits). Higher childhood BMI was associated with a reduced overall health rating (β = - 0.10, 95% CI - 0.13 to - 0.07, P = 6.26 × 10-11). Specifically, higher childhood BMI was associated with increased odds of coronary artery disease (OR = 1.09, 95% CI 1.06 to 1.11, P = 4.28 × 10-11), essential hypertension (OR = 1.12, 95% CI 1.08 to 1.16, P = 1.27 × 10-11), type 2 diabetes (OR = 1.36, 95% CI 1.30 to 1.43, P = 1.57 × 10-34), and arthrosis (OR = 1.09, 95% CI 1.06 to 1.12, P = 8.80 × 10-9). However, after accounting for adult BMI, the detrimental effects of childhood BMI on disease-related traits were no longer present (P > 0.05). For dietary habits, different from conventional understanding, we found that higher childhood BMI was associated with low calorie density food intake. However, this association might be specific to the UK Biobank population.ConclusionsIn summary, we provided a phenome-wide view of the effects of childhood BMI on adult traits. Multivariable MR analysis suggested that the associations between childhood BMI and increased risks of diseases in adulthood are likely attributed to individuals remaining obese in later life. Therefore, ensuring that childhood obesity does not persist into later life might be useful for reducing the detrimental effects of childhood obesity on adult diseases.
| S-EPMC8004431 | biostudies-literature
Project description:BackgroundC-reactive protein (CRP) has been used as a biomarker of chronic low-grade inflammation in observational studies. We aimed to determine whether genetically determined CRP was associated with hundreds of human phenotypes to guide anti-inflammatory interventions.MethodsWe used individual data from the UK Biobank to perform a phenome-wide two-stage least squares (2SLS) Mendelian randomization (MR) analysis for CRP with 879 diseases. Summary-level data from the FinnGen consortium were utilized to perform phenome-wide two-sample MR analysis on 821 phenotypes. Systematic two-sample MR methods included MR-IVW, MR-WME, MR-Mod, and MR-PRESSO as sensitivity analyses combined with multivariable MR to identify robust associations. Genetic correlation analysis was applied to identify shared genetic risks.ResultsWe found genetically determined CRP was robustly associated with 15 diseases in the UK Biobank and 11 diseases in the FinnGen population (P < 0.05 for all MR analyses). CRP was positively associated with tongue cancer, bronchitis, hydronephrosis, and acute pancreatitis and negatively associated with colorectal cancer, colon cancer, cerebral ischemia, electrolyte imbalance, Parkinson's disease, epilepsy, anemia of chronic disease, encephalitis, psychophysical visual disturbances, and aseptic necrosis of bone in the UK Biobank. There were positive associations with impetigo, vascular dementia, bipolar disorders, hypercholesterolemia, vertigo, and neurological diseases, and negative correlations with degenerative macular diseases, metatarsalgia, interstitial lung disease, and idiopathic pulmonary fibrosis, and others. in the FinnGen population. The electrolyte imbalance and anemia of chronic disease in UK Biobank and hypercholesterolemia and neurological diseases in FinnGen pass the FDR corrections. Neurological diseases and bipolar disorders also presented positive genetic correlations with CRP. We found no overlapping causal associations between the populations. Previous causal evidence also failed to support these associations (except for bipolar disorders).ConclusionsGenetically determined CRP was robustly associated with several diseases in the UK Biobank and the FinnGen population, but could not be replicated, suggesting heterogeneous and non-repeatable effects of CRP across populations. This implies that interventions at CRP are unlikely to result in decreased risk for most human diseases in the general population but may benefit specific high-risk populations. The limited causal evidence and potential double-sided effects remind us to be cautious about CRP interventions.
| S-EPMC8353321 | biostudies-literature