70 results on '"Stanaway IB"'
Search Results
2. Hemochromatosis risk genotype is not associated with colorectal cancer or age at its diagnosis
- Author
-
Jarvik, GP, Wang, X, Fontanillas, P, Kim, E, Chanprasert, S, Gordon, AS, Bastarache, L, Kowdley, KV, Harrison, T, Rosenthal, EA, Stanaway, IB, Bézieau, S, Weinstein, SJ, Newcomb, PA, Casey, G, Platz, EA, Visvanathan, K, Le Marchand, L, Ulrich, CM, Hardikar, S, Li, CI, van Duijnhoven, FJB, Gsur, A, Campbell, PT, Moreno, V, Vodička, P, Brenner, H, Chang-Claude, J, Hoffmeister, M, Slattery, ML, Gunter, MJ, Aglago, EK, Castellví-Bel, S, Kweon, S-S, Chan, AT, Li, L, Zheng, W, Bishop, DT, Giles, GG, Rennert, G, Offit, K, Keku, TO, Woods, MO, Hampe, J, Van Guelpen, B, Gallinger, SJ, de la Chapelle, A, Hampel, H, Berndt, SI, Tangen, CM, Lindblom, A, Wolk, A, Burnett-Hartman, A, Wu, AH, White, E, Gruber, SB, Jenkins, MA, Mountain, J, Peters, U, Crosslin, DR, Jarvik, GP, Wang, X, Fontanillas, P, Kim, E, Chanprasert, S, Gordon, AS, Bastarache, L, Kowdley, KV, Harrison, T, Rosenthal, EA, Stanaway, IB, Bézieau, S, Weinstein, SJ, Newcomb, PA, Casey, G, Platz, EA, Visvanathan, K, Le Marchand, L, Ulrich, CM, Hardikar, S, Li, CI, van Duijnhoven, FJB, Gsur, A, Campbell, PT, Moreno, V, Vodička, P, Brenner, H, Chang-Claude, J, Hoffmeister, M, Slattery, ML, Gunter, MJ, Aglago, EK, Castellví-Bel, S, Kweon, S-S, Chan, AT, Li, L, Zheng, W, Bishop, DT, Giles, GG, Rennert, G, Offit, K, Keku, TO, Woods, MO, Hampe, J, Van Guelpen, B, Gallinger, SJ, de la Chapelle, A, Hampel, H, Berndt, SI, Tangen, CM, Lindblom, A, Wolk, A, Burnett-Hartman, A, Wu, AH, White, E, Gruber, SB, Jenkins, MA, Mountain, J, Peters, U, and Crosslin, DR
- Abstract
Homozygotes for the higher penetrance hemochromatosis risk allele, HFE c.845G>A (p.Cys282Tyr, or C282Y), have been reported to be at a 2- to 3-fold increased risk for colorectal cancer (CRC). These results have been reported for small sample size studies with no information about age at diagnosis for CRC. An association with age at diagnosis might alter CRC screening recommendations. We analyzed two large European ancestry datasets to assess the association of HFE genotype with CRC risk and age at CRC diagnosis. The first dataset included 59,733 CRC or advanced adenoma cases and 72,351 controls from a CRC epidemiological study consortium. The second dataset included 13,564 self-reported CRC cases and 2,880,218 controls from the personal genetics company, 23andMe. No association of the common hereditary hemochromatosis (HH) risk genotype and CRC was found in either dataset. The odds ratios (ORs) for the association of CRC and HFE C282Y homozygosity were 1.08 (95% confidence interval [CI], 0.91–1.29; p = 0.4) and 1.01 (95% CI, 0.78–1.31, p = 0.9) in the two cohorts, respectively. Age at CRC diagnosis also did not differ by HFE C282Y/C282Y genotype in either dataset. These results indicate no increased CRC risk in individuals with HH genotypes and suggest that persons with HH risk genotypes can follow population screening recommendations for CRC.
- Published
- 2020
3. Plasma proteomics of acute tubular injury.
- Author
-
Schmidt IM, Surapaneni AL, Zhao R, Upadhyay D, Yeo WJ, Schlosser P, Huynh C, Srivastava A, Palsson R, Kim T, Stillman IE, Barwinska D, Barasch J, Eadon MT, El-Achkar TM, Henderson J, Moledina DG, Rosas SE, Claudel SE, Verma A, Wen Y, Lindenmayer M, Huber TB, Parikh SV, Shapiro JP, Rovin BH, Stanaway IB, Sathe NA, Bhatraju PK, Coresh J, Rhee EP, Grams ME, and Waikar SS
- Subjects
- Humans, Male, Female, Middle Aged, Tenascin blood, Tenascin genetics, Tenascin metabolism, Kidney Tubules metabolism, Kidney Tubules pathology, Aged, Adult, SARS-CoV-2, Single-Cell Analysis, Blood Proteins metabolism, Acute Kidney Injury blood, Proteomics methods, Biomarkers blood, COVID-19 blood, Osteopontin blood
- Abstract
The kidney tubules constitute two-thirds of the cells of the kidney and account for the majority of the organ's metabolic energy expenditure. Acute tubular injury (ATI) is observed across various types of kidney diseases and may significantly contribute to progression to kidney failure. Non-invasive biomarkers of ATI may allow for early detection and drug development. Using the SomaScan proteomics platform on 434 patients with biopsy-confirmed kidney disease, we here identify plasma biomarkers associated with ATI severity. We employ regional transcriptomics and proteomics, single-cell RNA sequencing, and pathway analysis to explore biomarker protein and gene expression and enriched biological pathways. Additionally, we examine ATI biomarker associations with acute kidney injury (AKI) in the Kidney Precision Medicine Project (KPMP) (n = 44), the Atherosclerosis Risk in Communities (ARIC) study (n = 4610), and the COVID-19 Host Response and Clinical Outcomes (CHROME) study (n = 268). Our findings indicate 156 plasma proteins significantly linked to ATI with osteopontin, macrophage mannose receptor 1, and tenascin C showing the strongest associations. Pathway analysis highlight immune regulation and organelle stress responses in ATI pathogenesis., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
4. Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis.
- Author
-
Canny SP, Stanaway IB, Holton SE, Mitchem M, O'Rourke AR, Pribitzer S, Baxter SK, Wurfel MM, Malhotra U, Buckner JH, Bhatraju PK, Morrell ED, Speake C, Mikacenic C, and Hamerman JA
- Abstract
Objectives: We aimed to define and validate novel biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system., Design: In two cohorts of adult patients presenting with COVID-19 in 2020 and 2021, clinical lab values and serum proteomics were assessed. Subjects identified as having sHLH were compared to those with COVID-19 without sHLH. Eight deceased patients defined as COVID-sHLH underwent genomic sequencing in order to identify variants in immune-related genes., Setting: Two tertiary care hospitals in Seattle, Washington (Virginia Mason Medical Center and Harborview Medical Center)., Patients: 186 patients with COVID-19., Interventions: None., Measurements and Main Results: Nine percent of enrolled COVID-19 subjects met our defined criteria for sHLH. Using broad serum proteomic approaches (O-link and SomaScan), we identified three biomarkers for COVID-19 associated sHLH (soluble PD-L1, TNF-R1, and IL-18BP), supporting a role for proteins previously associated with other forms of sHLH (IL-18BP and sTNF-R1). We also identified novel biomarkers and pathways of COVID-sHLH, including sPD-L1 and the syntaxin pathway. We detected variants in several genes involved in immune responses in individuals with COVID-sHLH, including in DOCK8 and in TMPRSS15 , suggesting that genetic alterations in immune-related genes may contribute to hyperinflammation and fatal outcomes in COVID-19., Conclusions: Biomarkers of COVID-19 associated sHLH, such as soluble PD-L1, and pathways, such as the syntaxin pathway, and variants in immune genes in these individuals, suggest critical roles for the immune response in driving sHLH in the context of COVID-19.
- Published
- 2024
- Full Text
- View/download PDF
5. Acute kidney injury genetic risks: taking it 1 SNP at a time.
- Author
-
Himmelfarb J, Stanaway IB, and Bhatraju PK
- Subjects
- Humans, Risk Factors, Phenotype, Risk Assessment, Acute Kidney Injury genetics, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease
- Abstract
This commentary addresses some of the strengths, shortcomings, and challenges of the genome-wide association study of acute kidney injury (AKI) report in this issue. This AKI genome-wide association study is well executed and provides significant progress in finding 2 genome-wide significant loci. However, significant interpretive challenges remain, where advancements in methods are needed because of the clinical heterogeneity of the AKI phenotype, plus possible bias due to genetic correlation between index hospitalization risk and AKI risk., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
6. Genetic predictors of blood pressure traits are associated with preeclampsia.
- Author
-
Jasper EA, Hellwege JN, Breeyear JH, Xiao B, Jarvik GP, Stanaway IB, Leppig KA, Chittoor G, Hayes MG, Dikilitas O, Kullo IJ, Holm IA, Verma SS, Edwards TL, and Velez Edwards DR
- Subjects
- Humans, Female, Pregnancy, Adult, Genetic Predisposition to Disease, Multifactorial Inheritance, White People genetics, Polymorphism, Single Nucleotide, Pre-Eclampsia genetics, Blood Pressure genetics
- Abstract
Preeclampsia, a pregnancy complication characterized by hypertension after 20 gestational weeks, is a major cause of maternal and neonatal morbidity and mortality. Mechanisms leading to preeclampsia are unclear; however, there is evidence of high heritability. We evaluated the association of polygenic scores (PGS) for blood pressure traits and preeclampsia to assess whether there is shared genetic architecture. Non-Hispanic Black and White reproductive age females with pregnancy indications and genotypes were obtained from Vanderbilt University's BioVU, Electronic Medical Records and Genomics network, and Penn Medicine Biobank. Preeclampsia was defined by ICD codes. Summary statistics for diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) PGS were acquired from Giri et al. Associations between preeclampsia and each PGS were evaluated separately by race and data source before subsequent meta-analysis. Ten-fold cross validation was used for prediction modeling. In 3504 Black and 5009 White included individuals, the rate of preeclampsia was 15.49%. In cross-ancestry meta-analysis, all PGSs were associated with preeclampsia (OR
DBP = 1.10, 95% CI 1.02-1.17, p = 7.68 × 10-3 ; ORSBP = 1.16, 95% CI 1.09-1.23, p = 2.23 × 10-6 ; ORPP = 1.14, 95% CI 1.07-1.27, p = 9.86 × 10-5 ). Addition of PGSs to clinical prediction models did not improve predictive performance. Genetic factors contributing to blood pressure regulation in the general population also predispose to preeclampsia., (© 2024. The Author(s).)- Published
- 2024
- Full Text
- View/download PDF
7. No evidence for causal effects of C-reactive protein (CRP) on chronic pain conditions: a Mendelian randomization study.
- Author
-
Suri P, Tsepilov YA, Elgaeva EE, Williams FMK, Freidin MB, and Stanaway IB
- Abstract
Objective: We conducted a Mendelian randomization (MR) study to examine causal associations of C-reactive protein (CRP) with (1) spinal pain; (2) extent of multisite chronic pain; and (3) chronic widespread musculoskeletal pain., Design: Two-sample MR study., Setting/subjects: We used summary statistics from publicly available genome-wide association studies (GWAS) conducted in multiple cohorts and biobanks. Genetic instrumental variables were taken from an exposure GWAS of CRP (n=204,402). Outcome GWASs examined spinal pain (n=1,028,947), extent of multisite chronic pain defined as the number of locations with chronic pain (n=387,649), and chronic widespread pain (n=249,843)., Methods: We examined MR evidence for causal associations using inverse-variance weighted (IVW) analysis and sensitivity analyses using other methods. We calculated odds ratios (ORs), 95% confidence intervals (95% CIs), and p-values, using a Bonferroni correction (p<0.0166) to account for 3 primary comparisons., Results: Greater serum CRP (mg/L) was not significantly causally associated with spinal pain (OR=1.04, 95% CI 1.00-1.08; p=0.07) in IVW analysis. Greater serum CRP also showed no significant causal association with extent of multisite chronic pain in IVW analysis (beta coefficient= 0.014, standard error=0.011; p=0.19). CRP also showed no significant causal association with chronic widespread pain in IVW analysis (OR=1.00, 95% CI 1.00-1.00; p=0.75). All secondary and sensitivity analyses also showed no significant associations., Conclusions: This MR study found no causal association of CRP on spinal pain, the extent of chronic pain, or chronic widespread pain. Future studies examining mechanistic biomarkers for pain conditions should consider other candidates besides CRP., Competing Interests: Potential Conflicts of Interest: None of the authors has potential conflicts of interest to report.
- Published
- 2024
- Full Text
- View/download PDF
8. PD-L1 and PD-1 Are Associated with Clinical Outcomes and Alveolar Immune Cell Activation in ARDS.
- Author
-
Morrell ED, Holton SE, Wiedeman A, Kosamo S, Mitchem MA, Dmyterko V, Franklin Z, Garay A, Stanaway IB, Liu T, Sathe NA, Mabrey FL, Stapleton RD, Malhotra U, Speake C, Hamerman JA, Pipavath S, Evans L, Bhatraju PK, Long SA, Wurfel MM, and Mikacenic C
- Abstract
The relationship between the Programmed Death-Ligand 1 (PD-L1)/Programmed Death-1 (PD-1) pathway, lung inflammation, and clinical outcomes in acute respiratory distress syndrome (ARDS) is poorly understood. We sought to determine whether PD-L1/PD-1 in the lung or blood is associated with ARDS and associated severity. We measured soluble PD-L1 (sPD-L1) in plasma and lower respiratory tract samples (ARDS1 (n = 59) and ARDS2 (n = 78)) or plasma samples alone (ARDS3 (n = 149)) collected from subjects with ARDS and tested for associations with mortality using multiple regression. We used mass cytometry to measure PD-L1/PD-1 expression and intracellular cytokine staining in cells isolated from bronchoalveolar lavage fluid (BALF) (n = 18) and blood (n = 16) from critically-ill subjects with or without ARDS enrolled from a fourth cohort. Higher plasma levels of sPD-L1 were associated with mortality in ARDS1, ARDS2, and ARDS3. In contrast, higher levels of sPD-L1 in the lung were either not associated with mortality (ARDS2) or were associated with survival (ARDS1). Alveolar PD-1
POS T cells had more intracellular cytokine staining compared with PD-1NEG T cells. Subjects without ARDS had a higher ratio of PD-L1POS alveolar macrophages to PD-1POS T cells compared with subjects with ARDS. We conclude that sPD-L1 may have divergent cellular sources and/or functions in the alveolar vs. blood compartments given distinct associations with mortality. Alveolar leukocyte subsets defined by PD-L1/PD-1 cell-surface expression have distinct cytokine secretion profiles, and the relative proportions of these subsets are associated with ARDS.- Published
- 2024
- Full Text
- View/download PDF
9. Acute Kidney Injury, Systemic Inflammation, and Long-Term Cognitive Function: ASSESS-AKI.
- Author
-
Bhatraju PK, Zelnick LR, Stanaway IB, Ikizler TA, Menez S, Chinchilli VM, Coca SG, Kaufman JS, Kimmel PL, Parikh CR, Go AS, Siew ED, Wurfel MM, and Himmelfarb J
- Subjects
- Humans, Biomarkers blood, Cognitive Dysfunction etiology, Cognitive Dysfunction diagnosis, Cognitive Dysfunction psychology, Time Factors, Acute Kidney Injury diagnosis, Acute Kidney Injury physiopathology, Acute Kidney Injury therapy, Cognition, Inflammation
- Published
- 2024
- Full Text
- View/download PDF
10. Interferon-γ induces combined pyroptotic angiopathy and APOL1 expression in human kidney disease.
- Author
-
Juliar BA, Stanaway IB, Sano F, Fu H, Smith KD, Akilesh S, Scales SJ, El Saghir J, Bhatraju PK, Liu E, Yang J, Lin J, Eddy S, Kretzler M, Zheng Y, Himmelfarb J, Harder JL, and Freedman BS
- Subjects
- Humans, COVID-19 metabolism, COVID-19 pathology, COVID-19 genetics, Endothelial Cells metabolism, Endothelial Cells pathology, Kidney metabolism, Kidney pathology, SARS-CoV-2 metabolism, Signal Transduction, Apolipoprotein L1 metabolism, Apolipoprotein L1 genetics, Interferon-gamma metabolism, Kidney Diseases metabolism, Kidney Diseases pathology, Kidney Diseases genetics, Pyroptosis genetics
- Abstract
Elevated interferon (IFN) signaling is associated with kidney diseases including COVID-19, HIV, and apolipoprotein-L1 (APOL1) nephropathy, but whether IFNs directly contribute to nephrotoxicity remains unclear. Using human kidney organoids, primary endothelial cells, and patient samples, we demonstrate that IFN-γ induces pyroptotic angiopathy in combination with APOL1 expression. Single-cell RNA sequencing, immunoblotting, and quantitative fluorescence-based assays reveal that IFN-γ-mediated expression of APOL1 is accompanied by pyroptotic endothelial network degradation in organoids. Pharmacological blockade of IFN-γ signaling inhibits APOL1 expression, prevents upregulation of pyroptosis-associated genes, and rescues vascular networks. Multiomic analyses in patients with COVID-19, proteinuric kidney disease, and collapsing glomerulopathy similarly demonstrate increased IFN signaling and pyroptosis-associated gene expression correlating with accelerated renal disease progression. Our results reveal that IFN-γ signaling simultaneously induces endothelial injury and primes renal cells for pyroptosis, suggesting a combinatorial mechanism for APOL1-mediated collapsing glomerulopathy, which can be targeted therapeutically., Competing Interests: Declaration of interests B.S.F. is an inventor on patents and/or patent applications related to human kidney organoid differentiation and modeling of disease in this system (these include “Three-dimensional differentiation of epiblast spheroids into kidney tubular organoids modeling human microphysiology, toxicology, and morphogenesis” [Japan, US, and Australia], licensed to STEMCELL Technologies; “High-throughput automation of organoids for identifying therapeutic strategies” [PTC patent application pending]; and “Systems and methods for characterizing pathophysiology” [PTC patent application pending]). B.S.F. and H.F. hold ownership interest in Plurexa, LLC. None of the preceding interests affected in any way the results of the paper or would be affected by them but are shared by way of transparency., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
11. Identification of prognostic biomarkers for antibiotic associated nephrotoxicity in cystic fibrosis.
- Author
-
Hart A, Cesar F, Zelnick LR, O'Connor N, Bailey Z, Lo J, Van Ness K, Stanaway IB, Bammler TK, MacDonald JW, Thau MR, Himmelfarb J, Goss CH, Aitken M, Kelly EJ, and Bhatraju PK
- Subjects
- Humans, Male, Female, Prognosis, Kidney Tubules, Proximal drug effects, Kidney Tubules, Proximal metabolism, Adult, fas Receptor, Aminoglycosides adverse effects, Prospective Studies, Acute Kidney Injury chemically induced, Acute Kidney Injury diagnosis, Cystic Fibrosis drug therapy, Anti-Bacterial Agents adverse effects, Biomarkers urine
- Abstract
Background: Our objective was to discover novel urinary biomarkers of antibiotic-associated nephrotoxicity using an ex-vivo human microphysiological system (MPS) and to translate these findings to a prospectively enrolled cystic fibrosis (CF) population receiving aminoglycosides and/or polymyxin E (colistin) for a pulmonary exacerbation., Methods: We populated the MPS with primary human kidney proximal tubule epithelial cells (PTECs) from three donors and modeled nephrotoxin injury through exposure to 50 µg/mL polymyxin E for 72 h. We analyzed gene transcriptional responses by RNAseq and tested MPS effluents. We translated candidate biomarkers to a CF cohort via analysis of urine collected prior to, during and two weeks after antibiotics and patients were followed for a median of 3 years after antibiotic use., Results: Polymyxin E treatment resulted in a statistically significant increase in the pro-apoptotic Fas gene relative to control in RNAseq of MPS: fold-change = 1.63, FDR q-value = 7.29 × 10
-5 . Effluent analysis demonstrated an acute rise of soluble Fas (sFas) concentrations that correlated with cellular injury. In 16 patients with CF, urinary sFas concentrations were significantly elevated during antibiotic treatment, regardless of development of AKI. Over a median of three years of follow up, we identified seven cases of incident chronic kidney disease (CKD). Urinary sFas concentrations during antibiotic treatment were significantly associated with subsequent development of incident CKD (unadjusted relative risk = 2.02 per doubling of urinary sFas, 95 % CI = 1.40, 2.90, p < 0.001)., Conclusions: Using an ex-vivo MPS, we identified a novel biomarker of proximal tubule epithelial cell injury, sFas, and translated these findings to a clinical cohort of patients with CF., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest for the research work submitted., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
12. Mitochondrial N-formyl methionine peptides contribute to exaggerated neutrophil activation in patients with COVID-19.
- Author
-
Kuley R, Duvvuri B, Wallin JJ, Bui N, Adona MV, O'Connor NG, Sahi SK, Stanaway IB, Wurfel MM, Morrell ED, Liles WC, Bhatraju PK, and Lood C
- Subjects
- Humans, Neutrophil Activation, Peptides, N-Formylmethionine pharmacology, Racemethionine, Neutrophils, Leukocyte L1 Antigen Complex, Methionine, COVID-19
- Abstract
Neutrophil dysregulation is well established in COVID-19. However, factors contributing to neutrophil activation in COVID-19 are not clear. We assessed if N-formyl methionine (fMet) contributes to neutrophil activation in COVID-19. Elevated levels of calprotectin, neutrophil extracellular traps (NETs) and fMet were observed in COVID-19 patients ( n = 68), particularly in critically ill patients, as compared to HC ( n = 19, p < 0.0001). Of note, the levels of NETs were higher in ICU patients with COVID-19 than in ICU patients without COVID-19 ( p < 0.05), suggesting a prominent contribution of NETs in COVID-19. Additionally, plasma from COVID-19 patients with mild and moderate/severe symptoms induced in vitro neutrophil activation through fMet/FPR1 (formyl peptide receptor-1) dependent mechanisms ( p < 0.0001). fMet levels correlated with calprotectin levels validating fMet-mediated neutrophil activation in COVID-19 patients ( r = 0.60, p = 0.0007). Our data indicate that fMet is an important factor contributing to neutrophil activation in COVID-19 disease and may represent a potential target for therapeutic intervention.
- Published
- 2023
- Full Text
- View/download PDF
13. Genome-wide association study of susceptibility to hospitalised respiratory infections.
- Author
-
Williams AT, Shrine N, Naghra-van Gijzel H, Betts JC, Chen J, Hessel EM, John C, Packer R, Reeve NF, Yeo AJ, Abner E, Åsvold BO, Auvinen J, Bartz TM, Bradford Y, Brumpton B, Campbell A, Cho MH, Chu S, Crosslin DR, Feng Q, Esko T, Gharib SA, Hayward C, Hebbring S, Hveem K, Järvelin MR, Jarvik GP, Landis SH, Larson EB, Liu J, Loos RJF, Luo Y, Moscati A, Mullerova H, Namjou B, Porteous DJ, Quint JK, Ritchie MD, Sliz E, Stanaway IB, Thomas L, Wilson JF, Hall IP, Wain LV, Michalovich D, and Tobin MD
- Abstract
Background : Globally, respiratory infections contribute to significant morbidity and mortality. However, genetic determinants of respiratory infections are understudied and remain poorly understood. Methods : We conducted a genome-wide association study in 19,459 hospitalised respiratory infection cases and 101,438 controls from UK Biobank (Stage 1). We followed-up well-imputed top signals from our Stage 1 analysis in 50,912 respiratory infection cases and 150,442 controls from 11 cohorts (Stage 2). We aggregated effect estimates across studies using inverse variance-weighted meta-analyses. Additionally, we investigated the function of the top signals in order to gain understanding of the underlying biological mechanisms. Results : From our Stage 1 analysis, we report 56 signals at P <5×10
-6 , one of which was genome-wide significant ( P <5×10-8 ). The genome-wide significant signal was in an intron of PBX3 , a gene that encodes pre-B-cell leukaemia transcription factor 3, a homeodomain-containing transcription factor. Further, the genome-wide significant signal was found to colocalise with gene-specific expression quantitative trait loci (eQTLs) affecting expression of PBX3 in lung tissue, where the respiratory infection risk alleles were associated with decreased PBX3 expression in lung tissue, highlighting a possible biological mechanism. Of the 56 signals, 40 were well-imputed in UK Biobank and were investigated in Stage 2. None of the 40 signals replicated, with effect estimates attenuated. Conclusions : Our Stage 1 analysis implicated PBX3 as a candidate causal gene and suggests a possible role of transcription factor binding activity in respiratory infection susceptibility. However, the PBX3 signal, and the other well-imputed signals, did not replicate in the meta-analysis of Stages 1 and 2. Significant phenotypic heterogeneity and differences in study ascertainment may have contributed to this lack of statistical replication. Overall, our study highlighted putative associations and possible biological mechanisms that may provide insight into respiratory infection susceptibility., Competing Interests: Competing interests: IPH has funded research collaborations with GSK, Boehringer Ingelheim and Orion. LVW and MDT receive funding from GSK for a collaborative research project outside of the submitted work. JCB, AJY and HNG are employees of GSK and may own company stock. At the time of this study, DM, SHL, HM and EMH were employees of GSK and may own company stock. MHC has received grant support from GSK and Bayer, consulting or speaking fees from Genentech, AstraZeneca, and Illumina, outside of the submitted work., (Copyright: © 2023 Williams AT et al.)- Published
- 2023
- Full Text
- View/download PDF
14. Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies.
- Author
-
Thau MR, Liu T, Sathe NA, O'Keefe GE, Robinson BRH, Bulger E, Wade CE, Fox EE, Holcomb JB, Liles WC, Stanaway IB, Mikacenic C, Wurfel MM, Bhatraju PK, and Morrell ED
- Subjects
- Humans, Male, Adult, Blood Transfusion, Resuscitation methods, Injury Severity Score, Hemostatics, Shock, Hemorrhagic therapy
- Abstract
Importance: It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies., Objective: To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies., Design, Setting, and Participants: This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022., Exposures: TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival., Main Outcomes and Measures: An association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS., Results: A total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001)., Conclusions and Relevance: Results of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.
- Published
- 2023
- Full Text
- View/download PDF
15. Genome-wide Association Study for AKI.
- Author
-
Bhatraju PK, Stanaway IB, Palmer MR, Menon R, Schaub JA, Menez S, Srivastava A, Wilson FP, Kiryluk K, Palevsky PM, Naik AS, Sakr SS, Jarvik GP, Parikh CR, Ware LB, Ikizler TA, Siew ED, Chinchilli VM, Coca SG, Garg AX, Go AS, Kaufman JS, Kimmel PL, Himmelfarb J, and Wurfel MM
- Subjects
- Humans, Genome-Wide Association Study, Acute Kidney Injury diagnosis, Acute Kidney Injury genetics
- Published
- 2023
- Full Text
- View/download PDF
16. Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.
- Author
-
Bitto A, Grillo AS, Ito TK, Stanaway IB, Nguyen BMG, Ying K, Tung H, Smith K, Tran N, Velikanje G, Urfer SR, Snyder JM, Barton J, Sharma A, Kayser EB, Wang L, Smith DL Jr, Thompson JW, DuBois L, DePaolo W, and Kaeberlein M
- Subjects
- Mice, Animals, Acarbose pharmacology, Acarbose therapeutic use, Mitochondria genetics, Sirolimus pharmacology, Sirolimus therapeutic use, Disease Models, Animal, Electron Transport Complex I, Leigh Disease drug therapy, Leigh Disease genetics, Mitochondrial Diseases drug therapy
- Abstract
Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during normative ageing, also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh syndrome. The Ndufs4 knockout (Ndufs4
-/- ) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh syndrome. Here we show that another drug that extends lifespan and delays normative ageing in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of inhibition of the mechanistic target of rapamycin. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short-chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression, while depletion of the endogenous microbiome in Ndufs4-/- mice appears to fully recapitulate the effects of acarbose on healthspan and lifespan in these animals. To our knowledge, this study provides the first evidence that alteration of the gut microbiome plays a significant role in severe mitochondrial disease and provides further support for the model that biological ageing and severe mitochondrial disorders share underlying common mechanisms., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2023
- Full Text
- View/download PDF
17. Alteration of oral microbiome composition in children living with pesticide-exposed farm workers.
- Author
-
Stanaway IB, Wallace JC, Hong S, Wilder CS, Green FH, Tsai J, Knight M, Workman T, Vigoren EM, Smith MN, Griffith WC, Thompson B, Shojaie A, and Faustman EM
- Subjects
- Adult, Humans, Child, Farmers, Azinphosmethyl analysis, RNA, Ribosomal, 16S, Agriculture, Pesticides analysis, Occupational Exposure analysis, Microbiota
- Abstract
Our prior work shows that azinphos-methyl pesticide exposure is associated with altered oral microbiomes in exposed farmworkers. Here we extend this analysis to show the same association pattern is also evident in their children. Oral buccal swab samples were analyzed at two time points, the apple thinning season in spring-summer 2005 for 78 children and 101 adults and the non-spray season in winter 2006 for 62 children and 82 adults. The pesticide exposure for the children were defined by the farmworker occupation of the cohabitating household adult and the blood azinphos-methyl detection of the cohabitating adult. Oral buccal swab 16S rRNA sequencing determined taxonomic microbiota proportional composition from concurrent samples from both adults and children. Analysis of the identified bacteria showed significant proportional changes for 12 of 23 common oral microbiome genera in association with azinphos-methyl detection and farmworker occupation. The most common significantly altered genera had reductions in the abundance of Streptococcus, suggesting an anti-microbial effect of the pesticide. Principal component analysis of the microbiome identified two primary clusters, with association of principal component 1 to azinphos-methyl blood detection and farmworker occupational status of the household. The children's buccal microbiota composition clustered with their household adult in ∼95% of the households. Household adult farmworker occupation and household pesticide exposure is associated with significant alterations in their children's oral microbiome composition. This suggests that parental occupational exposure and pesticide take-home exposure pathways elicit alteration of their children's microbiomes., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier GmbH. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
18. Genetic Predictors of Blood Pressure Traits are Associated with Preeclampsia.
- Author
-
Jasper EA, Hellwege JN, Breeyear JH, Xiao B, Jarvik GP, Stanaway IB, Leppig KA, Chittoor G, Hayes MG, Dikilitas O, Kullo IJ, Holm IA, Verma SS, Edwards TL, and Velez Edwards DR
- Abstract
Background: Preeclampsia, a pregnancy complication characterized by hypertension after 20 gestational weeks, is a major cause of maternal and neonatal morbidity and mortality. The mechanisms leading to preeclampsia are unclear; however, there is evidence that preeclampsia is highly heritable. We evaluated the association of polygenic risk scores (PRS) for blood pressure traits and preeclampsia to assess whether there is shared genetic architecture., Methods: Participants were obtained from Vanderbilt University's BioVU, the Electronic Medical Records and Genomics network, and the Penn Medicine Biobank. Non-Hispanic Black and White females of reproductive age with indications of pregnancy and genotype information were included. Preeclampsia was defined by ICD codes. Summary statistics for diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse pressure (PP) PRS were obtained from Giri et al 2019. Associations between preeclampsia and each PRS were evaluated separately by race and study population before evidence was meta-analyzed. Prediction models were developed and evaluated using 10-fold cross validation., Results: In the 3,504 Black and 5,009 White individuals included, the rate of preeclampsia was 15.49%. The DBP and SBP PRSs were associated with preeclampsia in Whites but not Blacks. The PP PRS was significantly associated with preeclampsia in Blacks and Whites. In trans-ancestry meta-analysis, all PRSs were associated with preeclampsia (OR
DBP =1.10, 95% CI=1.02-1.17, p =7.68×10-3 ; ORSBP =1.16, 95% CI=1.09-1.23, p =2.23×10-6 ; ORPP =1.14, 95% CI=1.07-1.27, p =9.86×10-5 ). However, addition of PRSs to clinical prediction models did not improve predictive performance., Conclusions: Genetic factors contributing to blood pressure regulation in the general population also predispose to preeclampsia.- Published
- 2023
- Full Text
- View/download PDF
19. Author Correction: Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits.
- Author
-
Liu L, Khan A, Sanchez-Rodriguez E, Zanoni F, Li Y, Steers N, Balderes O, Zhang J, Krithivasan P, LeDesma RA, Fischman C, Hebbring SJ, Harley JB, Moncrieffe H, Kottyan LC, Namjou-Khales B, Walunas TL, Knevel R, Raychaudhuri S, Karlson EW, Denny JC, Stanaway IB, Crosslin D, Rauen T, Floege J, Eitner F, Moldoveanu Z, Reily C, Knoppova B, Hall S, Sheff JT, Julian BA, Wyatt RJ, Suzuki H, Xie J, Chen N, Zhou X, Zhang H, Hammarström L, Viktorin A, Magnusson PKE, Shang N, Hripcsak G, Weng C, Rundek T, Elkind MSV, Oelsner EC, Barr RG, Ionita-Laza I, Novak J, Gharavi AG, and Kiryluk K
- Published
- 2023
- Full Text
- View/download PDF
20. Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity.
- Author
-
Bhatraju PK, Morrell ED, Stanaway IB, Sathe NA, Srivastava A, Postelnicu R, Green R, Andrews A, Gonzalez M, Kratochvil CJ, Kumar VK, Hsiang TY, Gale M Jr, Anesi GL, Wyles D, Broadhurst MJ, Brett-Major D, Mukherjee V, Sevransky JE, Landsittel D, Hung C, Altemeier WA, Gharib SA, Uyeki TM, Cobb JP, Liebler JM, Crosslin DR, Jarvik GP, Segal LN, Evans L, Mikacenic C, and Wurfel MM
- Abstract
Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak., Objectives: To assess the role of ANGPTL4 in COVID-19-related outcomes., Design Setting and Participants: Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University., Main Outcomes and Measures: Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4., Results: Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log
2 increase, 1.53; 95% CI, 1.17-2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors ( p for interaction = 8.1 × 10-5 ). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls., Conclusions and Relevance: ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)- Published
- 2022
- Full Text
- View/download PDF
21. Quantifying the phenome-wide disease burden of obesity using electronic health records and genomics.
- Author
-
Robinson JR, Carroll RJ, Bastarache L, Chen Q, Pirruccello J, Mou Z, Wei WQ, Connolly J, Mentch F, Crane PK, Hebbring SJ, Crosslin DR, Gordon AS, Rosenthal EA, Stanaway IB, Hayes MG, Wei W, Petukhova L, Namjou-Khales B, Zhang G, Safarova MS, Walton NA, Still C, Bottinger EP, Loos RJF, Murphy SN, Jackson GP, Abumrad N, Kullo IJ, Jarvik GP, Larson EB, Weng C, Roden D, Khera AV, and Denny JC
- Subjects
- Humans, Electronic Health Records, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Genomics, Genetic Predisposition to Disease, Obesity epidemiology, Obesity genetics, Phenotype, Cost of Illness, Phenomics, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 genetics
- Abstract
Objective: High BMI is associated with many comorbidities and mortality. This study aimed to elucidate the overall clinical risk of obesity using a genome- and phenome-wide approach., Methods: This study performed a phenome-wide association study of BMI using a clinical cohort of 736,726 adults. This was followed by genetic association studies using two separate cohorts: one consisting of 65,174 adults in the Electronic Medical Records and Genomics (eMERGE) Network and another with 405,432 participants in the UK Biobank., Results: Class 3 obesity was associated with 433 phenotypes, representing 59.3% of all billing codes in individuals with severe obesity. A genome-wide polygenic risk score for BMI, accounting for 7.5% of variance in BMI, was associated with 296 clinical diseases, including strong associations with type 2 diabetes, sleep apnea, hypertension, and chronic liver disease. In all three cohorts, 199 phenotypes were associated with class 3 obesity and polygenic risk for obesity, including novel associations such as increased risk of renal failure, venous insufficiency, and gastroesophageal reflux., Conclusions: This combined genomic and phenomic systematic approach demonstrated that obesity has a strong genetic predisposition and is associated with a considerable burden of disease across all disease classes., (© 2022 The Obesity Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)
- Published
- 2022
- Full Text
- View/download PDF
22. Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits.
- Author
-
Liu L, Khan A, Sanchez-Rodriguez E, Zanoni F, Li Y, Steers N, Balderes O, Zhang J, Krithivasan P, LeDesma RA, Fischman C, Hebbring SJ, Harley JB, Moncrieffe H, Kottyan LC, Namjou-Khales B, Walunas TL, Knevel R, Raychaudhuri S, Karlson EW, Denny JC, Stanaway IB, Crosslin D, Rauen T, Floege J, Eitner F, Moldoveanu Z, Reily C, Knoppova B, Hall S, Sheff JT, Julian BA, Wyatt RJ, Suzuki H, Xie J, Chen N, Zhou X, Zhang H, Hammarström L, Viktorin A, Magnusson PKE, Shang N, Hripcsak G, Weng C, Rundek T, Elkind MSV, Oelsner EC, Barr RG, Ionita-Laza I, Novak J, Gharavi AG, and Kiryluk K
- Subjects
- Humans, Mice, Animals, Genome-Wide Association Study, Genetic Predisposition to Disease, Immunoglobulin A genetics, Kidney metabolism, Glomerulonephritis, IGA genetics, Glomerulonephritis, IGA complications, Celiac Disease genetics, Diabetes Mellitus, Type 2 complications, Inflammatory Bowel Diseases
- Abstract
Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individuals of diverse ancestries and identified 20 genome-wide significant loci, including 9 known and 11 novel loci. Co-localization analyses with expression QTLs prioritized candidate genes for 14 of 20 significant loci. Most loci encoded genes that produced immune defects and IgA abnormalities when genetically manipulated in mice. We also observed positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease, and several infections. Mendelian randomization supported elevated serum IgA as a causal factor in IgA nephropathy. African ancestry was consistently associated with higher serum IgA levels and greater frequency of IgA-increasing alleles compared to other ancestries. Our findings provide novel insights into the genetic regulation of IgA levels and its potential role in human disease., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
23. Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.
- Author
-
Tcheandjieu C, Zhu X, Hilliard AT, Clarke SL, Napolioni V, Ma S, Lee KM, Fang H, Chen F, Lu Y, Tsao NL, Raghavan S, Koyama S, Gorman BR, Vujkovic M, Klarin D, Levin MG, Sinnott-Armstrong N, Wojcik GL, Plomondon ME, Maddox TM, Waldo SW, Bick AG, Pyarajan S, Huang J, Song R, Ho YL, Buyske S, Kooperberg C, Haessler J, Loos RJF, Do R, Verbanck M, Chaudhary K, North KE, Avery CL, Graff M, Haiman CA, Le Marchand L, Wilkens LR, Bis JC, Leonard H, Shen B, Lange LA, Giri A, Dikilitas O, Kullo IJ, Stanaway IB, Jarvik GP, Gordon AS, Hebbring S, Namjou B, Kaufman KM, Ito K, Ishigaki K, Kamatani Y, Verma SS, Ritchie MD, Kember RL, Baras A, Lotta LA, Kathiresan S, Hauser ER, Miller DR, Lee JS, Saleheen D, Reaven PD, Cho K, Gaziano JM, Natarajan P, Huffman JE, Voight BF, Rader DJ, Chang KM, Lynch JA, Damrauer SM, Wilson PWF, Tang H, Sun YV, Tsao PS, O'Donnell CJ, and Assimes TL
- Subjects
- Genetic Predisposition to Disease genetics, Humans, Polymorphism, Single Nucleotide genetics, Risk Factors, Coronary Artery Disease genetics, Genome-Wide Association Study
- Abstract
We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2022
- Full Text
- View/download PDF
24. Large-scale genomic analyses reveal insights into pleiotropy across circulatory system diseases and nervous system disorders.
- Author
-
Zhang X, Lucas AM, Veturi Y, Drivas TG, Bone WP, Verma A, Chung WK, Crosslin D, Denny JC, Hebbring S, Jarvik GP, Kullo I, Larson EB, Rasmussen-Torvik LJ, Schaid DJ, Smoller JW, Stanaway IB, Wei WQ, Weng C, and Ritchie MD
- Subjects
- Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Cardiovascular Diseases genetics, Nervous System Diseases genetics
- Abstract
Clinical and epidemiological studies have shown that circulatory system diseases and nervous system disorders often co-occur in patients. However, genetic susceptibility factors shared between these disease categories remain largely unknown. Here, we characterized pleiotropy across 107 circulatory system and 40 nervous system traits using an ensemble of methods in the eMERGE Network and UK Biobank. Using a formal test of pleiotropy, five genomic loci demonstrated statistically significant evidence of pleiotropy. We observed region-specific patterns of direction of genetic effects for the two disease categories, suggesting potential antagonistic and synergistic pleiotropy. Our findings provide insights into the relationship between circulatory system diseases and nervous system disorders which can provide context for future prevention and treatment strategies., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
25. Mendelian randomization analysis of plasma levels of CD209 and MICB proteins and the risk of varicose veins of lower extremities.
- Author
-
Shadrina AS, Elgaeva EE, Stanaway IB, Jarvik GP, Namjou B, Wei WQ, Glessner J, Hakonarson H, Suri P, and Tsepilov YA
- Subjects
- Genome-Wide Association Study, Humans, Lower Extremity pathology, Polymorphism, Single Nucleotide, Mendelian Randomization Analysis, Varicose Veins genetics, Varicose Veins pathology
- Abstract
Varicose veins of lower extremities (VVs) are a highly prevalent condition, the pathogenesis of which is still not fully elucidated. Mendelian randomization (MR) can provide useful preliminary information on the traits that are potentially causally related to the disease. The aim of the present study is to replicate the effects of the plasma levels of MHC class I polypeptide-related sequence B (MICB) and cluster of differentiation 209 (CD209) proteins reported in a previous hypothesis-free MR study. We conducted MR analysis using a fixed effects inverse-variance weighted meta-analysis of Wald ratios method. For MICB and CD209, we used data from a large-scale genome-wide association study (GWAS) for plasma protein levels (N = 3,301). For VVs, we used GWAS data obtained in the FinnGen project (N = 128,698), the eMERGE network (phase 3, N = 48,429), and the UK Biobank data available in the Gene ATLAS (N = 452,264). The data used in the study were obtained in individuals of European descent. The results for MICB did not pass criteria for statistical significance and replication. The results for CD209 passed all statistical significance thresholds, indicating that the genetically predicted increase in CD209 level is associated with increased risk of VVs (βMR (SE) = 0.07 (0.01), OR (95% CI) = 1.08 (1.05-1.10), P-value = 5.9 ×10-11 in the meta-analysis of three cohorts). Our findings provide further support that CD209 can potentially be involved in VVs. In future studies, independent validation of our results using data from more powerful GWASs for CD209 measured by different methods would be beneficial., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
- Full Text
- View/download PDF
26. Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach.
- Author
-
Feng YA, Stanaway IB, Connolly JJ, Denny JC, Luo Y, Weng C, Wei WQ, Weiss ST, Karlson EW, and Smoller JW
- Subjects
- Genetic Variation, Genomics methods, Humans, Mutation, Phenotype, Exome, Genetic Testing methods
- Abstract
Background: As genomic sequencing moves closer to clinical implementation, there has been an increasing acceptance of returning incidental findings to research participants and patients for mutations in highly penetrant, medically actionable genes. A curated list of genes has been recommended by the American College of Medical Genetics and Genomics (ACMG) for return of incidental findings. However, the pleiotropic effects of these genes are not fully known. Such effects could complicate genetic counseling when returning incidental findings. In particular, there has been no systematic evaluation of psychiatric manifestations associated with rare variation in these genes., Results: Here, we leveraged a targeted sequence panel and real-world electronic health records from the eMERGE network to assess the burden of rare variation in the ACMG-56 genes and two psychiatric-associated genes (CACNA1C and TCF4) across common mental health conditions in 15,181 individuals of European descent. As a positive control, we showed that this approach replicated the established association between rare mutations in LDLR and hypercholesterolemia with no visible inflation from population stratification. However, we did not identify any genes significantly enriched with rare deleterious variants that confer risk for common psychiatric disorders after correction for multiple testing. Suggestive associations were observed between depression and rare coding variation in PTEN (P = 1.5 × 10
-4 ), LDLR (P = 3.6 × 10-4 ), and CACNA1S (P = 5.8 × 10-4 ). We also observed nominal associations between rare variants in KCNQ1 and substance use disorders (P = 2.4 × 10-4 ), and APOB and tobacco use disorder (P = 1.1 × 10-3 )., Conclusions: Our results do not support an association between psychiatric disorders and incidental findings in medically actionable gene mutations, but power was limited with the available sample sizes. Given the phenotypic and genetic complexity of psychiatric phenotypes, future work will require a much larger sequencing dataset to determine whether incidental findings in these genes have implications for risk of psychopathology., (© 2022. The Author(s).)- Published
- 2022
- Full Text
- View/download PDF
27. Angiopoietins as Prognostic Markers for Future Kidney Disease and Heart Failure Events after Acute Kidney Injury.
- Author
-
Mansour SG, Bhatraju PK, Coca SG, Obeid W, Wilson FP, Stanaway IB, Jia Y, Thiessen-Philbrook H, Go AS, Ikizler TA, Siew ED, Chinchilli VM, Hsu CY, Garg AX, Reeves WB, Liu KD, Kimmel PL, Kaufman JS, Wurfel MM, Himmelfarb J, Parikh SM, and Parikh CR
- Subjects
- Aged, Angiopoietins, Female, Humans, Male, Prognosis, Prospective Studies, Risk Factors, Acute Kidney Injury complications, Heart Failure complications, Renal Insufficiency, Chronic complications
- Abstract
Background: The mechanisms underlying long-term sequelae after AKI remain unclear. Vessel instability, an early response to endothelial injury, may reflect a shared mechanism and early trigger for CKD and heart failure., Methods: To investigate whether plasma angiopoietins, markers of vessel homeostasis, are associated with CKD progression and heart failure admissions after hospitalization in patients with and without AKI, we conducted a prospective cohort study to analyze the balance between angiopoietin-1 (Angpt-1), which maintains vessel stability, and angiopoietin-2 (Angpt-2), which increases vessel destabilization. Three months after discharge, we evaluated the associations between angiopoietins and development of the primary outcomes of CKD progression and heart failure and the secondary outcome of all-cause mortality 3 months after discharge or later., Results: Median age for the 1503 participants was 65.8 years; 746 (50%) had AKI. Compared with the lowest quartile, the highest quartile of the Angpt-1:Angpt-2 ratio was associated with 72% lower risk of CKD progression (adjusted hazard ratio [aHR], 0.28; 95% confidence interval [CI], 0.15 to 0.51), 94% lower risk of heart failure (aHR, 0.06; 95% CI, 0.02 to 0.15), and 82% lower risk of mortality (aHR, 0.18; 95% CI, 0.09 to 0.35) for those with AKI. Among those without AKI, the highest quartile of Angpt-1:Angpt-2 ratio was associated with 71% lower risk of heart failure (aHR, 0.29; 95% CI, 0.12 to 0.69) and 68% less mortality (aHR, 0.32; 95% CI, 0.15 to 0.68). There were no associations with CKD progression., Conclusions: A higher Angpt-1:Angpt-2 ratio was strongly associated with less CKD progression, heart failure, and mortality in the setting of AKI., (Copyright © 2022 by the American Society of Nephrology.)
- Published
- 2022
- Full Text
- View/download PDF
28. Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations.
- Author
-
Helms L, Marchiano S, Stanaway IB, Hsiang TY, Juliar BA, Saini S, Zhao YT, Khanna A, Menon R, Alakwaa F, Mikacenic C, Morrell ED, Wurfel MM, Kretzler M, Harder JL, Murry CE, Himmelfarb J, Ruohola-Baker H, Bhatraju PK, Gale M Jr, and Freedman BS
- Subjects
- Acute Kidney Injury etiology, Adult, Aged, Angiotensin-Converting Enzyme 2 genetics, Animals, Apoptosis, Bowman Capsule cytology, Bowman Capsule virology, COVID-19 complications, Chlorocebus aethiops, Female, Gene Knockout Techniques, Hospital Mortality, Hospitalization, Humans, Kidney metabolism, Kidney pathology, Kidney Tubules, Proximal metabolism, Kidney Tubules, Proximal pathology, Male, Middle Aged, Organoids metabolism, Podocytes virology, Polycystic Kidney Diseases, Protein Kinase D2 genetics, Proteome, Receptors, Coronavirus genetics, Reproducibility of Results, Transcriptome, Vero Cells, Viral Tropism, Virus Replication, Acute Kidney Injury urine, COVID-19 urine, Kidney virology, Kidney Tubules, Proximal virology, Organoids virology, SARS-CoV-2 pathogenicity
- Abstract
Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo-designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies.
- Published
- 2021
- Full Text
- View/download PDF
29. A genome-wide association study suggests correlations of common genetic variants with peritoneal solute transfer rates in patients with kidney failure receiving peritoneal dialysis.
- Author
-
Mehrotra R, Stanaway IB, Jarvik GP, Lambie M, Morelle J, Perl J, Himmelfarb J, Heimburger O, Johnson DW, Imam TH, Robinson B, Stenvinkel P, Devuyst O, and Davies SJ
- Subjects
- Creatinine, Dialysis Solutions, Genome-Wide Association Study, Humans, Peritoneum, Kidney Failure, Chronic, Peritoneal Dialysis adverse effects, Renal Insufficiency
- Abstract
Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
30. Genomic and functional characterization of a mucosal symbiont involved in early-stage colorectal cancer.
- Author
-
Kordahi MC, Stanaway IB, Avril M, Chac D, Blanc MP, Ross B, Diener C, Jain S, McCleary P, Parker A, Friedman V, Huang J, Burke W, Gibbons SM, Willis AD, Darveau RP, Grady WM, Ko CW, and DePaolo RW
- Subjects
- Aged, Bacteroides fragilis classification, Bacteroides fragilis physiology, Colonic Polyps immunology, Colonic Polyps microbiology, Colonic Polyps pathology, Colorectal Neoplasms genetics, Colorectal Neoplasms immunology, Colorectal Neoplasms pathology, Cytokines genetics, Cytokines immunology, Female, Gastrointestinal Microbiome, Genome, Bacterial, Genomics, Humans, Intestinal Mucosa immunology, Intestinal Mucosa pathology, Male, Middle Aged, Neoplasm Staging, Phylogeny, Symbiosis, Bacteroides fragilis genetics, Bacteroides fragilis isolation & purification, Colorectal Neoplasms microbiology, Intestinal Mucosa microbiology
- Abstract
Colorectal cancer is a major health concern worldwide. Growing evidence for the role of the gut microbiota in the initiation of CRC has sparked interest in approaches that target these microorganisms. However, little is known about the composition and role of the microbiota associated with precancerous polyps. Here, we found distinct microbial signatures between patients with and without polyps and between polyp subtypes using sequencing and culturing techniques. We found a correlation between Bacteroides fragilis recovered and the level of inflammatory cytokines in the mucosa adjacent to the polyp. Additional analysis revealed that B. fragilis from patients with polyps are bft-negative, activate NF-κB through Toll-like receptor 4, induce a pro-inflammatory response, and are enriched in genes associated with LPS biosynthesis. This study provides fundamental insight into the microbial microenvironment of the pre-neoplastic polyp by highlighting strain-specific genomic and proteomic differences, as well as more broad compositional differences in the microbiome., Competing Interests: Declaration of interests The authors declare the following competing interests. R.W.D. is on the advisory board of MicrobiomX. W.M.G. is on the advisory board of Guardant Health, Freenome, SEngine, and consults for Diacarta and receives research support from Jannsen and Tempus. . C.W.K. receives research support from Freenome., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
31. The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene.
- Author
-
Bagheri M, Wang C, Shi M, Manouchehri A, Murray KT, Murphy MB, Shaffer CM, Singh K, Davis LK, Jarvik GP, Stanaway IB, Hebbring S, Reilly MP, Gerszten RE, Wang TJ, Mosley JD, and Ferguson JF
- Subjects
- Humans, Animals, Mice, Male, Mice, Knockout, Female, Inflammation genetics, Inflammation blood, Cardiovascular Diseases genetics, Cardiovascular Diseases blood, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins genetics, Biomarkers blood, Middle Aged, Adult, Endotoxemia genetics, Endotoxemia blood, Kynurenine blood, Kynurenine metabolism, Polymorphism, Single Nucleotide, Adaptor Proteins, Signal Transducing genetics
- Abstract
Inflammation increases the risk of cardiometabolic disease. Delineating specific inflammatory pathways and biomarkers of their activity could identify the mechanistic underpinnings of the increased risk. Plasma levels of kynurenine, a metabolite involved in inflammation, associates with cardiometabolic disease risk. We used genetic approaches to identify inflammatory mechanisms associated with kynurenine variability and their relationship to cardiometabolic disease. We identified single-nucleotide polymorphisms (SNPs) previously associated with plasma kynurenine, including a missense-variant (rs3184504) in the inflammatory gene SH2B3/LNK. We examined the association between rs3184504 and plasma kynurenine in independent human samples, and measured kynurenine levels in SH2B3-knock-out mice and during human LPS-evoked endotoxemia. We conducted phenome scanning to identify clinical phenotypes associated with each kynurenine-related SNP and with a kynurenine polygenic score using the UK-Biobank (n = 456,422), BioVU (n = 62,303), and Electronic Medical Records and Genetics (n = 32,324) databases. The SH2B3 missense variant associated with plasma kynurenine levels and SH2B3
-/- mice had significant tissue-specific differences in kynurenine levels.LPS, an acute inflammatory stimulus, increased plasma kynurenine in humans. Mendelian randomization showed increased waist-circumference, a marker of central obesity, associated with increased kynurenine, and increased kynurenine associated with C-reactive protein (CRP). We found 30 diagnoses associated (FDR q < 0.05) with the SH2B3 variant, but not with SNPs mapping to genes known to regulate tryptophan-kynurenine metabolism. Plasma kynurenine may be a biomarker of acute and chronic inflammation involving the SH2B3 pathways. Its regulation lies upstream of CRP, suggesting that kynurenine may be a biomarker of one inflammatory mechanism contributing to increased cardiometabolic disease risk., (© 2021. The Author(s).)- Published
- 2021
- Full Text
- View/download PDF
32. Genome-wide association studies of low back pain and lumbar spinal disorders using electronic health record data identify a locus associated with lumbar spinal stenosis.
- Author
-
Suri P, Stanaway IB, Zhang Y, Freidin MB, Tsepilov YA, Carrell DS, Williams FMK, Aulchenko YS, Hakonarson H, Namjou B, Crosslin DR, Jarvik GP, and Lee MT
- Subjects
- Electronic Health Records, Genome-Wide Association Study, Humans, Lumbar Vertebrae, Prevalence, Low Back Pain genetics, Spinal Stenosis genetics
- Abstract
Abstract: Identifying genetic risk factors for lumbar spine disorders may lead to knowledge regarding underlying mechanisms and the development of new treatments. We conducted a genome-wide association study involving 100,811 participants with genotypes and longitudinal electronic health record data from the Electronic Medical Records and Genomics Network and Geisinger Health. Cases and controls were defined using validated algorithms and clinical diagnostic codes. Electronic health record-defined phenotypes included low back pain requiring healthcare utilization (LBP-HC), lumbosacral radicular syndrome (LSRS), and lumbar spinal stenosis (LSS). Genome-wide association study used logistic regression with additive genetic effects adjusting for age, sex, site-specific factors, and ancestry (principal components). A fixed-effect inverse-variance weighted meta-analysis was conducted. Genetic variants of genome-wide significance (P < 5 × 10-8) were carried forward for replication in an independent sample from UK Biobank. Phenotype prevalence was 48.8% for LBP-HC, 19.8% for LSRS, and 7.9% for LSS. No variants were significantly associated with LBP-HC. One locus was associated with LSRS (lead variant rs146153280:C>G, odds ratio [OR] = 1.17 for G, P = 2.1 × 10-9), but was not replicated. Another locus on chromosome 2 spanning GFPT1, NFU1, and AAK1 was associated with LSS (lead variant rs13427243:G>A, OR = 1.10 for A, P = 4.3 × 10-8) and replicated in UK Biobank (OR = 1.11, P = 5.4 × 10-5). This was the first genome-wide association study meta-analysis of lumbar spinal disorders using electronic health record data. We identified 2 novel associations with LSRS and LSS; the latter was replicated in an independent sample., (Copyright © 2021 International Association for the Study of Pain.)
- Published
- 2021
- Full Text
- View/download PDF
33. Medical Records-Based Genetic Studies of the Complement System.
- Author
-
Khan A, Shang N, Petukhova L, Zhang J, Shen Y, Hebbring SJ, Moncrieffe H, Kottyan LC, Namjou-Khales B, Knevel R, Raychaudhuri S, Karlson EW, Harley JB, Stanaway IB, Crosslin D, Denny JC, Elkind MSV, Gharavi AG, Hripcsak G, Weng C, and Kiryluk K
- Subjects
- Adult, Aged, Alleles, Complement Activation genetics, Databases, Genetic, Epidemiologic Studies, Female, Gene Dosage, Genetic Loci, Genome-Wide Association Study, Humans, Male, Medical Record Linkage, Middle Aged, Young Adult, Complement C3 genetics, Complement C3 metabolism, Complement C4 genetics, Complement C4 metabolism, Genetic Variation, Medical Records
- Abstract
Background: Genetic variants in complement genes have been associated with a wide range of human disease states, but well-powered genetic association studies of complement activation have not been performed in large multiethnic cohorts., Methods: We performed medical records-based genome-wide and phenome-wide association studies for plasma C3 and C4 levels among participants of the Electronic Medical Records and Genomics (eMERGE) network., Results: In a GWAS for C3 levels in 3949 individuals, we detected two genome-wide significant loci: chr.1q31.3 (CFH locus; rs3753396-A; β =0.20; 95% CI, 0.14 to 0.25; P =1.52x10
-11 ) and chr.19p13.3 (C3 locus; rs11569470-G; β =0.19; 95% CI, 0.13 to 0.24; P =1.29x10-8 ). These two loci explained approximately 2% of variance in C3 levels. GWAS for C4 levels involved 3998 individuals and revealed a genome-wide significant locus at chr.6p21.32 (C4 locus; rs3135353-C; β =0.40; 95% CI, 0.34 to 0.45; P =4.58x10-35 ). This locus explained approximately 13% of variance in C4 levels. The multiallelic copy number variant analysis defined two structural genomic C4 variants with large effect on blood C4 levels: C4-BS ( β =-0.36; 95% CI, -0.42 to -0.30; P =2.98x10-22 ) and C4-AL-BS ( β =0.25; 95% CI, 0.21 to 0.29; P =8.11x10-23 ). Overall, C4 levels were strongly correlated with copy numbers of C4A and C4B genes. In comprehensive phenome-wide association studies involving 102,138 eMERGE participants, we cataloged a full spectrum of autoimmune, cardiometabolic, and kidney diseases genetically related to systemic complement activation., Conclusions: We discovered genetic determinants of plasma C3 and C4 levels using eMERGE genomic data linked to electronic medical records. Genetic variants regulating C3 and C4 levels have large effects and multiple clinical correlations across the spectrum of complement-related diseases in humans., (Copyright © 2021 by the American Society of Nephrology.)- Published
- 2021
- Full Text
- View/download PDF
34. Penetrance of Breast Cancer Susceptibility Genes From the eMERGE III Network.
- Author
-
Fan X, Wynn J, Shang N, Liu C, Fedotov A, Hallquist MLG, Buchanan AH, Williams MS, Smith ME, Hoell C, Rasmussen-Torvik LJ, Peterson JF, Wiesner GL, Murad AM, Jarvik GP, Gordon AS, Rosenthal EA, Stanaway IB, Crosslin DR, Larson EB, Leppig KA, Henrikson NB, Williams JL, Li R, Hebbring S, Weng C, Shen Y, Crew KD, and Chung WK
- Subjects
- Adult, Ataxia Telangiectasia Mutated Proteins genetics, Breast Neoplasms diagnosis, Checkpoint Kinase 2 genetics, Confidence Intervals, Fanconi Anemia Complementation Group N Protein genetics, Female, Genes, BRCA1, Genes, BRCA2, Genes, p53, Genetic Testing, Humans, Kaplan-Meier Estimate, Middle Aged, PTEN Phosphohydrolase genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Penetrance
- Abstract
Background: Unbiased estimates of penetrance are challenging but critically important to make informed choices about strategies for risk management through increased surveillance and risk-reducing interventions., Methods: We studied the penetrance and clinical outcomes of 7 breast cancer susceptibility genes ( BRCA1 , BRCA2 , TP53 , CHEK2 , ATM , PALB2 , and PTEN ) in almost 13 458 participants unselected for personal or family history of breast cancer. We identified 242 female participants with pathogenic or likely pathogenic variants in 1 of the 7 genes for penetrance analyses, and 147 women did not previously know their genetic results., Results: Out of the 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 17.8% to 43.8%, depending on the gene. In clinical-impact analysis, 42.3% (95% confidence interval = 31.3% to 53.3%) of women had taken actions related to their genetic results, and 2 new breast cancer cases were identified within the first 12 months after genetic results disclosure., Conclusions: Our study provides population-based penetrance estimates for the understudied genes CHEK2 , ATM , and PALB2 and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve health care through early diagnosis and preventative screening., (© The Author(s) 2021. Published by Oxford University Press.)
- Published
- 2021
- Full Text
- View/download PDF
35. Medical records-based chronic kidney disease phenotype for clinical care and "big data" observational and genetic studies.
- Author
-
Shang N, Khan A, Polubriaginof F, Zanoni F, Mehl K, Fasel D, Drawz PE, Carrol RJ, Denny JC, Hathcock MA, Arruda-Olson AM, Peissig PL, Dart RA, Brilliant MH, Larson EB, Carrell DS, Pendergrass S, Verma SS, Ritchie MD, Benoit B, Gainer VS, Karlson EW, Gordon AS, Jarvik GP, Stanaway IB, Crosslin DR, Mohan S, Ionita-Laza I, Tatonetti NP, Gharavi AG, Hripcsak G, Weng C, and Kiryluk K
- Abstract
Chronic Kidney Disease (CKD) represents a slowly progressive disorder that is typically silent until late stages, but early intervention can significantly delay its progression. We designed a portable and scalable electronic CKD phenotype to facilitate early disease recognition and empower large-scale observational and genetic studies of kidney traits. The algorithm uses a combination of rule-based and machine-learning methods to automatically place patients on the staging grid of albuminuria by glomerular filtration rate ("A-by-G" grid). We manually validated the algorithm by 451 chart reviews across three medical systems, demonstrating overall positive predictive value of 95% for CKD cases and 97% for healthy controls. Independent case-control validation using 2350 patient records demonstrated diagnostic specificity of 97% and sensitivity of 87%. Application of the phenotype to 1.3 million patients demonstrated that over 80% of CKD cases are undetected using ICD codes alone. We also demonstrated several large-scale applications of the phenotype, including identifying stage-specific kidney disease comorbidities, in silico estimation of kidney trait heritability in thousands of pedigrees reconstructed from medical records, and biobank-based multicenter genome-wide and phenome-wide association studies.
- Published
- 2021
- Full Text
- View/download PDF
36. Sex- and age-specific genetic analysis of chronic back pain.
- Author
-
Freidin MB, Tsepilov YA, Stanaway IB, Meng W, Hayward C, Smith BH, Khoury S, Parisien M, Bortsov A, Diatchenko L, Børte S, Winsvold BS, Brumpton BM, Zwart JA, Aulchenko YS, Suri P, and Williams FMK
- Subjects
- Age Factors, Aged, Aged, 80 and over, Back Pain epidemiology, Back Pain genetics, Female, Genetic Loci, Humans, Infant, Male, Polymorphism, Single Nucleotide genetics, Proteoglycans, Genetic Predisposition to Disease genetics, Genome-Wide Association Study
- Abstract
Abstract: Sex differences for chronic back pain (cBP) have been reported, with females usually exhibiting greater morbidity, severity, and poorer response to treatment. Genetic factors acting in an age-specific manner have been implicated but never comprehensively explored. We performed sex- and age-stratified genome-wide association study and single nucleotide polymorphism-by-sex interaction analysis for cBP defined as "Back pain for 3+ months" in 202,077 males and 237,754 females of European ancestry from UK Biobank. Two and 7 nonoverlapping genome-wide significant loci were identified for males and females, respectively. A male-specific locus on chromosome 10 near SPOCK2 gene was replicated in 4 independent cohorts. Four loci demonstrated single nucleotide polymorphism-by-sex interaction, although none of them were formally replicated. Single nucleotide polymorphism-explained heritability was higher in females (0.079 vs 0.067, P = 0.006). There was a high, although not complete, genetic correlation between the sexes (r = 0.838 ± 0.041, different from 1 with P = 7.8E-05). Genetic correlation between the sexes for cBP decreased with age (0.858 ± 0.049 in younger people vs 0.544 ± 0.157 in older people; P = 4.3E-05). There was a stronger genetic correlation of cBP with self-reported diagnosis of intervertebral disk degeneration in males than in females (0.889 vs 0.638; P = 3.7E-06). Thus, the genetic component of cBP in the UK Biobank exhibits a mild sex- and age-dependency. This provides an insight into the possible causes of sex- and age-specificity in epidemiology and pathophysiology of cBP and chronic pain at other anatomical sites., (Copyright © 2020 International Association for the Study of Pain.)
- Published
- 2021
- Full Text
- View/download PDF
37. Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.
- Author
-
Verbitsky M, Krithivasan P, Batourina E, Khan A, Graham SE, Marasà M, Kim H, Lim TY, Weng PL, Sánchez-Rodríguez E, Mitrotti A, Ahram DF, Zanoni F, Fasel DA, Westland R, Sampson MG, Zhang JY, Bodria M, Kil BH, Shril S, Gesualdo L, Torri F, Scolari F, Izzi C, van Wijk JAE, Saraga M, Santoro D, Conti G, Barton DE, Dobson MG, Puri P, Furth SL, Warady BA, Pisani I, Fiaccadori E, Allegri L, Degl'Innocenti ML, Piaggio G, Alam S, Gigante M, Zaza G, Esposito P, Lin F, Simões-E-Silva AC, Brodkiewicz A, Drozdz D, Zachwieja K, Miklaszewska M, Szczepanska M, Adamczyk P, Tkaczyk M, Tomczyk D, Sikora P, Mizerska-Wasiak M, Krzemien G, Szmigielska A, Zaniew M, Lozanovski VJ, Gucev Z, Ionita-Laza I, Stanaway IB, Crosslin DR, Wong CS, Hildebrandt F, Barasch J, Kenny EE, Loos RJF, Levy B, Ghiggeri GM, Hakonarson H, Latos-Bieleńska A, Materna-Kiryluk A, Darlow JM, Tasic V, Willer C, Kiryluk K, Sanna-Cherchi S, Mendelsohn CL, and Gharavi AG
- Abstract
Background: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood., Methods: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry., Results: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P =6.35×10
-8 ) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract ( WDPCP, OTX1, BMP5, VANGL1, and WNT5A ). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P =1.86×10-9 ). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis., Conclusions: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR., (Copyright © 2021 by the American Society of Nephrology.)- Published
- 2021
- Full Text
- View/download PDF
38. Response to Li and Hopper.
- Author
-
Thomas M, Sakoda LC, Hoffmeister M, Rosenthal EA, Lee JK, van Duijnhoven FJB, Platz EA, Wu AH, Dampier CH, de la Chapelle A, Wolk A, Joshi AD, Burnett-Hartman A, Gsur A, Lindblom A, Castells A, Win AK, Namjou B, Van Guelpen B, Tangen CM, He Q, Li CI, Schafmayer C, Joshu CE, Ulrich CM, Bishop DT, Buchanan DD, Schaid D, Drew DA, Muller DC, Duggan D, Crosslin DR, Albanes D, Giovannucci EL, Larson E, Qu F, Mentch F, Giles GG, Hakonarson H, Hampel H, Stanaway IB, Figueiredo JC, Huyghe JR, Minnier J, Chang-Claude J, Hampe J, Harley JB, Visvanathan K, Curtis KR, Offit K, Li L, Le Marchand L, Vodickova L, Gunter MJ, Jenkins MA, Slattery ML, Lemire M, Woods MO, Song M, Murphy N, Lindor NM, Dikilitas O, Pharoah PDP, Campbell PT, Newcomb PA, Milne RL, MacInnis RJ, Castellví-Bel S, Ogino S, Berndt SI, Bézieau S, Thibodeau SN, Gallinger SJ, Zaidi SH, Harrison TA, Keku TO, Hudson TJ, Vymetalkova V, Moreno V, Martín V, Arndt V, Wei WQ, Chung W, Su YR, Hayes RB, White E, Vodicka P, Casey G, Gruber SB, Schoen RE, Chan AT, Potter JD, Brenner H, Jarvik GP, Corley DA, Peters U, and Hsu L
- Subjects
- Humans, Risk Factors, Colorectal Neoplasms
- Published
- 2021
- Full Text
- View/download PDF
39. Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network.
- Author
-
Palmer MR, Kim DS, Crosslin DR, Stanaway IB, Rosenthal EA, Carrell DS, Cronkite DJ, Gordon A, Du X, Li YK, Williams MS, Weng C, Feng Q, Li R, Pendergrass SA, Hakonarson H, Fasel D, Sohn S, Sleiman P, Handelman SK, Speliotes E, Kullo IJ, Larson EB, and Jarvik GP
- Subjects
- Electronic Health Records, Genetic Predisposition to Disease, Genomics, Humans, Lipoprotein(a) genetics, Models, Genetic, Polymorphism, Single Nucleotide, Carotid Stenosis, Genome-Wide Association Study
- Abstract
Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30-1.73), p = 2.1 × 10
-8 ) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16-1.36), p = 4.3 × 10-8 ). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13-1.43), p = 5 × 10-5 ) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97-1.09), p = .37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD., (© 2020 The Authors. Genetic Epidemiology published by Wiley Periodicals LLC.)- Published
- 2021
- Full Text
- View/download PDF
40. Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort.
- Author
-
Rosenthal EA, Crosslin DR, Gordon AS, Carrell DS, Stanaway IB, Larson EB, Grafton J, Wei WQ, Denny JC, Feng QP, Shah AS, Sturm AC, Ritchie MD, Pacheco JA, Hakonarson H, Rasmussen-Torvik LJ, Connolly JJ, Fan X, Safarova M, Kullo IJ, and Jarvik GP
- Subjects
- Humans, Male, Female, Cohort Studies, Middle Aged, Hypertriglyceridemia genetics, Genetic Predisposition to Disease, Adult, Risk Factors, Aged, Triglycerides blood, Polymorphism, Single Nucleotide
- Abstract
Background: Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample., Methods: Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry., Results: We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP., Conclusions: Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.
- Published
- 2021
- Full Text
- View/download PDF
41. Evaluation of the MC4R gene across eMERGE network identifies many unreported obesity-associated variants.
- Author
-
Namjou B, Stanaway IB, Lingren T, Mentch FD, Benoit B, Dikilitas O, Niu X, Shang N, Shoemaker AH, Carey DJ, Mirshahi T, Singh R, Nestor JG, Hakonarson H, Denny JC, Crosslin DR, Jarvik GP, Kullo IJ, Williams MS, and Harley JB
- Subjects
- Adult, Aged, Body Mass Index, Cohort Studies, Female, Humans, Male, Middle Aged, Genetic Variation genetics, Genome-Wide Association Study, Obesity epidemiology, Obesity genetics, Receptor, Melanocortin, Type 4 genetics
- Abstract
Background/objectives: Melanocortin-4 receptor (MC4R) plays an essential role in food intake and energy homeostasis. More than 170 MC4R variants have been described over the past two decades, with conflicting reports regarding the prevalence and phenotypic effects of these variants in diverse cohorts. To determine the frequency of MC4R variants in large cohort of different ancestries, we evaluated the MC4R coding region for 20,537 eMERGE participants with sequencing data plus additional 77,454 independent individuals with genome-wide genotyping data at this locus., Subjects/methods: The sequencing data were obtained from the eMERGE phase III study, in which multisample variant call format calls have been generated, curated, and annotated. In addition to penetrance estimation using body mass index (BMI) as a binary outcome, GWAS and PheWAS were performed using median BMI in linear regression analyses. All results were adjusted for principal components, age, sex, and sites of genotyping., Results: Targeted sequencing data of MC4R revealed 125 coding variants in 1839 eMERGE participants including 30 unreported coding variants that were predicted to be functionally damaging. Highly penetrant unreported variants included (L325I, E308K, D298N, S270F, F261L, T248A, D111V, and Y80F) in which seven participants had obesity class III defined as BMI ≥ 40 kg/m
2 . In GWAS analysis, in addition to known risk haplotype upstream of MC4R (best variant rs6567160 (P = 5.36 × 10-25 , Beta = 0.37), a novel rare haplotype was detected which was protective against obesity and encompassed the V103I variant with known gain-of-function properties (P = 6.23 × 10-08 , Beta = -0.62). PheWAS analyses extended this protective effect of V103I to type 2 diabetes, diabetic nephropathy, and chronic renal failure independent of BMI., Conclusions: MC4R screening in a large eMERGE cohort confirmed many previous findings, extend the MC4R pleotropic effects, and discovered additional MC4R rare alleles that probably contribute to obesity.- Published
- 2021
- Full Text
- View/download PDF
42. A genome-wide association study of polycystic ovary syndrome identified from electronic health records.
- Author
-
Zhang Y, Ho K, Keaton JM, Hartzel DN, Day F, Justice AE, Josyula NS, Pendergrass SA, Actkins K, Davis LK, Velez Edwards DR, Holohan B, Ramirez A, Stanaway IB, Crosslin DR, Jarvik GP, Sleiman P, Hakonarson H, Williams MS, and Lee MTM
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Adult, Case-Control Studies, Electronic Health Records, Female, Genome-Wide Association Study, Humans, Hyperandrogenism genetics, Infertility, Female genetics, Middle Aged, Oligomenorrhea genetics, Ovarian Cysts genetics, Polycystic Ovary Syndrome diagnosis, Polycystic Ovary Syndrome physiopathology, Polymorphism, Single Nucleotide, Superoxide Dismutase genetics, Transcription Factors metabolism, Transcriptional Coactivator with PDZ-Binding Motif Proteins, YAP-Signaling Proteins, Polycystic Ovary Syndrome genetics, Receptor, ErbB-4 genetics, Trans-Activators genetics
- Abstract
Background: Polycystic ovary syndrome is the most common endocrine disorder affecting women of reproductive age. A number of criteria have been developed for clinical diagnosis of polycystic ovary syndrome, with the Rotterdam criteria being the most inclusive. Evidence suggests that polycystic ovary syndrome is significantly heritable, and previous studies have identified genetic variants associated with polycystic ovary syndrome diagnosed using different criteria. The widely adopted electronic health record system provides an opportunity to identify patients with polycystic ovary syndrome using the Rotterdam criteria for genetic studies., Objective: To identify novel associated genetic variants under the same phenotype definition, we extracted polycystic ovary syndrome cases and unaffected controls based on the Rotterdam criteria from the electronic health records and performed a discovery-validation genome-wide association study., Study Design: We developed a polycystic ovary syndrome phenotyping algorithm on the basis of the Rotterdam criteria and applied it to 3 electronic health record-linked biobanks to identify cases and controls for genetic study. In the discovery phase, we performed an individual genome-wide association study using the Geisinger MyCode and the Electronic Medical Records and Genomics cohorts, which were then meta-analyzed. We attempted validation of the significant association loci (P<1×10
-6 ) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed-effect model was adopted for meta-analysis. In addition, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used the STRING database to characterize protein-protein interaction network., Results: Using the same algorithm based on the Rotterdam criteria, we identified 2995 patients with polycystic ovary syndrome and 53,599 population controls in total (2742 cases and 51,438 controls from the discovery phase; 253 cases and 2161 controls in the validation phase). We identified 1 novel genome-wide significant variant rs17186366 (odds ratio [OR]=1.37 [1.23, 1.54], P=2.8×10-8 ) located near SOD2. In addition, 2 loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42, 2.10], P=5.2×10-8 ), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52, 2.86], P=8.45×10-7 ), a novel intronic variant in WWTR1. In the further association tests of the top 3 single-nucleotide polymorphisms with each criterion in the polycystic ovary syndrome algorithm, we found that rs17186366 (SOD2) was associated with polycystic ovaries and hyperandrogenism, whereas rs11316812 (ERBB4) and rs144248326 (WWTR1) were mainly associated with oligomenorrhea or infertility. We also validated the previously reported association with DENND1A1. Using the STRING database to characterize protein-protein interactions, we found both ERBB4 and WWTR1 can interact with YAP1, which has been previously associated with polycystic ovary syndrome., Conclusion: Through a discovery-validation genome-wide association study on polycystic ovary syndrome identified from electronic health records using an algorithm based on Rotterdam criteria, we identified and validated a novel genome-wide significant association with a variant near SOD2. We also identified a novel independent variant within ERBB4 and a suggestive association with WWTR1. With previously identified polycystic ovary syndrome gene YAP1, the ERBB4-YAP1-WWTR1 network suggests involvement of the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of polycystic ovary syndrome., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
43. Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
- Author
-
Thomas M, Sakoda LC, Hoffmeister M, Rosenthal EA, Lee JK, van Duijnhoven FJB, Platz EA, Wu AH, Dampier CH, de la Chapelle A, Wolk A, Joshi AD, Burnett-Hartman A, Gsur A, Lindblom A, Castells A, Win AK, Namjou B, Van Guelpen B, Tangen CM, He Q, Li CI, Schafmayer C, Joshu CE, Ulrich CM, Bishop DT, Buchanan DD, Schaid D, Drew DA, Muller DC, Duggan D, Crosslin DR, Albanes D, Giovannucci EL, Larson E, Qu F, Mentch F, Giles GG, Hakonarson H, Hampel H, Stanaway IB, Figueiredo JC, Huyghe JR, Minnier J, Chang-Claude J, Hampe J, Harley JB, Visvanathan K, Curtis KR, Offit K, Li L, Le Marchand L, Vodickova L, Gunter MJ, Jenkins MA, Slattery ML, Lemire M, Woods MO, Song M, Murphy N, Lindor NM, Dikilitas O, Pharoah PDP, Campbell PT, Newcomb PA, Milne RL, MacInnis RJ, Castellví-Bel S, Ogino S, Berndt SI, Bézieau S, Thibodeau SN, Gallinger SJ, Zaidi SH, Harrison TA, Keku TO, Hudson TJ, Vymetalkova V, Moreno V, Martín V, Arndt V, Wei WQ, Chung W, Su YR, Hayes RB, White E, Vodicka P, Casey G, Gruber SB, Schoen RE, Chan AT, Potter JD, Brenner H, Jarvik GP, Corley DA, Peters U, and Hsu L
- Subjects
- Aged, Asian People genetics, Bayes Theorem, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Multifactorial Inheritance genetics, Polymorphism, Single Nucleotide genetics, Risk Factors, Colorectal Neoplasms epidemiology, Genetic Predisposition to Disease, Genome, Human genetics, Risk Assessment
- Abstract
Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
44. Hemochromatosis risk genotype is not associated with colorectal cancer or age at its diagnosis.
- Author
-
Jarvik GP, Wang X, Fontanillas P, Kim E, Chanprasert S, Gordon AS, Bastarache L, Kowdley KV, Harrison T, Rosenthal EA, Stanaway IB, Bézieau S, Weinstein SJ, Newcomb PA, Casey G, Platz EA, Visvanathan K, Le Marchand L, Ulrich CM, Hardikar S, Li CI, van Duijnhoven FJB, Gsur A, Campbell PT, Moreno V, Vodička P, Brenner H, Chang-Claude J, Hoffmeister M, Slattery ML, Gunter MJ, Aglago EK, Castellví-Bel S, Kweon SS, Chan AT, Li L, Zheng W, Bishop DT, Giles GG, Rennert G, Offit K, Keku TO, Woods MO, Hampe J, Van Guelpen B, Gallinger SJ, de la Chapelle A, Hampel H, Berndt SI, Tangen CM, Lindblom A, Wolk A, Burnett-Hartman A, Wu AH, White E, Gruber SB, Jenkins MA, Mountain J, Peters U, and Crosslin DR
- Abstract
Homozygotes for the higher penetrance hemochromatosis risk allele, HFE c.845G>A (p.Cys282Tyr, or C282Y), have been reported to be at a 2- to 3-fold increased risk for colorectal cancer (CRC). These results have been reported for small sample size studies with no information about age at diagnosis for CRC. An association with age at diagnosis might alter CRC screening recommendations. We analyzed two large European ancestry datasets to assess the association of HFE genotype with CRC risk and age at CRC diagnosis. The first dataset included 59,733 CRC or advanced adenoma cases and 72,351 controls from a CRC epidemiological study consortium. The second dataset included 13,564 self-reported CRC cases and 2,880,218 controls from the personal genetics company, 23andMe. No association of the common hereditary hemochromatosis (HH) risk genotype and CRC was found in either dataset. The odds ratios (ORs) for the association of CRC and HFE C282Y homozygosity were 1.08 (95% confidence interval [CI], 0.91-1.29; p = 0.4) and 1.01 (95% CI, 0.78-1.31, p = 0.9) in the two cohorts, respectively. Age at CRC diagnosis also did not differ by HFE C282Y/C282Y genotype in either dataset. These results indicate no increased CRC risk in individuals with HH genotypes and suggest that persons with HH risk genotypes can follow population screening recommendations for CRC., Competing Interests: D.R.C. is a paid consultant for UnitedHealth Group Research and Development. H.H. is on the Scientific Advisory Boards of Invitae Genetics, Genome Medical, and Promega. She is a consultant for 23and Me. She conducts collaborative research with Invitae Genetics, Myriad Genetic Laboratories, and Ambry Genetics. She holds stocks in Genome Medical. J.M., P.F., E.K., and members of the 23andMe Research Team are current or former employees of 23andMe and hold stock or stock options in 23andMe. S.B.G. is a founder of Brogent International with equity., (© 2020 The Authors.)
- Published
- 2020
- Full Text
- View/download PDF
45. A Polygenic and Phenotypic Risk Prediction for Polycystic Ovary Syndrome Evaluated by Phenome-Wide Association Studies.
- Author
-
Joo YY, Actkins K, Pacheco JA, Basile AO, Carroll R, Crosslin DR, Day F, Denny JC, Velez Edwards DR, Hakonarson H, Harley JB, Hebbring SJ, Ho K, Jarvik GP, Jones M, Karaderi T, Mentch FD, Meun C, Namjou B, Pendergrass S, Ritchie MD, Stanaway IB, Urbanek M, Walunas TL, Smith M, Chisholm RL, Kho AN, Davis L, and Hayes MG
- Subjects
- Adolescent, Aged, Case-Control Studies, Child, Electronic Health Records, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Middle Aged, Polycystic Ovary Syndrome epidemiology, Polycystic Ovary Syndrome genetics, Prognosis, Risk Factors, Algorithms, Genome-Wide Association Study, Multifactorial Inheritance genetics, Phenomics methods, Phenotype, Polycystic Ovary Syndrome diagnosis
- Abstract
Context: As many as 75% of patients with polycystic ovary syndrome (PCOS) are estimated to be unidentified in clinical practice., Objective: Utilizing polygenic risk prediction, we aim to identify the phenome-wide comorbidity patterns characteristic of PCOS to improve accurate diagnosis and preventive treatment., Design, Patients, and Methods: Leveraging the electronic health records (EHRs) of 124 852 individuals, we developed a PCOS risk prediction algorithm by combining polygenic risk scores (PRS) with PCOS component phenotypes into a polygenic and phenotypic risk score (PPRS). We evaluated its predictive capability across different ancestries and perform a PRS-based phenome-wide association study (PheWAS) to assess the phenomic expression of the heightened risk of PCOS., Results: The integrated polygenic prediction improved the average performance (pseudo-R2) for PCOS detection by 0.228 (61.5-fold), 0.224 (58.8-fold), 0.211 (57.0-fold) over the null model across European, African, and multi-ancestry participants respectively. The subsequent PRS-powered PheWAS identified a high level of shared biology between PCOS and a range of metabolic and endocrine outcomes, especially with obesity and diabetes: "morbid obesity", "type 2 diabetes", "hypercholesterolemia", "disorders of lipid metabolism", "hypertension", and "sleep apnea" reaching phenome-wide significance., Conclusions: Our study has expanded the methodological utility of PRS in patient stratification and risk prediction, especially in a multifactorial condition like PCOS, across different genetic origins. By utilizing the individual genome-phenome data available from the EHR, our approach also demonstrates that polygenic prediction by PRS can provide valuable opportunities to discover the pleiotropic phenomic network associated with PCOS pathogenesis., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
- Full Text
- View/download PDF
46. Anchoring a dynamic in vitro model of human neuronal differentiation to key processes of early brain development in vivo.
- Author
-
Wegner SH, Park JJ, Workman T, Hermsen SAB, Wallace J, Stanaway IB, Kim HY, Griffith WC, Hong S, and Faustman EM
- Subjects
- Brain growth & development, Cell Survival, Cells, Cultured, Female, Humans, Neurotoxicity Syndromes, Transcriptome, Models, Biological, Neural Stem Cells metabolism, Neurogenesis
- Abstract
We characterize temporal pathway dynamics of differentiation in an in vitro neurotoxicity model with the aim of informing design and interpretation of toxicological assays. Human neural progenitor cells (hNPCs) were cultured in differentiation conditions up to 21 days. Genes significantly changed through time were identified and grouped according to temporal dynamics. Quantitative pathway analysis identified gene ontology (GO) terms enriched among significantly changed genes and provided a temporal roadmap of pathway trends in vitro. Gene expression in hNPCs was compared with publicly available gene expression data from developing human brain tissue in vivo. Quantitative pathway analysis of significantly changed genes and targeted analysis of specific pathways of interest identified concordance between in vivo and in vitro expression associated with proliferation, migration, differentiation, synapse formation, and neurotransmission. Our analysis anchors gene expression patterns in vitro to sensitive windows of in vivo development, helping to define appropriate applications of the model., (Published by Elsevier Inc.)
- Published
- 2020
- Full Text
- View/download PDF
47. Association of Genetic Risk of Obesity with Postoperative Complications Using Mendelian Randomization.
- Author
-
Robinson JR, Carroll RJ, Bastarache L, Chen Q, Mou Z, Wei WQ, Connolly JJ, Mentch F, Sleiman P, Crane PK, Hebbring SJ, Stanaway IB, Crosslin DR, Gordon AS, Rosenthal EA, Carrell D, Hayes MG, Wei W, Petukhova L, Namjou B, Zhang G, Safarova MS, Walton NA, Still C, Bottinger EP, Loos RJF, Murphy SN, Jackson GP, Kullo IJ, Hakonarson H, Jarvik GP, Larson EB, Weng C, Roden DM, and Denny JC
- Subjects
- Adult, Body Mass Index, Female, Humans, Logistic Models, Male, Middle Aged, Polymorphism, Single Nucleotide, Postoperative Complications etiology, Retrospective Studies, Risk Factors, Mendelian Randomization Analysis methods, Obesity complications, Postoperative Complications genetics
- Abstract
Background: The extent to which obesity and genetics determine postoperative complications is incompletely understood., Methods: We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990 and 2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records and Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score was constructed from 97 obesity-risk single-nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk of obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components., Results: Individuals with overweight or obese BMI (≥25 kg/m
2 ) had increased risk of incisional hernia (odds ratio [OR] 1.7-5.5, p < 3.1 × 10-20 ), and people with obesity (BMI ≥ 30 kg/m2 ) had increased risk of postoperative infection (OR 1.2-2.3, p < 2.5 × 10-5 ). In the eMERGE cohort, genetically predicted BMI was associated with incisional hernia (OR 2.1 [95% CI 1.8-2.5], p = 1.4 × 10-6 ) and postoperative infection (OR 1.6 [95% CI 1.4-1.9], p = 3.1 × 10-6 ). Association findings were similar after limitation of the cohorts to those who underwent abdominal procedures., Conclusions: Clinical and Mendelian randomization studies suggest that obesity, as measured by BMI, is associated with the development of postoperative incisional hernia and infection.- Published
- 2020
- Full Text
- View/download PDF
48. Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting.
- Author
-
Gordon AS, Rosenthal EA, Carrell DS, Amendola LM, Dorschner MO, Scrol A, Stanaway IB, DeVange S, Ralston JD, Zouk H, Rehm HL, Larson E, Crosslin DR, Leppig KA, and Jarvik GP
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Colonic Polyps genetics, Colorectal Neoplasms genetics
- Abstract
As clinical testing for Mendelian causes of colorectal cancer (CRC) is largely driven by recognition of family history and early age of onset, the rates of such findings among individuals with prevalent CRC not recognized to have these features is largely unknown. We evaluated actionable genomic findings in community-based participants ascertained by three phenotypes: (1) CRC, (2) one or more adenomatous colon polyps, and (3) control participants over age 59 years without CRC or colon polyps. These participants underwent sequencing for a panel of genes that included colorectal cancer/polyp (CRC/P)-associated and actionable incidental findings genes. Those with CRC had a 3.8% rate of positive results (pathogenic or likely pathogenic) for a CRC-associated gene variant, despite generally being older at CRC onset (mean 72 years). Those ascertained for polyps had a 0.8% positive rate and those with no CRC/P had a positive rate of 0.2%. Though incidental finding rates unrelated to colon cancer were similar for all groups, our positive rate for cardiovascular findings exceeds disease prevalence, suggesting that variant interpretation challenges or low penetrance in these genes. The rate of HFE c.845G>A (p.Cys282Tyr) homozygotes in the CRC group reinforces a previously reported, but relatively unexplored, association between hemochromatosis and CRC. These results in a general clinical population suggest that current testing strategies could be improved in order to better detect Mendelian CRC-associated conditions. These data also underscore the need for additional functional and familial evidence to clarify the pathogenicity and penetrance of variants deemed pathogenic or likely pathogenic, particularly among the actionable genes associated with cardiovascular disease., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
49. Unfolding of hidden white blood cell count phenotypes for gene discovery using latent class mixed modeling.
- Author
-
Hall TO, Stanaway IB, Carrell DS, Carroll RJ, Denny JC, Hakonarson H, Larson EB, Mentch FD, Peissig PL, Pendergrass SA, Rosenthal EA, Jarvik GP, and Crosslin DR
- Subjects
- Adult, Aged, Databases, Genetic, Electronic Health Records, Female, Genome-Wide Association Study, Humans, Latent Class Analysis, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide genetics, Proteins genetics, Receptors, Colony-Stimulating Factor genetics, Ubiquitin-Protein Ligases genetics, Leukocyte Count methods, Leukocytes classification
- Abstract
Resting-state white blood cell (WBC) count is a marker of inflammation and immune system health. There is evidence that WBC count is not fixed over time and there is heterogeneity in WBC trajectory that is associated with morbidity and mortality. Latent class mixed modeling (LCMM) is a method that can identify unobserved heterogeneity in longitudinal data and attempts to classify individuals into groups based on a linear model of repeated measurements. We applied LCMM to repeated WBC count measures derived from electronic medical records of participants of the National Human Genetics Research Institute (NHRGI) electronic MEdical Record and GEnomics (eMERGE) network study, revealing two WBC count trajectory phenotypes. Advancing these phenotypes to GWAS, we found genetic associations between trajectory class membership and regions on chromosome 1p34.3 and chromosome 11q13.4. The chromosome 1 region contains CSF3R, which encodes the granulocyte colony-stimulating factor receptor. This protein is a major factor in neutrophil stimulation and proliferation. The association on chromosome 11 contain genes RNF169 and XRRA1; both involved in the regulation of double-strand break DNA repair.
- Published
- 2019
- Full Text
- View/download PDF
50. GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network.
- Author
-
Namjou B, Lingren T, Huang Y, Parameswaran S, Cobb BL, Stanaway IB, Connolly JJ, Mentch FD, Benoit B, Niu X, Wei WQ, Carroll RJ, Pacheco JA, Harley ITW, Divanovic S, Carrell DS, Larson EB, Carey DJ, Verma S, Ritchie MD, Gharavi AG, Murphy S, Williams MS, Crosslin DR, Jarvik GP, Kullo IJ, Hakonarson H, Li R, Xanthakos SA, and Harley JB
- Subjects
- Adult, Aged, Body Mass Index, Case-Control Studies, Community Networks organization & administration, Community Networks statistics & numerical data, Disease Progression, Electronic Health Records organization & administration, Electronic Health Records statistics & numerical data, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics organization & administration, Genomics statistics & numerical data, Humans, Lipase genetics, Male, Membrane Proteins genetics, Middle Aged, Morbidity, Non-alcoholic Fatty Liver Disease epidemiology, Phenotype, Polymorphism, Single Nucleotide, Signal Transduction genetics, Non-alcoholic Fatty Liver Disease genetics
- Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition., Methods: First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI)., Results: Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10
- 20 ). This effect was consistent in both pediatric (p = 9.92 × 10- 6 ) and adult (p = 9.73 × 10- 15 ) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10- 8 , beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10- 4 ). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10- 8 ), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10- 11 ). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses., Conclusions: In summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings.- Published
- 2019
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.