36 results on '"Jacob M. Keaton"'
Search Results
2. Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management
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Nikhil K. Khankari, Jacob M. Keaton, Venexia M. Walker, Kyung Min Lee, Megan M. Shuey, Shoa L. Clarke, Kent R. Heberer, Donald R. Miller, Peter D. Reaven, Julie A. Lynch, Marijana Vujkovic, and Todd L. Edwards
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Mendelian randomisation ,Lipids ,Statins ,Icosapent ethyl ,Gene expression ,Type 2 diabetes ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Maintaining a healthy lifestyle to reduce type 2 diabetes (T2D) risk is challenging and additional strategies for T2D prevention are needed. We evaluated several lipid control medications as potential therapeutic options for T2D prevention using tissue-specific predicted gene expression summary statistics in a two-sample Mendelian randomisation (MR) design. Methods: Large-scale European genome-wide summary statistics for lipids and T2D were leveraged in our multi-stage analysis to estimate changes in either lipid levels or T2D risk driven by tissue-specific predicted gene expression. We incorporated tissue-specific predicted gene expression summary statistics to proxy therapeutic effects of three lipid control medications [i.e., statins, icosapent ethyl (IPE), and proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK-9i)] on T2D susceptibility using two-sample Mendelian randomisation (MR). Findings: IPE, as proxied via increased FADS1 expression, was predicted to lower triglycerides and was associated with a 53% reduced risk of T2D. Statins and PCSK-9i, as proxied by reduced HMGCR and PCSK9 expression, respectively, were predicted to lower LDL-C levels but were not associated with T2D susceptibility. Interpretation: Triglyceride lowering via IPE may reduce the risk of developing T2D in populations of European ancestry. However, experimental validation using animal models is needed to substantiate our results and to motivate randomized control trials (RCTs) for IPE as putative treatment for T2D prevention. Funding: Only summary statistics were used in this analysis. Funding information is detailed under Acknowledgments.
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- 2022
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3. Large-Scale Multi-Omics Studies Provide New Insights into Blood Pressure Regulation
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Zoha Kamali, Jacob M. Keaton, Shaghayegh Haghjooy Javanmard, International Consortium of Blood Pressure, Million Veteran Program, eQTLGen Consortium, BIOS Consortium, Todd L. Edwards, Harold Snieder, and Ahmad Vaez
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blood pressure ,genome ,epigenome ,gene expression ,functional enrichment ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Recent genome-wide association studies uncovered part of blood pressure’s heritability. However, there is still a vast gap between genetics and biology that needs to be bridged. Here, we followed up blood pressure genome-wide summary statistics of over 750,000 individuals, leveraging comprehensive epigenomic and transcriptomic data from blood with a follow-up in cardiovascular tissues to prioritise likely causal genes and underlying blood pressure mechanisms. We first prioritised genes based on coding consequences, multilayer molecular associations, blood pressure-associated expression levels, and coregulation evidence. Next, we followed up the prioritised genes in multilayer studies of genomics, epigenomics, and transcriptomics, functional enrichment, and their potential suitability as drug targets. Our analyses yielded 1880 likely causal genes for blood pressure, tens of which are targets of the available licensed drugs. We identified 34 novel genes for blood pressure, supported by more than one source of biological evidence. Twenty-eight (82%) of these new genes were successfully replicated by transcriptome-wide association analyses in a large independent cohort (n = ~220,000). We also found a substantial mediating role for epigenetic regulation of the prioritised genes. Our results provide new insights into genetic regulation of blood pressure in terms of likely causal genes and involved biological pathways offering opportunities for future translation into clinical practice.
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- 2022
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4. Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program
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Jacklyn N. Hellwege, Digna R. Velez Edwards, Ayush Giri, Chengxiang Qiu, Jihwan Park, Eric S. Torstenson, Jacob M. Keaton, O. D. Wilson, Cassianne Robinson-Cohen, Cecilia P. Chung, Christianne L. Roumie, Derek Klarin, Scott M. Damrauer, Scott L. DuVall, Edward Siew, Elvis A. Akwo, Matthias Wuttke, Mathias Gorski, Man Li, Yong Li, J. Michael Gaziano, Peter W. F. Wilson, Philip S. Tsao, Christopher J. O’Donnell, Csaba P. Kovesdy, Cristian Pattaro, Anna Köttgen, Katalin Susztak, Todd L. Edwards, and Adriana M. Hung
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Science - Abstract
Persistently low levels of estimated glomerular filtration rate (eGFR) are a biomarker of chronic kidney disease. Here, the authors reinterpret the genetic architecture of kidney function across ancestries, to identify not only genes, but the tissue and anatomical contexts of renal homeostasis.
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- 2019
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5. Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans
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Meijian Guan, Jacob M. Keaton, Latchezar Dimitrov, Pamela J. Hicks, Jianzhao Xu, Nicholette D. Palmer, Lijun Ma, Swapan K. Das, Yii-Der I. Chen, Josef Coresh, Myriam Fornage, Nora Franceschini, Holly Kramer, Carl D. Langefeld, Josyf C. Mychaleckyj, Rulan S. Parekh, Wendy S. Post, Laura J. Rasmussen-Torvik, Stephen S. Rich, Jerome I. Rotter, John R. Sedor, Denyse Thornley-Brown, Adrienne Tin, James G. Wilson, Barry I. Freedman, Donald W. Bowden, Maggie C. Y. Ng, and FIND Consortium
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African Americans ,Genome-wide association study ,Type 2 diabetes ,Diabetic kidney disease ,End-stage kidney disease ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants. Results Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P
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- 2019
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6. An Exome-wide Association Study for Type 2 Diabetes–Attributed End-Stage Kidney Disease in African Americans
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Meijian Guan, Jacob M. Keaton, Latchezar Dimitrov, Pamela J. Hicks, Jianzhao Xu, Nicholette D. Palmer, James G. Wilson, Barry I. Freedman, Donald W. Bowden, and Maggie C.Y. Ng
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Introduction: Compared with European Americans, African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD). Genome-wide association studies (GWAS) have identified >70 genetic variants associated with kidney function and chronic kidney disease (CKD) in patients with and without diabetes. However, these variants explain a small proportion of disease liability. This study examined the contribution of coding genetic variants for risk of type 2 diabetes (T2D)-attributed ESKD and advanced CKD in AAs. Methods: Exome sequencing was performed in 456 AA T2D-ESKD cases, and 936 AA nondiabetic, non-nephropathy control individuals at the discovery stage. A mixed logistic regression model was used for association analysis. Nominal associations (P < 0.05) were replicated in an additional 2020 T2D-ESKD cases and 1121 nondiabetic, non-nephropathy control individuals. A meta-analysis combining 4533 discovery and replication samples was performed. Putative T2D-ESKD associations were tested in additional 1910 nondiabetic ESKD and 219 T2D-ESKD cases, as well as 912 AA nondiabetic non-nephropathy control individuals. Results: A total of 11 suggestive T2D-ESKD associations (P < 1 x 10−4) from 8 loci (PLEKHN1, NADK, RAD51AP2, RREB1, PEX6, GRM8, PRX, APOL1) were apparent in the meta-analysis. Exclusion of APOL1 renal-risk genotype carriers identified 3 additional suggestive loci (OTUD7B, IFITM3, DLGAP5). Rs41302867 in RREB1 displayed consistent association with T2D-ESKD and nondiabetic ESKD (odds ratio: 0.47; P = 1.2 x 10−6 in 4605 all-cause ESKD and 2969 nondiabetic non-nephropathy control individuals). Conclusion: Our findings suggest that coding genetic variants are implicated in predisposition to T2D-ESKD in AAs. Keywords: African Americans, chronic kidney disease, end-stage kidney disease, exome sequencing, genetics, type 2 diabetes
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- 2018
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7. A Trans-Ethnic Genome-Wide Association Study of Uterine Fibroids
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Todd L. Edwards, Ayush Giri, Jacklyn N. Hellwege, Katherine E. Hartmann, Elizabeth A. Stewart, Janina M. Jeff, Michael J. Bray, Sarah A. Pendergrass, Eric S. Torstenson, Jacob M. Keaton, Sarah H. Jones, Radhika P. Gogoi, Helena Kuivaniemi, Kathryn L. Jackson, Abel N. Kho, Iftikhar J. Kullo, Catherine A. McCarty, Hae Kyung Im, Jennifer A. Pacheco, Jyotishman Pathak, Marc S. Williams, Gerard Tromp, Eimear E. Kenny, Peggy L. Peissig, Joshua C. Denny, Dan M. Roden, and Digna R. Velez Edwards
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uterine fibroids ,genome-wide association study (GWAS) ,trans-ethnic ,meta-analysis electronic health record (EHR) ,genetically predicted gene expression (GPGE) ,genetic architecture ,Genetics ,QH426-470 - Abstract
Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS (P < 1 × 10-5) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; P = 4.7 × 10-8), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10-9) and chromosome 20q13.1 (sentinel-SNP rs6094982; P = 2.6 × 10-8). Our statistically significant findings further support previously reported loci including SNPs near WT1, TNRC6B, SYNE1, BET1L, and CDC42/WNT4. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the CDC42/WNT4 locus (P = 1.76 × 10-24). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1 in vagina (P = 4.6 × 10-8), OBFC1 in esophageal mucosa (P = 8.7 × 10-8), NUDT13 in multiple tissues including subcutaneous adipose tissue (P = 3.3 × 10-6), and HEATR3 in skeletal muscle tissue (P = 5.8 × 10-6) were associated with fibroids. The finding for HEATR3 was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.
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- 2019
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8. Systematic replication of smoking disease associations using survey responses and EHR data in the All of Us Research Program.
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David J. Schlueter, Lina M. Sulieman, Huan Mo, Jacob M. Keaton, Tracey M. Ferrara, Ariel Williams, Jun Qian, Onajia J. Stubblefield, Chenjie Zeng, Tam C. Tran, Lisa Bastarache, Jian Dai, Anav Babbar, Andrea H. Ramirez, Slavina Goleva, and Joshua C. Denny
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- 2023
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9. Systematic replication of smoking disease associations in the All of Us Research Program.
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David J. Schlueter, Lina M. Sulieman, Jacob M. Keaton, Tracey Ferrara, Kyle Webb, Ariel Williams, Francis Ratsimbazafy, Jun Qian, Lisa Bastarache, Andrea H. Ramirez, and Joshua C. Denny
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- 2021
10. Genome-Wide Interaction with Selected Type 2 Diabetes Loci Reveals Novel Loci for Type 2 Diabetes in African Americans.
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Jacob M. Keaton, Jacklyn N. Hellwege, Maggie C. Y. Ng, Nicholette D. Palmer, James S. Pankow, Myriam Fornage, James G. Wilson, Adolfo Correa, Laura Rasmussen-Torvik, Jerome I. Rotter, Yii-Der Ida Chen, Kent D. Taylor, Stephen S. Rich, Lynne E. Wagenknecht, Barry I. Freedman, and Donald W. Bowden
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- 2017
11. Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry
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Fei Chen, Ravi K. Madduri, Alex A. Rodriguez, Burcu F. Darst, Alisha Chou, Xin Sheng, Anqi Wang, Jiayi Shen, Edward J. Saunders, Suhn K. Rhie, Jeannette T. Bensen, Sue A. Ingles, Rick A. Kittles, Sara S. Strom, Benjamin A. Rybicki, Barbara Nemesure, William B. Isaacs, Janet L. Stanford, Wei Zheng, Maureen Sanderson, Esther M. John, Jong Y. Park, Jianfeng Xu, Ying Wang, Sonja I. Berndt, Chad D. Huff, Edward D. Yeboah, Yao Tettey, Joseph Lachance, Wei Tang, Christopher T. Rentsch, Kelly Cho, Benjamin H. Mcmahon, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Thomas A. Sellers, Kosj Yamoah, Adam B. Murphy, Dana C. Crawford, Alpa V. Patel, William S. Bush, Melinda C. Aldrich, Olivier Cussenot, Gyorgy Petrovics, Jennifer Cullen, Christine M. Neslund-Dudas, Mariana C. Stern, Zsofia Kote-Jarai, Koveela Govindasami, Michael B. Cook, Anand P. Chokkalingam, Ann W. Hsing, Phyllis J. Goodman, Thomas J. Hoffmann, Bettina F. Drake, Jennifer J. Hu, Jacob M. Keaton, Jacklyn N. Hellwege, Peter E. Clark, Mohamed Jalloh, Serigne M. Gueye, Lamine Niang, Olufemi Ogunbiyi, Michael O. Idowu, Olufemi Popoola, Akindele O. Adebiyi, Oseremen I. Aisuodionoe-Shadrach, Hafees O. Ajibola, Mustapha A. Jamda, Olabode P. Oluwole, Maxwell Nwegbu, Ben Adusei, Sunny Mante, Afua Darkwa-Abrahams, James E. Mensah, Halimatou Diop, Stephen K. Van Den Eeden, Pascal Blanchet, Jay H. Fowke, Graham Casey, Anselm J. Hennis, Alexander Lubwama, Ian M. Thompson, Robin Leach, Douglas F. Easton, Michael H. Preuss, Ruth J. Loos, Susan M. Gundell, Peggy Wan, James L. Mohler, Elizabeth T. Fontham, Gary J. Smith, Jack A. Taylor, Shiv Srivastava, Rosaline A. Eeles, John D. Carpten, Adam S. Kibel, Luc Multigner, Marie-Élise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Eric A. Klein, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stefan Ambs, Todd L. Edwards, Stephen Watya, Stephen J. Chanock, John S. Witte, William J. Blot, J. Michael Gaziano, Amy C. Justice, David V. Conti, Christopher A. Haiman, University of Southern California (USC), Keck School of Medicine [Los Angeles], Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
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Prostate cancer ,MESH: Humans ,Urology ,MESH: Genetic Predisposition to Disease ,MESH: Black People ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,MESH: Male ,Polygenic risk score ,African ancestry ,MESH: Risk Factors ,MESH: Prostatic Neoplasms ,MESH: Genome-Wide Association Study ,Susceptibility loci ,Aggressive prostate cancer - Abstract
Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4).Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.
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- 2023
12. Population pharmacokinetic analysis of dexmedetomidine in children using real‐world data from electronic health records and remnant specimens
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Nathan T. James, Joseph H. Breeyear, Richard Caprioli, Todd Edwards, Brian Hachey, Prince J. Kannankeril, Jacob M. Keaton, Matthew D. Marshall, Sara L. Van Driest, and Leena Choi
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Adult ,Pharmacology ,Electronic Health Records ,Humans ,Hypnotics and Sedatives ,Pharmacology (medical) ,Cardiac Surgical Procedures ,Glucuronosyltransferase ,Child ,Models, Biological ,Article ,Dexmedetomidine - Abstract
AIM: Our objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and electronic health records (EHRs) and explore the impact of patient’s characteristics and pharmacogenetics on dexmedetomidine clearance. METHODS: Dexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modeling. Stage one developed a model without genotype variables; Stage two added pharmacogenetic effects. RESULTS: Our final study population included 354 post-cardiac surgery patients age 0 to 22 years (median 16 months). The data were best described with a two-compartment model with allometric scaling for weight and Hill maturation function for age. Population parameter estimates and 95% confidence intervals were 27.3 L/hr (24.0 – 31.1 L/hr) for total clearance (CL), 161 L (139 – 187 L) for central compartment volume of distribution (V(1)), 26.0 L/hr (22.5 – 30.0 L/hr) for intercompartmental clearance (Q), and 7903 L (5617 – 11119 L) for peripheral compartment volume of distribution (V(2)). The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0 weeks (41.5 – 42.5 weeks) and the Hill coefficient estimate was 7.04 (6.99 – 7.08). Genotype was not statistically or clinically significant. CONCLUSION: Our study demonstrates the use of real-world EHR data and remnant specimens to perform a population PK analysis and investigate covariate effects in a large pediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects of UGT1A4 or UGT2B10 genotype or CYP2A6 risk score.
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- 2022
13. Evidence that geographic variation in genetic ancestry associates with uterine fibroids
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Elizabeth A. Jasper, Todd L. Edwards, Jacklyn N. Hellwege, Digna R. Velez Edwards, Eric S. Torstenson, Sarah H. Jones, and Jacob M. Keaton
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Adult ,Uterine fibroids ,Genetic genealogy ,Ethnic group ,Geographic variation ,Disease ,Biology ,White People ,Risk Factors ,Ethnicity ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,1000 Genomes Project ,Genetics (clinical) ,Aged ,Aged, 80 and over ,Black women ,Geography ,Leiomyoma ,Genetic Variation ,Middle Aged ,medicine.disease ,female genital diseases and pregnancy complications ,Race Factors ,Black or African American ,Uterine Neoplasms ,Trait ,Female ,Demography - Abstract
Uterine fibroids disproportionately impact Black women. Evidence suggests Black women have earlier onset and higher cumulative risk. This risk disparity may be due an imbalance of risk alleles in one parental geographic ancestry subgroup relative to others. We investigated ancestry proportions for the 1000 Genomes phase 3 populations clustered into six geographic groups for association with fibroid traits in Black women (n = 583 cases, 797 controls) and White women (n = 1195 cases, 1164 controls). Global ancestry proportions were estimated using ADMIXTURE. Dichotomous (fibroids status and multiple fibroid status) and continuous outcomes (volume and largest dimension) were modeled for association with ancestry proportions using logistic and linear regression adjusting for age. Effect estimates are reported per 10% increase in genetically inferred ancestry proportion. Among Black women, West African (WAFR) ancestry was associated with fibroid risk, East African ancestry was associated with risk of multiple fibroids, Northern European (NEUR) ancestry was protective for multiple fibroids, Southern European ancestry was protective for fibroids and multiple fibroids, and South Asian (SAS) ancestry was positively associated with volume and largest dimension. In White women, NEUR ancestry was protective for fibroids, SAS ancestry was associated with fibroid risk, and WAFR ancestry was positively associated with volume and largest dimension. These results suggest that a proportion of fibroid risk and fibroid trait racial disparities are due to genetic differences between geographic groups. Further investigation at the local ancestry and single variant levels may yield novel insights into disease architecture and genetic mechanisms underlying ethnic disparities in fibroid risk.
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- 2021
14. Association Between Genetic Variation in Blood Pressure and Increased Lifetime Risk of Peripheral Artery Disease
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Michael G. Levin, Neil M Davies, Julie Lynch, Pradeep Natarajan, Todd L. Edwards, Philip S. Tsao, Daniel J. Rader, Dipender Gill, Benjamin F. Voight, Kyung Min Lee, Derek Klarin, Kyong-Mi Chang, Venexia M Walker, Scott M. Damrauer, Themistocles L. Assimes, Jacklyn N. Hellwege, J. Michael Gaziano, Adriana M. Hung, and Jacob M. Keaton
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0301 basic medicine ,medicine.medical_specialty ,Mean arterial pressure ,Databases, Factual ,medicine.drug_class ,Diastole ,Blood Pressure ,030204 cardiovascular system & hematology ,Polymorphism, Single Nucleotide ,Risk Assessment ,Article ,Coronary artery disease ,Peripheral Arterial Disease ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Antihypertensive Agents ,Thiazide ,business.industry ,Odds ratio ,Mendelian Randomization Analysis ,Protective Factors ,Loop diuretic ,medicine.disease ,United Kingdom ,United States ,Pulse pressure ,Phenotype ,030104 developmental biology ,Blood pressure ,Hypertension ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Genome-Wide Association Study ,medicine.drug - Abstract
Objective: We aimed to estimate the effect of blood pressure (BP) traits and BP-lowering medications (via genetic proxies) on peripheral artery disease. Approach and Results: Genome-wide association studies summary statistics were obtained for BP, peripheral artery disease (PAD), and coronary artery disease. Causal effects of BP on PAD were estimated by 2-sample Mendelian randomization using a range of pleiotropy-robust methods. Increased systolic BP (SBP), diastolic BP, mean arterial pressure (MAP), and pulse pressure each significantly increased risk of PAD (SBP odds ratio [OR], 1.20 [1.16–1.25] per 10 mm Hg increase, P =1×10 −24 ; diastolic BP OR, 1.27 [1.18–1.35], P =4×10 −11 ; MAP OR, 1.26 [1.19–1.33], P =6×10 −16 ; pulse pressure OR, 1.31 [1.24–1.39], P =9×10 −23 ). The effects of SBP, diastolic BP, and MAP were greater for coronary artery disease than PAD (SBP ratio of OR [ROR], 1.06 [1.0–1.12], P = 0.04; MAP ratio of OR, 1.15 [1.06–1.26], P =8.6×10 −4 ; diastolic BP ratio of OR, 1.21 [1.08–1.35], P =6.9×10 −4 ). Considered jointly, both pulse pressure and MAP directly increased risk of PAD (pulse pressure OR, 1.26 [1.17–1.35], P =3×10 −10 ; MAP OR, 1.14 [1.06–1.23], P =2×10 −4 ). The effects of antihypertensive medications were estimated using genetic instruments. SBP-lowering via β-blocker (OR, 0.74 per 10 mm Hg decrease in SBP [95% CI, 0.65–0.84]; P =5×10 −6 ), loop diuretic (OR, 0.66 [0.48–0.91], P =0.01), and thiazide diuretic (OR, 0.57 [0.41–0.79], P =6×10 −4 ) associated variants were protective of PAD. Conclusions: Higher BP is likely to cause PAD. BP-lowering through β blockers, loop diuretics, and thiazide diuretics (as proxied by genetic variants) was associated with decreased risk of PAD. Future study is needed to clarify the specific mechanisms by which BP influences PAD.
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- 2021
15. Diastolic Blood Pressure Alleles Improve Congenital Heart Defect Repair Outcomes
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Joseph H. Breeyear, Jacob M. Keaton, Eric S. Torstenson, Andrew H. Smith, Derek Klarin, Scott M. Damrauer, Pradeep Natarajan, Sara L. Van Driest, Jeffrey G. Weiner, Prince J. Kannankeril, and Todd L. Edwards
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Adult ,Heart Defects, Congenital ,Physiology ,Humans ,Blood Pressure ,Genetic Predisposition to Disease ,Cardiology and Cardiovascular Medicine ,Child ,Alleles ,Article ,Genome-Wide Association Study - Abstract
Background: Congenital heart defects (CHDs) affect 40 000 US births per year, half of which require surgical intervention. Individual differences in surgical outcomes including mortality and complications are not well understood but may be due to genetic variability. We hypothesized that polygenic risk scores (PRSs) for blood pressure in adults are associated with treatments and postsurgical outcomes in children with CHD, as CHD survivors are at higher risk of negative cardiometabolic disease. Methods: We used imputed genotype data from pediatric participants requiring surgery for CHD (median age at surgery, 201 days; n max =2498). Base data for the systolic and diastolic blood pressure PRSs (n max =760 226) came from published genome-wide association study. The blood pressure PRSs were tested for association with postsurgical outcomes. All effects presented are per SD increase in PRS and adjusted for age, sex, body mass index, surgical complexity score, and first 10 principal components of ancestry. Results: A higher diastolic blood pressure PRS was associated with decreased in-hospital mortality risk (odds ratio, 0.57 [0.39–0.82]; P =0.0022). Additional analyses suggest an interaction between diastolic blood pressure PRS and vasopressor dose. Those with a diastolic blood pressure PRS 1 SD above the mean, receiving a vasopressor dose in the top tertile, were estimated to have 52% (32%–66%) lower risk of in-hospital mortality compared with those with a vasopressor dose in the bottom tertile. Conclusions: These results suggest a genetically determined postsurgical survival advantage for CHD patients with blood pressure increasing alleles. Further study may reveal novel mechanisms contributing to postoperative morbidity and mortality, and this approach may assist in early identification of children at risk for adverse postoperative outcomes.
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- 2022
16. Evidence That Geographic Variation in Genetic Ancestry Associates With Uterine Fibroids
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Jacob M. Keaton, Elizabeth A Jasper, Jacklyn N. Hellwege, Sarah H. Jones, Eric S. Torstenson, Todd L. Edwards, and Digna R. Velez Edwards
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female genital diseases and pregnancy complications - Abstract
Uterine fibroids disproportionately impact African American (AA) women. Evidence suggests AA women have earlier onset and higher cumulative risk. This risk disparity may be due an imbalance of risk alleles in one parental geographic subpopulation relative to others. We investigated ancestry proportions for the 1000 Genomes phase 3 populations clustered into 6 geographic groups for association with fibroid traits in AA women (n=583 cases, 797 controls) and European American (EA) women (n=1,195 cases, 1,164 controls). Global ancestry proportions were estimated using ADMIXTURE. Dichotomous (fibroids status and multiple fibroid status) and continuous outcomes (volume and largest dimension) were modeled for association with ancestry proportions using logistic and linear regression adjusting for age. Effect estimates are reported per 10% increase in genetically inferred ancestry proportion. Among AAs, West African (WAFR) ancestry was associated with fibroid risk, East African ancestry was associated with risk of multiple fibroids, Northern European (NEUR) ancestry was protective for multiple fibroids, Southern European ancestry was protective for fibroids and multiple fibroids, and South Asian (SAS) ancestry was positively associated with volume and largest dimension. In EAs, NEUR ancestry was protective for fibroids, SAS ancestry was associated with fibroid risk, and WAFR ancestry was positively associated with volume and largest dimension. These results suggest that a proportion of fibroid risk and fibroid trait racial disparities are due to genetic differences between geographic groups. Further investigation at the local ancestry and single variant levels may yield novel insights about disease architecture and genetic mechanisms underlying ethnic disparities in fibroid risk.
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- 2021
17. Population Pharmacokinetic Analysis of Dexmedetomidine in Children using Real World Data from Electronic Health Records and Remnant Specimens
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Brian Hachey, Sara L. Van Driest, Leena Choi, Prince J. Kannankeril, Richard M. Caprioli, Jacob M. Keaton, Joseph H. Breeyear, Todd L. Edwards, Nathan T. James, and Matthew D. Marshall
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Volume of distribution ,education.field_of_study ,business.industry ,Sedation ,Population ,Confidence interval ,Pharmacokinetics ,Anesthesia ,medicine ,Population study ,Dosing ,medicine.symptom ,Dexmedetomidine ,education ,business ,medicine.drug - Abstract
AimOur objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and data from electronic health records (EHRs) and explore the impact of patient’s characteristics and pharmacogenetics on dexmedetomidine clearance.MethodsDexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modeling. The first stage developed a model without genotype variables; the second stage added pharmacogenetic effects.ResultsOur final study population included 354 post-cardiac surgery patients age 0 to 22 years (median 16 months). The final two-compartment model included allometric weight scaling and age maturation. Population parameter estimates and 95% confidence intervals were 27.3 L/hr (24.0 – 31.1 L/hr) for total clearance (CL), 161 L (139 – 187 L) for central compartment volume of distribution (V1), 26.0 L/hr (22.5 – 30.0 L/hr) for intercompartmental clearance (Q), and 7903 L (5617 – 11119 L) for peripheral compartment volume of distribution (V2). The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0 weeks (41.5 – 42.5 weeks) and the Hill coefficient estimate was 7.04 (6.99 – 7.08). Genotype was not statistically or clinically significant.ConclusionOur study demonstrates the use of real-world EHR data and remnant specimens to perform a population PK analysis and investigate covariate effects in a large pediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects of UGT1A4 or UGT2B10 genotype or CYP2A6 risk score.What is already known about this subject∘Previous dexmedetomidine pharmacokinetic (PK) studies in pediatric populations have limited sample size.∘Smaller studies present a challenge for identifying covariates that may impact individual PK profiles.What this study adds∘We performed a dexmedetomidine population PK study with a large pediatric cohort using data obtained from electronic health records and remnant plasma specimens to enable increased sample size.∘xsDifferences in PK due to UGT1A4 or UGT2B10 variants or CYP2A6 risk score are not clinically impactful for this population.
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- 2021
18. Associations of biogeographic ancestry with hypertension traits
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Yan V. Sun, Csaba P. Kovesdy, Jacklyn N. Hellwege, Million Veteran Program, Jacob M. Keaton, Adriana M. Hung, Digna R. Velez Edwards, Eric S. Torstenson, Peter W.F. Wilson, Ayush Giri, Todd L. Edwards, and Christopher J. O'Donnell
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Physiology ,business.industry ,Genetic genealogy ,Hispanic american ,Blood Pressure ,Odds ratio ,Hispanic or Latino ,Hypertension risk ,White People ,Article ,Black or African American ,Blood pressure ,Negatively associated ,Hypertension prevalence ,Hypertension ,Internal Medicine ,Medicine ,Humans ,1000 Genomes Project ,Cardiology and Cardiovascular Medicine ,business ,Demography - Abstract
OBJECTIVES: Ethnic disparities in hypertension prevalence are well documented, though the influence of genetic ancestry is unclear. The aim of this study was to evaluate associations of geographic genetic ancestry with hypertension and underlying blood pressure traits. METHODS: We tested genetically inferred ancestry proportions from five 1000 Genomes reference populations (GBR, PEL, YRI, CHB, and LWK) for association with four continuous blood pressure (BP) traits (SBP, DBP, PP, MAP) and the dichotomous outcomes hypertension and apparent treatment-resistant hypertension in 220 495 European American, 59 927 African American, and 21 273 Hispanic American individuals from the Million Veteran Program. Ethnicity stratified results were meta-analyzed to report effect estimates per 10% difference for a given ancestry proportion in all samples. RESULTS: Percentage GBR was negatively associated with BP (P = 2.13 × 10(−19), 7.92 × 10(−8), 4.41 × 10(−11), and 3.57 × 10(−13) for SBP, DBP, PP, and MAP, respectively; coefficient range −0.10 to −0.21 mmHg per 10% increase in ancestry proportion) and was protective against hypertension [P = 2.59 × 10(−5), odds ratio (OR) = 0.98] relative to other ancestries. YRI percentage was positively associated with BP (P = 1.63 × 10(−23), 1.94 × 10(−26), 0.012, and 3.26 × 10(−29) for SBP, DBP, PP, and MAP, respectively; coefficient range 0.06–0.32 mmHg per 10% increase in ancestry proportion) and was positively associated with hypertension risk (P = 3.10 × 10(−11), OR = 1.04) and apparent treatment-resistant hypertension risk (P = 1.86 × 10(−4), OR = 1.04) compared with other ancestries. Percentage PEL was inversely associated with DBP (P = 2.84 × 10(−5), beta = −0.11 mmHg per 10% increase in ancestry proportion). CONCLUSION: These results demonstrate that risk for BP traits varies significantly by genetic ancestry. Our findings provide insight into the geographic origin of genetic factors underlying hypertension risk and establish that a portion of BP trait ethnic disparities are because of genetic differences between ancestries.
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- 2021
19. Genome-wide association study of vitamin D concentrations and bone mineral density in the African American-Diabetes Heart Study
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Leon Lenchik, Donald W. Bowden, S. Carrie Smith, Anthony J. Hanley, Jill M. Norris, Corinne D. Engelman, Nicholette D. Palmer, Pamela J. Hicks, Lingyi Lu, Jasmin Divers, Jacob M. Keaton, Yii-Der Ida Chen, Thomas C. Register, Lynne E. Wagenknecht, Carl D. Langefeld, Meijian Guan, Barry I. Freedman, Jianzhao Xu, Maggie C.Y. Ng, Latchezar Dimitrov, and J. Jeffrey Carr
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Male ,0301 basic medicine ,Bone density ,Vitamin D-binding protein ,Organic chemistry ,Genome-wide association study ,Type 2 diabetes ,Biochemistry ,Vascular Medicine ,Geographical Locations ,Endocrinology ,Medical Conditions ,0302 clinical medicine ,Bone Density ,Medicine and Health Sciences ,Ethnicities ,Vitamin D ,African American people ,Musculoskeletal System ,Bone mineral ,Multidisciplinary ,Vitamin D-Binding Protein ,Vitamins ,Genomics ,Middle Aged ,Population groupings ,Type 2 Diabetes ,Physical sciences ,Europe ,Chemistry ,Connective Tissue ,Medicine ,Female ,Anatomy ,Research Article ,medicine.medical_specialty ,Endocrine Disorders ,Bone and Mineral Metabolism ,Science ,030209 endocrinology & metabolism ,Biology ,Chemical compounds ,03 medical and health sciences ,Insulin resistance ,Internal medicine ,Diabetes mellitus ,Organic compounds ,Genome-Wide Association Studies ,Genetics ,Diabetes Mellitus ,medicine ,Vitamin D and neurology ,Humans ,Bone ,Skeleton ,Aged ,Polymorphism, Genetic ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,Genome Analysis ,Atherosclerosis ,medicine.disease ,Black or African American ,Biological Tissue ,Metabolism ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Metabolic Disorders ,People and places ,Genome-Wide Association Study - Abstract
Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (β = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (β = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; β = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; β = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; β = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.
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- 2021
20. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
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Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris
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0303 health sciences ,Transferability ,Translation (biology) ,Type 2 diabetes ,Biology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Evolutionary biology ,Global health ,medicine ,Genetic risk ,Gene ,030217 neurology & neurosurgery ,030304 developmental biology ,Genetic association - Abstract
We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.
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- 2020
21. A genome-wide association study of polycystic ovary syndrome identified from electronic health records
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Ky’Era Actkins, Kevin Ho, Gail P. Jarvik, Brody Holohan, Felix R. Day, Navya Shilpa Josyula, Yanfei Zhang, Hakon Hakonarson, Sarah A. Pendergrass, Digna R. Velez Edwards, Ming Ta Michael Lee, Jacob M. Keaton, Dustin N. Hartzel, David R. Crosslin, Patrick M. A. Sleiman, Lea K. Davis, Marc S. Williams, Anne E. Justice, Andrea H. Ramirez, and Ian B. Stanaway
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Adult ,Infertility ,Oncology ,medicine.medical_specialty ,Receptor, ErbB-4 ,Population ,Single-nucleotide polymorphism ,Genome-wide association study ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Electronic Health Records ,Humans ,030212 general & internal medicine ,education ,ERBB4 ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,education.field_of_study ,0303 health sciences ,030219 obstetrics & reproductive medicine ,Superoxide Dismutase ,business.industry ,Hyperandrogenism ,Obstetrics and Gynecology ,YAP-Signaling Proteins ,Middle Aged ,medicine.disease ,Phenotype ,Polycystic ovary ,Biobank ,3. Good health ,Oligomenorrhea ,Ovarian Cysts ,Case-Control Studies ,Transcriptional Coactivator with PDZ-Binding Motif Proteins ,Trans-Activators ,Etiology ,Female ,business ,Infertility, Female ,Genome-Wide Association Study ,Polycystic Ovary Syndrome ,Transcription Factors - Abstract
BackgroundPolycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. Previous studies have identified genetic variants associated with PCOS identified by different diagnostic criteria. The Rotterdam Criteria is the broadest and able to identify the most PCOS cases.ObjectivesTo identify novel associated genetic variants, we extracted PCOS cases and controls from the electronic health records (EHR) based on the Rotterdam Criteria and performed a genome-wide association study (GWAS).Study DesignWe developed a PCOS phenotyping algorithm based on the Rotterdam criteria and applied it to three EHR-linked biobanks to identify cases and controls for genetic study. In discovery phase, we performed individual GWAS using the Geisinger’s MyCode and the eMERGE cohorts, which were then meta-analyzed. We attempted validation of the significantly association loci (P−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-analyses. Additionally, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used STRING to identify protein-protein interaction network.ResultsWe identified 2,995 PCOS cases and 53,599 controls in total (2,742cases and 51,438 controls from the discovery phase; 253 cases and 2,161 controls in the validation phase). GWAS identified one novel genome-wide significant variant rs17186366 (OR=1.37 [1.23,1.54], P=2.8×10−8) located nearSOD2. Additionally, two loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42,2.10], P=5.2 x10−8), an intronic variant ofERBB4that 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 inWWTR1. In the further association tests of the top 3 SNPs with each criterion in the PCOS algorithm, we found that rs17186366 was associated with polycystic and hyperandrogenism, while rs11316812 and rs144248326 were mainly associated with oligomenorrhea or infertility. Besides ERBB4, we also validated the association withDENND1A1.ConclusionThrough a discovery-validation GWAS on PCOS cases and controls identified from EHR using an algorithm based on Rotterdam criteria, we identified and validated a novel association with variants withinERBB4. We also identified novel associations nearbySOD2andWWTR1. These results suggest the eGFR and Hippo pathways in the disease etiology. With previously identified PCOS-associated lociYAP1, theERBB4-YAP1-WWTR1network implicates the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of PCOS.
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- 2019
22. Discovery of 318 novel loci for type-2 diabetes and related micro- and macrovascular outcomes among 1.4 million participants in a multi-ethnic meta-analysis
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Kyung Min Lee, Yan V. Sun, Daniel J. Rader, Todd L. Edwards, Julie A. Lynch, Kyong-Mi Chang, Christopher J. O'Donnell, Danish Saleheen, Asif Rasheed, Jie Huang, Shahid Abbas, Olle Melander, Jennifer Lee, Muhammad Naeem Afzal, Saiju Pyarajan, Jacob M. Keaton, Marijana Vujkovic, Long Gao, James B. Meigs, Jennifer E. Huffman, Uzma Jahazaib, Peter W.F. Wilson, Renae Judy, Philip S. Tsao, Saqib Shafi Sheikh, John Michael Gaziano, Kelly Cho, Derek Klarin, Irshad Hussain Qureshi, Jin Zhou, Peter D. Reaven, Katalin Susztak, Lawrence S. Philips, John Danesh, Anjum Jalal, Scott L. DuVall, Shahid Hameed, Donald R. Miller, Klaus H. Kaestner, Xin Sheng, Scott M. Damrauer, Nadeem Qamar, Themistocles L. Assimes, Benjamin F. Voight, and Catherine Tcheandjieu
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0303 health sciences ,endocrine system diseases ,business.industry ,nutritional and metabolic diseases ,Disease ,Type 2 diabetes ,Bioinformatics ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Meta-analysis ,Genetic predisposition ,Medicine ,business ,Stroke ,030217 neurology & neurosurgery ,030304 developmental biology ,Genetic association ,Kidney disease ,Retinopathy - Abstract
We investigated type 2 diabetes (T2D) genetic susceptibility in a multi-ethnic meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP) and other biobanks. We identified 558 autosomal and 10 X-chromosome T2D-associated variants, of which 286 autosomal and 7 X-chromosome variants were previously unreported. Ancestry-specific analyses identified 25 additional novel T2D-susceptibility variants. Transcriptome-wide association analysis detected 3,568 T2D-associations with T2D-colocalized genetically predicted gene expression of 804 genes in 52 tissues, of which 687 are novel. Fifty-four of these genes are known to interact with FDA-approved drugs and chemical compounds. T2D polygenic risk score was strongly associated with increased the risk of T2D-related retinopathy, and additionally showed evidence for association with chronic kidney disease (CKD), neuropathy, and peripheral artery disease (PAD). We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including 3 for coronary heart disease, 1 for PAD, 2 for stroke, 4 for retinopathy, 2 for CKD, and 1 for neuropathy. Our findings may identify potential novel therapeutic targets for T2D and genomic pathways that link T2D and its vascular outcomes.
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- 2019
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23. Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis
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Marijana, Vujkovic, Jacob M, Keaton, Julie A, Lynch, Donald R, Miller, Jin, Zhou, Catherine, Tcheandjieu, Jennifer E, Huffman, Themistocles L, Assimes, Kimberly, Lorenz, Xiang, Zhu, Austin T, Hilliard, Renae L, Judy, Jie, Huang, Kyung M, Lee, Derek, Klarin, Saiju, Pyarajan, John, Danesh, Olle, Melander, Asif, Rasheed, Nadeem H, Mallick, Shahid, Hameed, Irshad H, Qureshi, Muhammad Naeem, Afzal, Uzma, Malik, Anjum, Jalal, Shahid, Abbas, Xin, Sheng, Long, Gao, Klaus H, Kaestner, Katalin, Susztak, Yan V, Sun, Scott L, DuVall, Kelly, Cho, Jennifer S, Lee, J Michael, Gaziano, Lawrence S, Phillips, James B, Meigs, Peter D, Reaven, Peter W, Wilson, Todd L, Edwards, Daniel J, Rader, Scott M, Damrauer, Christopher J, O'Donnell, Philip S, Tsao, Kyong-Mi, Chang, Benjamin F, Voight, and Sumitra, Muralidhar
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Oncology ,Male ,medicine.medical_specialty ,endocrine system diseases ,Type 2 diabetes ,Disease ,Biology ,Polymorphism, Single Nucleotide ,Risk Assessment ,Article ,Diabetes Complications ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,Genetics ,medicine ,Genetic predisposition ,Humans ,Hypoglycemic Agents ,Genetic Predisposition to Disease ,Genetic Association Studies ,030304 developmental biology ,Genetic association ,0303 health sciences ,Chromosomes, Human, X ,nutritional and metabolic diseases ,medicine.disease ,Black or African American ,Europe ,Diabetes Mellitus, Type 2 ,Meta-analysis ,Medical genetics ,Female ,030217 neurology & neurosurgery ,Diabetic Angiopathies ,Kidney disease - Abstract
We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.
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- 2019
24. An Exome-wide Association Study for Type 2 Diabetes–Attributed End-Stage Kidney Disease in African Americans
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Jianzhao Xu, Latchezar Dimitrov, Pamela J. Hicks, James G. Wilson, Meijian Guan, Barry I. Freedman, Nicholette D. Palmer, Maggie C.Y. Ng, Jacob M. Keaton, and Donald W. Bowden
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Genome-wide association study ,Type 2 diabetes ,lcsh:RC870-923 ,03 medical and health sciences ,Clinical Research ,Internal medicine ,Diabetes mellitus ,end-stage kidney disease ,Medicine ,genetics ,Exome ,Exome sequencing ,Genetic association ,African Americans ,business.industry ,Odds ratio ,medicine.disease ,lcsh:Diseases of the genitourinary system. Urology ,3. Good health ,030104 developmental biology ,Nephrology ,type 2 diabetes ,business ,exome sequencing ,chronic kidney disease ,Kidney disease - Abstract
Introduction: Compared with European Americans, African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD). Genome-wide association studies (GWAS) have identified >70 genetic variants associated with kidney function and chronic kidney disease (CKD) in patients with and without diabetes. However, these variants explain a small proportion of disease liability. This study examined the contribution of coding genetic variants for risk of type 2 diabetes (T2D)-attributed ESKD and advanced CKD in AAs. Methods: Exome sequencing was performed in 456 AA T2D-ESKD cases, and 936 AA nondiabetic, non-nephropathy control individuals at the discovery stage. A mixed logistic regression model was used for association analysis. Nominal associations (P < 0.05) were replicated in an additional 2020 T2D-ESKD cases and 1121 nondiabetic, non-nephropathy control individuals. A meta-analysis combining 4533 discovery and replication samples was performed. Putative T2D-ESKD associations were tested in additional 1910 nondiabetic ESKD and 219 T2D-ESKD cases, as well as 912 AA nondiabetic non-nephropathy control individuals. Results: A total of 11 suggestive T2D-ESKD associations (P < 1 x 10−4) from 8 loci (PLEKHN1, NADK, RAD51AP2, RREB1, PEX6, GRM8, PRX, APOL1) were apparent in the meta-analysis. Exclusion of APOL1 renal-risk genotype carriers identified 3 additional suggestive loci (OTUD7B, IFITM3, DLGAP5). Rs41302867 in RREB1 displayed consistent association with T2D-ESKD and nondiabetic ESKD (odds ratio: 0.47; P = 1.2 x 10−6 in 4605 all-cause ESKD and 2969 nondiabetic non-nephropathy control individuals). Conclusion: Our findings suggest that coding genetic variants are implicated in predisposition to T2D-ESKD in AAs. Keywords: African Americans, chronic kidney disease, end-stage kidney disease, exome sequencing, genetics, type 2 diabetes
- Published
- 2018
25. Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program
- Author
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Cecilia P. Chung, Edward D. Siew, Elvis A. Akwo, Cristian Pattaro, Yong Li, Philip S. Tsao, Derek Klarin, Peter W.F. Wilson, Man Li, Scott L. DuVall, Anna Köttgen, Jacob M. Keaton, Jacklyn N. Hellwege, Adriana M. Hung, Chengxiang Qiu, Mathias Gorski, J. Michael Gaziano, Matthias Wuttke, Scott M. Damrauer, Katalin Susztak, Todd L. Edwards, Christianne L. Roumie, Otis D. Wilson, Christopher J. O'Donnell, Csaba P. Kovesdy, Digna R. Velez Edwards, Ayush Giri, Eric S. Torstenson, Jihwan Park, and Cassianne Robinson-Cohen
- Subjects
Male ,0301 basic medicine ,Oncology ,General Physics and Astronomy ,Genome-wide association study ,02 engineering and technology ,Kidney ,Cohort Studies ,Mice ,Chronic kidney disease ,RNA-Seq ,lcsh:Science ,Veterans ,Multidisciplinary ,Chromosome Mapping ,Middle Aged ,021001 nanoscience & nanotechnology ,3. Good health ,United States Department of Veterans Affairs ,medicine.anatomical_structure ,Biomarker (medicine) ,Female ,0210 nano-technology ,Glomerular Filtration Rate ,Adult ,medicine.medical_specialty ,Science ,Renal function ,Context (language use) ,Polymorphism, Single Nucleotide ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Renal Insufficiency, Chronic ,Aged ,urogenital system ,business.industry ,Computational Biology ,Kidney metabolism ,General Chemistry ,medicine.disease ,United States ,030104 developmental biology ,Genetic Loci ,lcsh:Q ,Kidney stones ,Gene expression ,Transcriptome ,business ,Genome-Wide Association Study ,Kidney disease - Abstract
Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation., Persistently low levels of estimated glomerular filtration rate (eGFR) are a biomarker of chronic kidney disease. Here, the authors reinterpret the genetic architecture of kidney function across ancestries, to identify not only genes, but the tissue and anatomical contexts of renal homeostasis.
- Published
- 2019
26. Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans
- Author
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Jianzhao Xu, Nora Franceschini, Pamela J. Hicks, Meijian Guan, Wendy S. Post, Swapan K Das, Lijun Ma, Barry I. Freedman, John R. Sedor, Yii-Der Ida Chen, Denyse Thornley-Brown, Laura J. Rasmussen-Torvik, Donald W. Bowden, Josef Coresh, Jacob M. Keaton, Carl D. Langefeld, Maggie C.Y. Ng, Adrienne Tin, Holly Kramer, Josyf C. Mychaleckyj, Jerome I. Rotter, Stephen S. Rich, Nicholette D. Palmer, Myriam Fornage, Latchezar Dimitrov, Rulan S. Parekh, and James G. Wilson
- Subjects
Genome-wide association study ,medicine.medical_specialty ,lcsh:QH426-470 ,lcsh:Medicine ,Locus (genetics) ,Type 2 diabetes ,Disease ,03 medical and health sciences ,Internal medicine ,Drug Discovery ,Genotype ,Genetics ,Genetic predisposition ,Medicine ,Diabetic kidney disease ,1000 Genomes Project ,Molecular Biology ,African Americans ,0303 health sciences ,business.industry ,lcsh:R ,030305 genetics & heredity ,End-stage kidney disease ,medicine.disease ,3. Good health ,lcsh:Genetics ,Molecular Medicine ,Primary Research ,business ,Kidney disease - Abstract
Background End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N = 10,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants. Results Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P
- Published
- 2019
27. Trans-ethnic association study of blood pressure determinants in over 750,000 individuals
- Author
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Dennis O. Mook-Kanamori, J M Gaziano, Harst Pvd., Derek Klarin, K A Birdwell, Josh C. Denny, Martin Farrall, Thibaud Boutin, Najim Lahrouchi, Nabi Shah, Scott M. Damrauer, Cecilia P. Chung, Neil Poulter, Herzig K-H., E E Siew, John Concato, Yan V. Sun, Sara M. Willems, Louise V. Wain, Philip S. Tsao, Massimo Mangino, Wei W-Q., Ioanna Ntalla, Brian S. Mautz, David Schlessinger, Daniel I. Chasman, Branwen J. Hennig, Christopher Newton-Cheh, Michael E. Matheny, Palmer Cna., Caroline Hayward, Zhao J-H., Eleftheria Zeggini, Paul Elliott, C M Lindgren, Praveen Surendran, Csaba P. Kovesdy, Jacob M. Keaton, Chengxiang Qiu, Claudia Langenberg, Christopher Oldmeadow, Stéphanie Debette, D.R. Velez Edwards, Evangelos Evangelou, Howson Jmm., Adriana M. Hung, Yaomin Xu, Nicholas J. Wareham, James P. Cook, Scott L. DuVall, Peter Almgren, Jacklyn N. Hellwege, Sébastien Thériault, Helen R. Warren, Jian'an Luan, Ching-Ti Liu, Christopher J. O'Donnell, Michael Boehnke, Peter S. Sever, Ruifang Li-Gao, Cassianne Robinson-Cohen, Robert A. Scott, Muralidharan Sargurupremraj, Mark J. Caulfield, Jarvelin M-R., Tim D. Spector, Todd L. Edwards, Elena V. Feofanova, Francesco Cucca, Jihwan Park, Savita Karthikeyan, J C Smith, Wilson Pwf., Markku Laakso, Ayush Giri, Christianne L. Roumie, Rojesh Shrestha, Claudia P. Cabrera, Kelly Cho, Laura J. Scott, Elvis A. Akwo, Yu Wang, Tom G. Richardson, Patricia B. Munroe, Eric S. Torstenson, Katalin Susztak, John Attia, Bruce M. Psaty, Aldi T. Kraja, Olle Melander, Nicholas J. Timpson, George Dedoussis, Paul M. Ridker, Niek Verweij, David Conen, Philippe Amouyel, Otis D. Wilson, Nuno Sepúlveda, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiology, ACS - Heart failure & arrhythmias, Cardiovascular Centre (CVC), Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Surendran, Praveen [0000-0002-4911-6077], Karthikeyan, Savita [0000-0002-4798-5746], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Howson, Joanna [0000-0001-7618-0050], and Apollo - University of Cambridge Repository
- Subjects
Male ,LOCI ,Gene Expression ,Physiology ,Blood Pressure ,Genome-wide association study ,IDENTIFIES 8 ,Mice ,0302 clinical medicine ,Ethnicity ,PARTITIONING HERITABILITY ,Genetics & Heredity ,0303 health sciences ,Kidney ,Blood Pressure-International Consortium of Exome Chip Studies ,Million Veteran Program ,PULSE PRESSURE ,11 Medical And Health Sciences ,Middle Aged ,Up-Regulation ,3. Good health ,Pulse pressure ,Kidney Tubules ,medicine.anatomical_structure ,VINTAGE ,International Consortium for Blood Pressure ,AUTOSOMAL-DOMINANT HYPERTENSION ,Female ,Life Sciences & Biomedicine ,Understanding Society Scientific Group ,Adolescent ,Diastole ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Genetics ,medicine ,Animals ,Humans ,GENOME-WIDE ASSOCIATION ,Gene ,030304 developmental biology ,Genetic association ,Science & Technology ,06 Biological Sciences ,GLOBAL BURDEN ,MEAN ARTERIAL ,GENE ,Blood pressure ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,SOLUBLE GUANYLYL CYCLASE ,Transcriptome ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Developmental Biology - Abstract
International audience; In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.
- Published
- 2019
28. Association of kidney structure-related gene variants with type 2 diabetes-attributed end-stage kidney disease in African Americans
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Maggie C.Y. Ng, Latchezar Dimitrov, Mary Stromberg, Poorva Mudgal, Jun Ma, Jason A. Bonomo, Pamela J. Hicks, Meijian Guan, Barry I. Freedman, Donald W. Bowden, and Jacob M. Keaton
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Genotype ,Population ,030232 urology & nephrology ,Single-nucleotide polymorphism ,Type 2 diabetes ,Biology ,Polymorphism, Single Nucleotide ,White People ,Article ,Nephropathy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Glomerular Basement Membrane ,Genetics ,medicine ,Humans ,Diabetic Nephropathies ,Genetic Predisposition to Disease ,Alport syndrome ,Kidney Tubules, Distal ,education ,Genetics (clinical) ,Adaptor Proteins, Signal Transducing ,Aged ,Kidney ,education.field_of_study ,Podocytes ,Glomerular basement membrane ,Middle Aged ,medicine.disease ,Cytoskeletal Proteins ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Haplotypes ,Mesangial Cells ,Kidney Failure, Chronic ,Matrix Metalloproteinase 2 ,Female ,Genome-Wide Association Study ,Kidney disease - Abstract
African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D)-attributed ESKD in AAs. Single-variant association analysis was performed in the discovery stage, including 2041 T2D-ESKD cases and 1140 controls (non-diabetic, non-nephropathy). Discrimination analyses in 667 T2D cases-lacking nephropathy excluded T2D-associated SNPs. Nominal associations were tested in an additional 483 T2D-ESKD cases and 554 controls in the replication stage. Meta-analysis of 4218 discovery and replication samples revealed three significant associations with T2D-ESKD at CD2AP and MMP2 (P corr < 0.05 corrected for effective number of SNPs in each locus). Removal of APOL1 renal-risk genotype carriers revealed additional association at five loci, TTC21B, COL4A3, NPHP3-ACAD11, CLDN8, and ARHGAP24 (P corr
- Published
- 2016
29. Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans
- Author
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Myriam Fornage, Yii-Der Ida Chen, Maggie C.Y. Ng, James S. Pankow, Stephen S. Rich, Jerome I. Rotter, Adolfo Correa, Laura J. Rasmussen-Torvik, Donald W. Bowden, Kent D. Taylor, James G. Wilson, Meijian Guan, Barry I. Freedman, Chuan Gao, Lynne E. Wagenknecht, Jacob M. Keaton, Jacklyn N. Hellwege, and Nicholette D. Palmer
- Subjects
0301 basic medicine ,Male ,Epidemiology ,medicine.medical_treatment ,Genome-wide association study ,Type 2 diabetes ,Body Mass Index ,0302 clinical medicine ,Models ,insulin resistance ,Insulin Secretion ,2.1 Biological and endogenous factors ,Insulin ,Aetiology ,Genetics (clinical) ,Melatonin ,Genetics ,Diabetes ,Adaptor Proteins ,Single Nucleotide ,Middle Aged ,Public Health and Health Services ,Female ,Type 2 ,Receptor ,Adult ,030209 endocrinology & metabolism ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Insulin resistance ,Genetic ,Diabetes Mellitus ,medicine ,insulin sensitivity ,SNP ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,1000 Genomes Project ,Metabolic and endocrine ,Adaptor Proteins, Signal Transducing ,Aged ,Adiponectin ,Models, Genetic ,Receptor, Melatonin, MT2 ,Prevention ,MT2 ,Human Genome ,Signal Transducing ,nutritional and metabolic diseases ,Epistasis, Genetic ,medicine.disease ,Black or African American ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,Epistasis ,gene-gene interactions ,Genome-Wide Association Study - Abstract
Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P 
- Published
- 2018
30. Population Stratification in Genetic Association Studies
- Author
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Todd L. Edwards, Digna R. Velez Edwards, Xiaoyi Gao, Jacklyn N. Hellwege, Jacob M. Keaton, and Ayush Giri
- Subjects
0301 basic medicine ,Models, Statistical ,Models, Genetic ,Confounding ,Genetic admixture ,Chromosome Mapping ,Biology ,Population stratification ,Article ,Linkage Disequilibrium ,Evolution, Molecular ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Genetics, Population ,Quantitative Trait, Heritable ,Gene Frequency ,Genetics ,Humans ,030217 neurology & neurosurgery ,Genetics (clinical) ,Alleles ,Genetic Association Studies ,Demography ,Genetic association - Abstract
Population stratification (PS) is a primary consideration in studies of genetic determinants of human traits. Failure to control for PS may lead to confounding, causing a study to fail for lack of significant results, or resources to be wasted following false-positive signals. Here, historical and current approaches for addressing PS when performing genetic association studies in human populations are reviewed. Methods for detecting the presence of PS, including global and local ancestry methods, are described. Also described are approaches for accounting for PS when calculating association statistics, such that measures of association are not confounded. Many traits are being examined for the first time in minority populations, which may inherently feature PS. © 2017 by John Wiley & Sons, Inc.
- Published
- 2017
31. A comparison of type 2 diabetes risk allele load between African Americans and European Americans
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Jacob M. Keaton, Nicholette D. Palmer, Carl D. Langefeld, Maggie C.Y. Ng, Jessica N. Cooke Bailey, Barry I. Freedman, and Donald W. Bowden
- Subjects
Adult ,Male ,Risk ,endocrine system diseases ,Population ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Article ,White People ,Gene Frequency ,Genetics ,Humans ,Allele ,education ,Allele frequency ,Genetic Association Studies ,Genetics (clinical) ,Aged ,Genetic association ,education.field_of_study ,Middle Aged ,Genetic architecture ,Black or African American ,Diabetes Mellitus, Type 2 ,Kidney Failure, Chronic ,Female ,TCF7L2 ,Demography - Abstract
The prevalence of type 2 diabetes (T2D) is greater in populations of African descent compared to European-descent populations. Genetic risk factors may underlie the disparity in disease prevalence. Genome-wide association studies (GWAS) have identified >60 common genetic variants that contribute to T2D risk in populations of European, Asian, African and Hispanic descent. These studies have not comprehensively examined population differences in cumulative risk allele load. To investigate the relationship between risk allele load and T2D risk, 46 T2D single nucleotide polymorphisms (SNPs) in 43 loci from GWAS in European, Asian, and African-derived populations were genotyped in 1,990 African Americans (n = 963 T2D cases, n = 1,027 controls) and 1,644 European Americans (n = 719 T2D cases, n = 925 controls) ascertained and recruited using a common protocol in the southeast United States. A genetic risk score (GRS) was constructed from the cumulative risk alleles for each individual. In African American subjects, risk allele frequencies ranged from 0.024 to 0.964. Risk alleles from 26 SNPs demonstrated directional consistency with previous studies, and 3 SNPs from ADAMTS9, TCF7L2, and ZFAND6 showed nominal evidence of association (p < 0.05). African American individuals carried 38–67 (53.7 ± 4.0, mean ± SD) risk alleles. In European American subjects, risk allele frequencies ranged from 0.084 to 0.996. Risk alleles from 36 SNPs demonstrated directional consistency, and 10 SNPs from BCL11A, PSMD6, ADAMTS9, ZFAND3, ANK1, CDKN2A/B, TCF7L2, PRC1, FTO, and BCAR1 showed evidence of association (p < 0.05). European American individuals carried 38–65 (50.9 ± 4.4) risk alleles. African Americans have a significantly greater burden of 2.8 risk alleles (p = 3.97 × 10−89) compared to European Americans. However, GRS modeling showed that cumulative risk allele load was associated with risk of T2D in European Americans, but only marginally in African Americans. This result suggests that there are ethnic-specific differences in genetic architecture underlying T2D, and that these differences complicate our understanding of how risk allele load impacts disease susceptibility.
- Published
- 2014
32. Coding Variants in Nephrin (NPHS1) and Susceptibility to Nephropathy in African Americans
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Jason A. Bonomo, Christopher P. Larsen, Jacob M. Keaton, Carl D. Langefeld, Nicholette D. Palmer, Pamela J. Hicks, Donald W. Bowden, Barry I. Freedman, and Maggie C.Y. Ng
- Subjects
Male ,medicine.medical_specialty ,Epidemiology ,Critical Care and Intensive Care Medicine ,Polymorphism, Single Nucleotide ,Risk Assessment ,Nephropathy ,End stage renal disease ,Diabetic nephropathy ,Gene Frequency ,Risk Factors ,Internal medicine ,Odds Ratio ,Humans ,Medicine ,Diabetic Nephropathies ,Genetic Predisposition to Disease ,Allele frequency ,Exome sequencing ,Aged ,Transplantation ,business.industry ,Case-control study ,Membrane Proteins ,Original Articles ,Odds ratio ,Middle Aged ,Protective Factors ,Apolipoprotein L1 ,medicine.disease ,Black or African American ,Minor allele frequency ,Apolipoproteins ,Phenotype ,Diabetes Mellitus, Type 2 ,Nephrology ,Case-Control Studies ,Kidney Failure, Chronic ,Female ,Lipoproteins, HDL ,business - Abstract
Background and objectives Presumed genetic risk for diabetic and nondiabetic end stage renal disease is strong in African Americans. Design, setting, participants, & measurements Exome sequencing data from African Americans with type 2 diabetic end stage renal disease and nondiabetic, non-nephropathy controls in the T2D-GENES study (Discovery, n =529 patients and n =535 controls) were evaluated, focusing on missense variants in NPHS1 . Associated variants were then evaluated in independent type 2 diabetic end stage renal disease (Replication, n =1305 patients and n =760 controls), nondiabetic end stage renal disease ( n =1705), and type 2 diabetes-only, non-nephropathy samples ( n =503). All participants were recruited from dialysis facilities and internal medicine clinics across the southeastern United States from 1991 to present. Additional NPHS1 missense variants were identified from exome sequencing resources, genotyped, and sequence kernel association testing was then performed. Results Initial analysis identified rs35238405 (T233A; minor allele frequency=0.0096) as associated with type 2 diabetic end stage renal disease (adjustment for admixture P =0.042; adjustment for admixture+ APOL1 P=0.080; odds ratio, 2.89 and 2.36, respectively); with replication in independent type 2 diabetic end stage renal disease samples ( P =0.018; odds ratio, 4.30) and nondiabetic end stage renal disease samples ( P =0.016; odds ratio, 4.48). In a combined analysis (all patients with end stage renal disease versus all controls), T233A was associated with all-cause end stage renal disease ( P =0.0038; odds ratio, 2.82; n =3270 patients and n =1187 controls). A P -value of APOL1 in sequence kernel association testing. Two additional variants (H800R and Y1174H) were nominally associated with protection from end stage renal disease ( P =0.036; odds ratio, 0.44; P =0.0084; odds ratio, 0.040, respectively) in the locus-wide single-variant association tests. Conclusions Coding variants in NPHS1 are associated with both risk for and protection from common forms of nephropathy in African Americans.
- Published
- 2014
33. The ras responsive transcription factor RREB1 is a novel candidate gene for type 2 diabetes associated end-stage kidney disease
- Author
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Maggie C.Y. Ng, Donald W. Bowden, Pamela J. Hicks, Meijian Guan, Barry I. Freedman, Jason A. Bonomo, Nicholette D. Palmer, Carl D. Langefeld, Janice P. Lea, and Jacob M. Keaton
- Subjects
Male ,Candidate gene ,endocrine system diseases ,Angiotensinogen ,Mutation, Missense ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,White People ,Polymorphism (computer science) ,Odds Ratio ,Genetics ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,Molecular Biology ,Gene ,Genetics (clinical) ,Exome sequencing ,Aged ,Haplotype ,nutritional and metabolic diseases ,Articles ,General Medicine ,Odds ratio ,Middle Aged ,Black or African American ,DNA-Binding Proteins ,Alternative Splicing ,Diabetes Mellitus, Type 2 ,Haplotypes ,Genetic Loci ,Case-Control Studies ,Kidney Failure, Chronic ,Female ,Genome-Wide Association Study ,Transcription Factors - Abstract
Familial clustering and presumed genetic risk for type 2 diabetic (T2D) and non-diabetic end-stage kidney disease (ESKD) appear strong in African Americans. Examination of exome sequencing data in African American T2D-ESKD cases and non-diabetic non-nephropathy controls identified two low-frequency variants in the RREB1 gene, a repressor of the angiotensinogen (AGT) gene previously associated with kidney function, as being associated with T2D-ESKD: rs9379084 (P = 0.00087, OR = 0.26; D1171N) and rs41302867 (P = 0.00078, OR = 0.21; splice site variant). Rs41302867 replicated association in an independent sample of African Americans with T2D-ESKD [rs41302867 P = 0.033 (OR = 0.50)], and a trend towards rs9379084 association was observed (P = 0.070). In European Americans with T2D-ESKD compared with European American population based controls, both RREB1 variants replicated association [rs9379084 P = 1.67 × 10(-4) (OR = 0.54) and rs41302867 P = 0.013 (OR = 0.69)]. Rs9379084 was not associated with non-T2D-ESKD or T2D in African Americans (P = 0.55 and P = 0.37, respectively), but was associated with T2D in European Americans (P = 0.014, OR = 0.65). In African Americans, rs41302867 was associated with non-T2D-ESKD [P = 0.036 (OR = 0.54)] and hypertension attributed ESKD [H-ESKD, P = 0.029 (OR = 0.50)]. A meta-analysis combining African American and European American T2D-ESKD data revealed P = 3.52 × 10(-7) and 3.70 × 10(-5) for rs9379084 and rs41302867 association, respectfully. A locus-wide analysis evaluating putatively functional SNPs revealed several nominal associations with T2D-ESKD, non-T2D-ESKD and T2D in African and European Americans. RREB1 is a large, complex gene which codes a multidomain zinc finger binding protein and transcription factor. We posit that variants in RREB1 modulate seemingly disparate phenotypes (i.e. T2D, T2D-ESKD and non-T2D-ESKD) through altered activity resulting from splice site and missense variants.
- Published
- 2014
34. Interisland Range Expansion of Viola lanaiensis (Violaceae: Malpighiales), an Endangered Hawaiian Violet
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Krystal Piotrowski, Hank Oppenheimer, J. Christopher Havran, and Jacob M. Keaton
- Subjects
Polytomy ,Viola lanaiensis ,education.field_of_study ,Multidisciplinary ,Population ,Zoology ,Biology ,biology.organism_classification ,Maximum parsimony ,Malpighiales ,Botany ,Threatened species ,education ,Viola (butterfly) ,Violaceae - Abstract
The monophyletic Hawaiian violet lineage includes five species that are endangered or threatened. A new population of Viola was recently discovered on Helu Peak, West Maui. Individuals in the Helu Peak population appeared morphologically similar to critically imperiled Viola lanaiensis, endemic to the nearby island of Lāna'i. To identify the population on Maui, the Internal Transcribed Spacer sequence from the new population was compared with all other known Hawaiian violets using maximum parsimony. Leaf and floral traits were compared between the Helu Peak population, V. lanaiensis, and V. oahuensis. Maximum parsimony analysis placed the Helu Peak population in an unresolved polytomy with V. lanaiensis and V. oahuensis. Canonical Variates Analysis of leaf variables suggests that the Maui population is morphologically indistinguishable from V. lanaiensis. Floral organ lengths of the new population overlap with previously published values for V. lanaiensis. Due to similarities in morphology and c...
- Published
- 2012
35. GENOME-WIDE INTERACTION WITH SELECTED TYPE 2 DIABETES LOCI REVEALS NOVEL LOCI FOR TYPE 2 DIABETES IN AFRICAN AMERICANS
- Author
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Yii-Der Ida Chen, Jacob M. Keaton, Barry I. Freedman, Donald W. Bowden, Stephen S. Rich, Myriam Fornage, James S. Pankow, Nicholette D. Palmer, Jerome I. Rotter, James G. Wilson, Kent D. Taylor, Adolfo Correa, Laura J. Rasmussen-Torvik, Maggie C.Y. Ng, Lynne E. Wagenknecht, and Jacklyn N. Hellwege
- Subjects
0301 basic medicine ,endocrine system diseases ,FAM98A ,Locus (genetics) ,Single-nucleotide polymorphism ,Genome-wide association study ,Type 2 diabetes ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Insulin resistance ,Risk Factors ,Insulin-Secreting Cells ,medicine ,Humans ,Genetic association ,Genetics ,Principal Component Analysis ,Case-control study ,nutritional and metabolic diseases ,Computational Biology ,medicine.disease ,Black or African American ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,Insulin Resistance ,Genome-Wide Association Study - Abstract
Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with known T2D loci implicated in insulin secretion. To test this hypothesis, single nucleotide polymorphisms (SNPs) nominally associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, and previously associated with T2D in genome-wide association studies (GWAS) were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n=492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using GWAS data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n=2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction < 5×10-6) interactions were observed at several loci including DGKB (rs978989), CDK18 (rs12126276), CXCL12 (rs7921850), HCN1 (rs6895191), FAM98A (rs1900780), and MGMT (rs568530). Notable beta-cell GRS interactions included two SNPs at the DGKB locus (rs6976381; rs6962498). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.
- Published
- 2016
36. Genome-Wide Interaction with Insulin Secretion Loci Reveals Novel Loci for Type 2 Diabetes in African Americans.
- Author
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Jacob M Keaton, Jacklyn N Hellwege, Maggie C Y Ng, Nicholette D Palmer, James S Pankow, Myriam Fornage, James G Wilson, Adolfo Correa, Laura J Rasmussen-Torvik, Jerome I Rotter, Yii-Der I Chen, Kent D Taylor, Stephen S Rich, Lynne E Wagenknecht, Barry I Freedman, and Donald W Bowden
- Subjects
Medicine ,Science - Abstract
Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with insulin secretion loci. To test this hypothesis, single nucleotide polymorphisms (SNPs) associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n = 492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using genome-wide association study (GWAS) data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n = 2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction
- Published
- 2016
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