2,374 results on '"Langefeld, Carl D."'
Search Results
2. Metaboepigenetic regulation of gene expression in obesity and insulin resistance
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Das, Swapan K., Comeau, Mary E., and Langefeld, Carl D.
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- 2024
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3. Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification
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Kavousi, Maryam, Bos, Maxime M, Barnes, Hanna J, Lino Cardenas, Christian L, Wong, Doris, Lu, Haojie, Hodonsky, Chani J, Landsmeer, Lennart PL, Turner, Adam W, Kho, Minjung, Hasbani, Natalie R, de Vries, Paul S, Bowden, Donald W, Chopade, Sandesh, Deelen, Joris, Benavente, Ernest Diez, Guo, Xiuqing, Hofer, Edith, Hwang, Shih-Jen, Lutz, Sharon M, Lyytikäinen, Leo-Pekka, Slenders, Lotte, Smith, Albert V, Stanislawski, Maggie A, van Setten, Jessica, Wong, Quenna, Yanek, Lisa R, Becker, Diane M, Beekman, Marian, Budoff, Matthew J, Feitosa, Mary F, Finan, Chris, Hilliard, Austin T, Kardia, Sharon LR, Kovacic, Jason C, Kral, Brian G, Langefeld, Carl D, Launer, Lenore J, Malik, Shaista, Hoesein, Firdaus AA Mohamed, Mokry, Michal, Schmidt, Reinhold, Smith, Jennifer A, Taylor, Kent D, Terry, James G, van der Grond, Jeroen, van Meurs, Joyce, Vliegenthart, Rozemarijn, Xu, Jianzhao, Young, Kendra A, Zilhão, Nuno R, Zweiker, Robert, Assimes, Themistocles L, Becker, Lewis C, Bos, Daniel, Carr, J Jeffrey, Cupples, L Adrienne, de Kleijn, Dominique PV, de Winther, Menno, den Ruijter, Hester M, Fornage, Myriam, Freedman, Barry I, Gudnason, Vilmundur, Hingorani, Aroon D, Hokanson, John E, Ikram, M Arfan, Išgum, Ivana, Jacobs, David R, Kähönen, Mika, Lange, Leslie A, Lehtimäki, Terho, Pasterkamp, Gerard, Raitakari, Olli T, Schmidt, Helena, Slagboom, P Eline, Uitterlinden, André G, Vernooij, Meike W, Bis, Joshua C, Franceschini, Nora, Psaty, Bruce M, Post, Wendy S, Rotter, Jerome I, Björkegren, Johan LM, O’Donnell, Christopher J, Bielak, Lawrence F, Peyser, Patricia A, Malhotra, Rajeev, van der Laan, Sander W, and Miller, Clint L
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Biological Sciences ,Genetics ,Heart Disease - Coronary Heart Disease ,Human Genome ,Cardiovascular ,Prevention ,Heart Disease ,Atherosclerosis ,2.1 Biological and endogenous factors ,Aetiology ,Humans ,Black People ,Coronary Artery Disease ,Genome-Wide Association Study ,Risk Factors ,European People ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.
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- 2023
4. Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures
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Sluka, Kathleen A, Wager, Tor D, Sutherland, Stephani P, Labosky, Patricia A, Balach, Tessa, Bayman, Emine O, Berardi, Giovanni, Brummett, Chad M, Burns, John, Buvanendran, Asokumar, Caffo, Brian, Calhoun, Vince D, Clauw, Daniel, Chang, Andrew, Coffey, Christopher S, Dailey, Dana L, Ecklund, Dixie, Fiehn, Oliver, Fisch, Kathleen M, Law, Laura A Frey, Harris, Richard E, Harte, Steven E, Howard, Timothy D, Jacobs, Joshua, Jacobs, Jon M, Jepsen, Kristen, Johnston, Nicolas, Langefeld, Carl D, Laurent, Louise C, Lenzi, Rebecca, Lindquist, Martin A, Lokshin, Anna, Kahn, Ari, McCarthy, Robert J, Olivier, Michael, Porter, Linda, Qian, Wei-Jun, Sankar, Cheryse A, Satterlee, John, Swensen, Adam C, Vance, Carol GT, Waljee, Jennifer, Wandner, Laura D, Williams, David A, Wixson, Richard L, Zhou, Xiaohong Joe, and Consortium, the A2CPS
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Chronic Pain ,Clinical Research ,Prevention ,Pain Research ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,2.1 Biological and endogenous factors ,Aetiology ,Musculoskeletal ,Good Health and Well Being ,Humans ,Proteomics ,Pain ,Postoperative ,Acute Pain ,Biomarkers ,Pain ,Chronic pain ,Postsurgical pain ,Biomarker ,Biosignatures ,Omics ,Brain imaging ,Psychosocial ,A2CPS Consortium ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Anesthesiology ,Biomedical and clinical sciences ,Health sciences ,Psychology - Abstract
AbstractChronic pain affects more than 50 million Americans. Treatments remain inadequate, in large part, because the pathophysiological mechanisms underlying the development of chronic pain remain poorly understood. Pain biomarkers could potentially identify and measure biological pathways and phenotypical expressions that are altered by pain, provide insight into biological treatment targets, and help identify at-risk patients who might benefit from early intervention. Biomarkers are used to diagnose, track, and treat other diseases, but no validated clinical biomarkers exist yet for chronic pain. To address this problem, the National Institutes of Health Common Fund launched the Acute to Chronic Pain Signatures (A2CPS) program to evaluate candidate biomarkers, develop them into biosignatures, and discover novel biomarkers for chronification of pain after surgery. This article discusses candidate biomarkers identified by A2CPS for evaluation, including genomic, proteomic, metabolomic, lipidomic, neuroimaging, psychophysical, psychological, and behavioral measures. Acute to Chronic Pain Signatures will provide the most comprehensive investigation of biomarkers for the transition to chronic postsurgical pain undertaken to date. Data and analytic resources generatedby A2CPS will be shared with the scientific community in hopes that other investigators will extract valuable insights beyond A2CPS's initial findings. This article will review the identified biomarkers and rationale for including them, the current state of the science on biomarkers of the transition from acute to chronic pain, gaps in the literature, and how A2CPS will address these gaps.
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- 2023
5. High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus
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Wang, Qiang, Kim, Taehyeung, Martínez-Bonet, Marta, Aguiar, Vitor R. C., Sim, Sangwan, Cui, Jing, Sparks, Jeffrey A., Chen, Xiaoting, Todd, Marc, Wauford, Brian, Marion, Miranda C., Langefeld, Carl D., Weirauch, Matthew T., Gutierrez-Arcelus, Maria, and Nigrovic, Peter A.
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- 2024
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6. Molecular pathways identified from single nucleotide polymorphisms demonstrate mechanistic differences in systemic lupus erythematosus patients of Asian and European ancestry.
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Owen, Katherine A, Bell, Kristy A, Price, Andrew, Bachali, Prathyusha, Ainsworth, Hannah, Marion, Miranda C, Howard, Timothy D, Langefeld, Carl D, Shen, Nan, Yazdany, Jinoos, Dall'era, Maria, Grammer, Amrie C, and Lipsky, Peter E
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Humans ,Lupus Erythematosus ,Systemic ,Genetic Predisposition to Disease ,Case-Control Studies ,Genotype ,Polymorphism ,Single Nucleotide ,Genome-Wide Association Study ,Lupus ,Clinical Research ,Autoimmune Disease ,Human Genome ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system - Abstract
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of Asian-Ancestry (AsA) disproportionately experience more severe SLE compared to individuals of European-Ancestry (EA), including increased renal involvement and tissue damage. However, the mechanisms underlying elevated severity in the AsA population remain unclear. Here, we utilized available gene expression data and genotype data based on all non-HLA SNP associations in EA and AsA SLE patients detected using the Immunochip genotyping array. We identified 2778 ancestry-specific and 327 trans-ancestry SLE-risk polymorphisms. Genetic associations were examined using connectivity mapping and gene signatures based on predicted biological pathways and were used to interrogate gene expression datasets. SLE-associated pathways in AsA patients included elevated oxidative stress, altered metabolism and mitochondrial dysfunction, whereas SLE-associated pathways in EA patients included a robust interferon response (type I and II) related to enhanced cytosolic nucleic acid sensing and signaling. An independent dataset derived from summary genome-wide association data in an AsA cohort was interrogated and identified similar molecular pathways. Finally, gene expression data from AsA SLE patients corroborated the molecular pathways predicted by SNP associations. Identifying ancestry-related molecular pathways predicted by genetic SLE risk may help to disentangle the population differences in clinical severity that impact AsA and EA individuals with SLE.
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- 2023
7. Metabolomic profiling of glucose homeostasis in African Americans: the Insulin Resistance Atherosclerosis Family Study (IRAS-FS)
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Okut, Hayrettin, Lu, Yingchang, Palmer, Nicholette D, Chen, Yii-Der Ida, Taylor, Kent D, Norris, Jill M, Lorenzo, Carlos, Rotter, Jerome I, Langefeld, Carl D, Wagenknecht, Lynne E, Bowden, Donald W, and Ng, Maggie CY
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Medical Biochemistry and Metabolomics ,Analytical Chemistry ,Biomedical and Clinical Sciences ,Chemical Sciences ,Diabetes ,Prevention ,Nutrition ,Obesity ,Clinical Research ,Metabolic and endocrine ,Humans ,Atherosclerosis ,Black or African American ,Diabetes Mellitus ,Type 2 ,Glucose ,Glutamates ,Homeostasis ,Insulin Resistance ,Metabolomics ,Glucose homeostasis ,African Americans ,Biochemistry and Cell Biology ,Clinical Sciences ,Biochemistry and cell biology ,Medical biochemistry and metabolomics ,Analytical chemistry - Abstract
IntroductionAfrican Americans are at increased risk for type 2 diabetes.ObjectivesThis work aimed to examine metabolomic signature of glucose homeostasis in African Americans.MethodsWe used an untargeted liquid chromatography-mass spectrometry metabolomic approach to comprehensively profile 727 plasma metabolites among 571 African Americans from the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) and investigate the associations between these metabolites and both the dynamic (SI, insulin sensitivity; AIR, acute insulin response; DI, disposition index; and SG, glucose effectiveness) and basal (HOMA-IR and HOMA-B) measures of glucose homeostasis using univariate and regularized regression models. We also compared the results with our previous findings in the IRAS-FS Mexican Americans.ResultsWe confirmed increased plasma metabolite levels of branched-chain amino acids and their metabolic derivatives, 2-aminoadipate, 2-hydroxybutyrate, glutamate, arginine and its metabolic derivatives, carbohydrate metabolites, and medium- and long-chain fatty acids were associated with insulin resistance, while increased plasma metabolite levels in the glycine, serine and threonine metabolic pathway were associated with insulin sensitivity. We also observed a differential ancestral effect of glutamate on glucose homeostasis with significantly stronger effects observed in African Americans than those previously observed in Mexican Americans.ConclusionWe extended the observations that metabolites are useful biomarkers in the identification of prediabetes in individuals at risk of type 2 diabetes in African Americans. We revealed, for the first time, differential ancestral effect of certain metabolites (i.e., glutamate) on glucose homeostasis traits. Our study highlights the need for additional comprehensive metabolomic studies in well-characterized multiethnic cohorts.
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- 2023
8. Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits—The Hispanic/Latino Anthropometry Consortium
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Fernández-Rhodes, Lindsay, Graff, Mariaelisa, Buchanan, Victoria L, Justice, Anne E, Highland, Heather M, Guo, Xiuqing, Zhu, Wanying, Chen, Hung-Hsin, Young, Kristin L, Adhikari, Kaustubh, Palmer, Nicholette D, Below, Jennifer E, Bradfield, Jonathan, Pereira, Alexandre C, Glover, LáShauntá, Kim, Daeeun, Lilly, Adam G, Shrestha, Poojan, Thomas, Alvin G, Zhang, Xinruo, Chen, Minhui, Chiang, Charleston WK, Pulit, Sara, Horimoto, Andrea, Krieger, Jose E, Guindo-Martínez, Marta, Preuss, Michael, Schumann, Claudia, Smit, Roelof AJ, Torres-Mejía, Gabriela, Acuña-Alonzo, Victor, Bedoya, Gabriel, Bortolini, Maria-Cátira, Canizales-Quinteros, Samuel, Gallo, Carla, González-José, Rolando, Poletti, Giovanni, Rothhammer, Francisco, Hakonarson, Hakon, Igo, Robert, Adler, Sharon G, Iyengar, Sudha K, Nicholas, Susanne B, Gogarten, Stephanie M, Isasi, Carmen R, Papnicolaou, George, Stilp, Adrienne M, Qi, Qibin, Kho, Minjung, Smith, Jennifer A, Langefeld, Carl D, Wagenknecht, Lynne, Mckean-Cowdin, Roberta, Gao, Xiaoyi Raymond, Nousome, Darryl, Conti, David V, Feng, Ye, Allison, Matthew A, Arzumanyan, Zorayr, Buchanan, Thomas A, Chen, Yii-Der Ida, Genter, Pauline M, Goodarzi, Mark O, Hai, Yang, Hsueh, Willa, Ipp, Eli, Kandeel, Fouad R, Lam, Kelvin, Li, Xiaohui, Nadler, Jerry L, Raffel, Leslie J, Roll, Kathryn, Sandow, Kevin, Tan, Jingyi, Taylor, Kent D, Xiang, Anny H, Yao, Jie, Audirac-Chalifour, Astride, Peralta Romero, Jose de Jesus, Hartwig, Fernando, Horta, Bernando, Blangero, John, Curran, Joanne E, Duggirala, Ravindranath, Lehman, Donna E, Puppala, Sobha, Fejerman, Laura, John, Esther M, Aguilar-Salinas, Carlos, Burtt, Noël P, Florez, Jose C, García-Ortíz, Humberto, González-Villalpando, Clicerio, Mercader, Josep, Orozco, Lorena, Tusié-Luna, Teresa, Blanco, Estela, Gahagan, Sheila, Cox, Nancy J, and Hanis, Craig
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[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.].
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- 2023
9. Distinct genome-wide DNA methylation and gene expression signatures in classical monocytes from African American patients with systemic sclerosis
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Allen, Peter C., Smith, Sarah, Wilson, Robert C., Wirth, Jena R., Wilson, Nathan H., Baker Frost, DeAnna, Flume, Jonathan, Gilkeson, Gary S., Cunningham, Melissa A., Langefeld, Carl D., Absher, Devin M., and Ramos, Paula S.
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- 2023
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10. Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits—The Hispanic/Latino Anthropometry Consortium
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Fernández-Rhodes, Lindsay, Graff, Mariaelisa, Buchanan, Victoria L, Justice, Anne E, Highland, Heather M, Guo, Xiuqing, Zhu, Wanying, Chen, Hung-Hsin, Young, Kristin L, Adhikari, Kaustubh, Palmer, Nicholette D, Below, Jennifer E, Bradfield, Jonathan, Pereira, Alexandre C, Glover, LáShauntá, Kim, Daeeun, Lilly, Adam G, Shrestha, Poojan, Thomas, Alvin G, Zhang, Xinruo, Chen, Minhui, Chiang, Charleston WK, Pulit, Sara, Horimoto, Andrea, Krieger, Jose E, Guindo-Martínez, Marta, Preuss, Michael, Schumann, Claudia, Smit, Roelof AJ, Torres-Mejía, Gabriela, Acuña-Alonzo, Victor, Bedoya, Gabriel, Bortolini, Maria-Cátira, Canizales-Quinteros, Samuel, Gallo, Carla, González-José, Rolando, Poletti, Giovanni, Rothhammer, Francisco, Hakonarson, Hakon, Igo, Robert, Adler, Sharon G, Iyengar, Sudha K, Nicholas, Susanne B, Gogarten, Stephanie M, Isasi, Carmen R, Papnicolaou, George, Stilp, Adrienne M, Qi, Qibin, Kho, Minjung, Smith, Jennifer A, Langefeld, Carl D, Wagenknecht, Lynne, Mckean-Cowdin, Roberta, Gao, Xiaoyi Raymond, Nousome, Darryl, Conti, David V, Feng, Ye, Allison, Matthew A, Arzumanyan, Zorayr, Buchanan, Thomas A, Chen, Yii-Der Ida, Genter, Pauline M, Goodarzi, Mark O, Hai, Yang, Hsueh, Willa, Ipp, Eli, Kandeel, Fouad R, Lam, Kelvin, Li, Xiaohui, Nadler, Jerry L, Raffel, Leslie J, Roll, Kathryn, Sandow, Kevin, Tan, Jingyi, Taylor, Kent D, Xiang, Anny H, Yao, Jie, Audirac-Chalifour, Astride, de Jesus Peralta Romero, Jose, Hartwig, Fernando, Horta, Bernando, Blangero, John, Curran, Joanne E, Duggirala, Ravindranath, Lehman, Donna E, Puppala, Sobha, Fejerman, Laura, John, Esther M, Aguilar-Salinas, Carlos, Burtt, Noël P, Florez, Jose C, García-Ortíz, Humberto, González-Villalpando, Clicerio, Mercader, Josep, Orozco, Lorena, Tusié-Luna, Teresa, Blanco, Estela, Gahagan, Sheila, Cox, Nancy J, and Hanis, Craig
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Biological Sciences ,Genetics ,Obesity ,Human Genome ,Hispanic/Latino ,anthropometrics ,diversity ,fine-mapping ,obesity ,population stratification ,trans-ancestral or trans-ethnic - Abstract
Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.
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- 2022
11. Multi-Site Observational Study to Assess Biomarkers for Susceptibility or Resilience to Chronic Pain: The Acute to Chronic Pain Signatures (A2CPS) Study Protocol
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Berardi, Giovanni, Frey-Law, Laura, Sluka, Kathleen A, Bayman, Emine O, Coffey, Christopher S, Ecklund, Dixie, Vance, Carol GT, Dailey, Dana L, Burns, John, Buvanendran, Asokumar, McCarthy, Robert J, Jacobs, Joshua, Zhou, Xiaohong Joe, Wixson, Richard, Balach, Tessa, Brummett, Chad M, Clauw, Daniel, Colquhoun, Douglas, Harte, Steven E, Harris, Richard E, Williams, David A, Chang, Andrew C, Waljee, Jennifer, Fisch, Kathleen M, Jepsen, Kristen, Laurent, Louise C, Olivier, Michael, Langefeld, Carl D, Howard, Timothy D, Fiehn, Oliver, Jacobs, Jon M, Dakup, Panshak, Qian, Wei-Jun, Swensen, Adam C, Lokshin, Anna, Lindquist, Martin, Caffo, Brian S, Crainiceanu, Ciprian, Zeger, Scott, Kahn, Ari, Wager, Tor, Taub, Margaret, Ford, James, Sutherland, Stephani P, and Wandner, Laura D
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Clinical Research ,Prevention ,Chronic Pain ,Pain Research ,Neurological ,Musculoskeletal ,Good Health and Well Being ,postsurgical pain ,thoracic surgery ,pain ,biomarker ,risk factors ,protocol ,knee arthroplasty ,Biomedical and clinical sciences ,Health sciences - Abstract
Chronic pain has become a global health problem contributing to years lived with disability and reduced quality of life. Advances in the clinical management of chronic pain have been limited due to incomplete understanding of the multiple risk factors and molecular mechanisms that contribute to the development of chronic pain. The Acute to Chronic Pain Signatures (A2CPS) Program aims to characterize the predictive nature of biomarkers (brain imaging, high-throughput molecular screening techniques, or "omics," quantitative sensory testing, patient-reported outcome assessments and functional assessments) to identify individuals who will develop chronic pain following surgical intervention. The A2CPS is a multisite observational study investigating biomarkers and collective biosignatures (a combination of several individual biomarkers) that predict susceptibility or resilience to the development of chronic pain following knee arthroplasty and thoracic surgery. This manuscript provides an overview of data collection methods and procedures designed to standardize data collection across multiple clinical sites and institutions. Pain-related biomarkers are evaluated before surgery and up to 3 months after surgery for use as predictors of patient reported outcomes 6 months after surgery. The dataset from this prospective observational study will be available for researchers internal and external to the A2CPS Consortium to advance understanding of the transition from acute to chronic postsurgical pain.
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- 2022
12. Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes
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Lu, Yingchang, Dimitrov, Latchezar, Chen, Shyh-Huei, Bielak, Lawrence F, Bis, Joshua C, Feitosa, Mary F, Lu, Lingyi, Kavousi, Maryam, Raffield, Laura M, Smith, Albert V, Wang, Lihua, Weiss, Stefan, Yao, Jie, Zhu, Jiaxi, Gudmundsson, Elias F, Gudmundsdottir, Valborg, Bos, Daniel, Ghanbari, Mohsen, Ikram, M Arfan, Hwang, Shih-Jen, Taylor, Kent D, Budoff, Matthew J, Gíslason, Gauti K, O’Donnell, Christopher J, An, Ping, Franceschini, Nora, Freedman, Barry I, Fu, Yi-Ping, Guo, Xiuqing, Heiss, Gerardo, Kardia, Sharon LR, Wilson, James G, Langefeld, Carl D, Schminke, Ulf, Uitterlinden, André G, Lange, Leslie A, Peyser, Patricia A, Gudnason, Vilmundur G, Psaty, Bruce M, Rotter, Jerome I, Bowden, Donald W, and Ng, Maggie CY
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Genetics ,Diabetes ,Biotechnology ,Heart Disease ,Atherosclerosis ,Biomedical Imaging ,Aging ,Prevention ,Heart Disease - Coronary Heart Disease ,Cardiovascular ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Black People ,Diabetes Complications ,Diabetes Mellitus ,Type 2 ,Genetic Loci ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,White People ,atherosclerosis ,carotid intima-media thickness ,coronary artery disease ,genetics ,genome-wide association study ,Medical Biotechnology ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology - Abstract
BackgroundCoronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis.MethodsWe performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium.ResultsWe replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P=2.0×10-8 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN, encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (P
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- 2021
13. A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs
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Venema, Wouter J., Hiddingh, Sanne, van Loosdregt, Jorg, Bowes, John, Balliu, Brunilda, de Boer, Joke H., Ossewaarde-van Norel, Jeannette, Thompson, Susan D., Langefeld, Carl D., de Ligt, Aafke, van der Veken, Lars T., Krijger, Peter H.L., de Laat, Wouter, and Kuiper, Jonas J.W.
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- 2024
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14. Identification of a regulatory pathway governing TRAF1 via an arthritis-associated non-coding variant
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Wang, Qiang, Martínez-Bonet, Marta, Kim, Taehyeung, Sparks, Jeffrey A., Ishigaki, Kazuyoshi, Chen, Xiaoting, Sudman, Marc, Aguiar, Vitor, Sim, Sangwan, Hernandez, Marcos Chiñas, Chiu, Darren J., Wactor, Alexandra, Wauford, Brian, Marion, Miranda C., Gutierrez-Arcelus, Maria, Bowes, John, Eyre, Stephen, Nordal, Ellen, Prahalad, Sampath, Rygg, Marite, Videm, Vibeke, Raychaudhuri, Soumya, Weirauch, Matthew T., Langefeld, Carl D., Thompson, Susan D., and Nigrovic, Peter A.
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- 2023
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15. Integrative Analysis of Glucometabolic Traits, Adipose Tissue DNA Methylation and Gene Expression Identifies Epigenetic Regulatory Mechanisms of Insulin Resistance and Obesity in African Americans
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Sharma, Neeraj K, Comeau, Mary E, Montoya, Dennis, Pellegrini, Matteo, Howard, Timothy D, Langefeld, Carl D, and Das, Swapan K
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Biomedical and Clinical Sciences ,Obesity ,Diabetes ,Nutrition ,Genetics ,Biotechnology ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Adipose Tissue ,Adult ,Black or African American ,Computational Biology ,DNA Methylation ,Epigenesis ,Genetic ,Female ,Gene Expression Regulation ,Glucose ,Humans ,Insulin Resistance ,Male ,Transcriptome ,Medical and Health Sciences ,Endocrinology & Metabolism ,Biomedical and clinical sciences - Abstract
Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in type 2 diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans (AAs) from the African American Genetics of Metabolism and Expression cohort, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated cytosine-guanine dinucleotide regions for 82 transcripts (false discovery rate [FDR]-P < 0.05). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; ρ = -0.632, P = 4.70 × 10-27) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 cytosine-guanine dinucleotide regions associated (FDR-P < 0.05) with the Matsuda index, SI, and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, SI, and/or BMI in EWAS. These associated genes include FERMT3, ITGAM, ITGAX, and POMC In summary, applying an integrative multiomics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.
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- 2020
16. APOL1 Kidney-Risk Variants Induce Mitochondrial Fission
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Ma, Lijun, Ainsworth, Hannah C, Snipes, James A, Murea, Mariana, Choi, Young A, Langefeld, Carl D, Parks, John S, Bharadwaj, Manish S, Chou, Jeff W, Hemal, Ashok K, Petrovic, Snezana, Craddock, Ann L, Cheng, Dongmei, Hawkins, Gregory A, Miller, Lance D, Hicks, Pamela J, Saleem, Moin A, Divers, Jasmin, Molina, Anthony JA, and Freedman, Barry I
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Biomedical and Clinical Sciences ,Genetics ,Kidney Disease ,Biotechnology ,Prevention ,2.1 Biological and endogenous factors ,Aetiology ,Renal and urogenital ,African Americans ,APOL1 ,chronic kidney disease ,FSGS ,mitochondria ,Biomedical and clinical sciences ,Health sciences - Abstract
IntroductionAPOL1 G1 and G2 nephropathy-risk variants cause mitochondrial dysfunction and contribute to kidney disease. Analyses were performed to determine the genetic regulation of APOL1 and elucidate potential mechanisms in APOL1-nephropathy.MethodsA global gene expression analysis was performed in human primary renal tubule cell lines derived from 50 African American individuals. Follow-up gene knock out, cell-based rescue, and microscopy experiments were performed.ResultsAPOL1 genotypes did not alter APOL1 expression levels in the global gene expression analysis. Expression quantitative trait locus (eQTL) analysis in polyinosinic-polycytidylic acid (poly IC)-stimulated renal tubule cells revealed that single nucleotide polymorphism (SNP) rs513349 adjacent to BAK1 was a trans eQTL for APOL1 and a cis eQTL for BAK1; APOL1 and BAK1 were co-expressed in cells. BAK1 knockout in a human podocyte cell line resulted in diminished APOL1 protein, supporting a pivotal effect for BAK1 on APOL1 expression. Because BAK1 is involved in mitochondrial dynamics, mitochondrial morphology was examined in primary renal tubule cells and HEK293 Tet-on cells of various APOL1 genotypes. Mitochondria in APOL1 wild-type (G0G0) tubule cells maintained elongated morphology when stimulated by low-dose poly IC, whereas those with G1G1, G2G2, and G1G2 genotypes appeared to fragment. HEK293 Tet-on cells overexpressing APOL1 G0, G1, and G2 were created; G0 cells appeared to promote mitochondrial fusion, whereas G1 and G2 induced mitochondrial fission. The mitochondrial dynamic regulator Mdivi-1 significantly preserved cell viability and mitochondrial cristae structure and reversed mitochondrial fission induced by overexpression of G1 and G2.ConclusionResults suggest the mitochondrial fusion/fission pathway may be a therapeutic target in APOL1-nephropathy.
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- 2020
17. Complement genes contribute sex-biased vulnerability in diverse disorders.
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Kamitaki, Nolan, Sekar, Aswin, Handsaker, Robert E, de Rivera, Heather, Tooley, Katherine, Morris, David L, Taylor, Kimberly E, Whelan, Christopher W, Tombleson, Philip, Loohuis, Loes M Olde, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Boehnke, Michael, Kimberly, Robert P, Kaufman, Kenneth M, Harley, John B, Langefeld, Carl D, Seidman, Christine E, Pato, Michele T, Pato, Carlos N, Ophoff, Roel A, Graham, Robert R, Criswell, Lindsey A, Vyse, Timothy J, and McCarroll, Steven A
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Schizophrenia Working Group of the Psychiatric Genomics Consortium ,Humans ,Sjogren's Syndrome ,Lupus Erythematosus ,Systemic ,Genetic Predisposition to Disease ,HLA Antigens ,Major Histocompatibility Complex ,Sex Characteristics ,Haplotypes ,Alleles ,Adult ,Middle Aged ,Complement C3 ,Complement C4 ,Female ,Male ,Young Adult ,Lupus ,Brain Disorders ,Schizophrenia ,Biotechnology ,Genetics ,Mental Health ,Autoimmune Disease ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,General Science & Technology - Abstract
Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
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- 2020
18. APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale
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Freedman, Barry I, Moxey-Mims, Marva M, Alexander, Amir A, Astor, Brad C, Birdwell, Kelly A, Bowden, Donald W, Bowen, Gordon, Bromberg, Jonathan, Craven, Timothy E, Dadhania, Darshana M, Divers, Jasmin, Doshi, Mona D, Eidbo, Elling, Fornoni, Alessia, Gautreaux, Michael D, Gbadegesin, Rasheed A, Gee, Patrick O, Guerra, Giselle, Hsu, Chi-yuan, Iltis, Ana S, Jefferson, Nichole, Julian, Bruce A, Klassen, David K, Koty, Patrick P, Langefeld, Carl D, Lentine, Krista L, Ma, Lijun, Mannon, Roslyn B, Menon, Madhav C, Mohan, Sumit, Moore, J Brian, Murphy, Barbara, Newell, Kenneth A, Odim, Jonah, Ortigosa-Goggins, Mariella, Palmer, Nicholette D, Park, Meyeon, Parsa, Afshin, Pastan, Stephen O, Poggio, Emilio D, Rajapakse, Nishadi, Reeves-Daniel, Amber M, Rosas, Sylvia E, Russell, Laurie P, Sawinski, Deirdre, Smith, S Carrie, Spainhour, Mitzie, Stratta, Robert J, Weir, Matthew R, Reboussin, David M, Kimmel, Paul L, and Brennan, Daniel C
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Clinical Research ,Organ Transplantation ,Transplantation ,Kidney Disease ,Renal and urogenital ,Good Health and Well Being ,African Americans ,APOL1 ,chronic kidney disease ,graft failure ,kidney transplantation ,outcomes - Abstract
IntroductionMuch of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)-sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes.MethodsAPOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys.ResultsThe United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses.ConclusionThis article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation.
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- 2020
19. Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans
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Guan, Meijian, Keaton, Jacob M, Dimitrov, Latchezar, Hicks, Pamela J, Xu, Jianzhao, Palmer, Nicholette D, Ma, Lijun, Das, Swapan K, Chen, Yii-Der I, Coresh, Josef, Fornage, Myriam, Franceschini, Nora, Kramer, Holly, Langefeld, Carl D, Mychaleckyj, Josyf C, Parekh, Rulan S, Post, Wendy S, Rasmussen-Torvik, Laura J, Rich, Stephen S, Rotter, Jerome I, Sedor, John R, Thornley-Brown, Denyse, Tin, Adrienne, Wilson, James G, Freedman, Barry I, Bowden, Donald W, and Ng, Maggie CY
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Biological Sciences ,Genetics ,Human Genome ,Diabetes ,Prevention ,Kidney Disease ,2.1 Biological and endogenous factors ,Aetiology ,Renal and urogenital ,Metabolic and endocrine ,Good Health and Well Being ,African Americans ,Genome-wide association study ,Type 2 diabetes ,Diabetic kidney disease ,End-stage kidney disease ,FIND Consortium ,Genetics & Heredity ,Biochemistry and cell biology - Abstract
BackgroundEnd-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.ResultsSix independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P
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- 2019
20. Validation of Epigenetic Markers for the Prediction of Response to Topical Corticosteroid Treatment in Eosinophilic Esophagitis
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Jensen, Elizabeth T., Langefeld, Carl D., Howard, Timothy D., and Dellon, Evan S.
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- 2023
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21. Multi-omic integration reveals cell-type-specific regulatory networks of insulin resistance in distinct ancestry populations
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Xu, Peng, Wang, Minghui, Sharma, Neeraj K., Comeau, Mary E., Wabitsch, Martin, Langefeld, Carl D., Civelek, Mete, Zhang, Bin, and Das, Swapan K.
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- 2023
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22. DNA methylation of the TPMT gene and azathioprine pharmacokinetics in children with very early onset inflammatory bowel disease
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Selvestrel, Davide, Stocco, Gabriele, Aloi, Marina, Arrigo, Serena, Cardile, Sabrina, Cecchin, Erika, Congia, Mauro, Curci, Debora, Gatti, Simona, Graziano, Francesco, Langefeld, Carl D., Lucafò, Marianna, Martelossi, Stefano, Martinelli, Massimo, Pagarin, Sofia, Scarallo, Luca, Stacul, Elisabetta Francesca, Strisciuglio, Caterina, Thompson, Susan, Zuin, Giovanna, Decorti, Giuliana, and Bramuzzo, Matteo
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- 2023
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23. Mendelian randomization and pathway analysis demonstrate shared genetic associations between lupus and coronary artery disease
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Kain, Jessica, Owen, Katherine A., Marion, Miranda C., Langefeld, Carl D., Grammer, Amrie C., and Lipsky, Peter E.
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- 2022
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24. A Genomic Risk Score Identifies Individuals at High Risk for Intracerebral Hemorrhage
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Myserlis, Evangelos Pavlos, Georgakis, Marios K., Demel, Stacie L., Sekar, Padmini, Chung, Jaeyoon, Malik, Rainer, Hyacinth, Hyacinth I., Comeau, Mary E., Falcone, Guido J., Langefeld, Carl D., Rosand, Jonathan, Woo, Daniel, and Anderson, Christopher D.
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- 2023
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25. Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria.
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Teumer, Alexander, Li, Yong, Ghasemi, Sahar, Prins, Bram P, Wuttke, Matthias, Hermle, Tobias, Giri, Ayush, Sieber, Karsten B, Qiu, Chengxiang, Kirsten, Holger, Tin, Adrienne, Chu, Audrey Y, Bansal, Nisha, Feitosa, Mary F, Wang, Lihua, Chai, Jin-Fang, Cocca, Massimiliano, Fuchsberger, Christian, Gorski, Mathias, Hoppmann, Anselm, Horn, Katrin, Li, Man, Marten, Jonathan, Noce, Damia, Nutile, Teresa, Sedaghat, Sanaz, Sveinbjornsson, Gardar, Tayo, Bamidele O, van der Most, Peter J, Xu, Yizhe, Yu, Zhi, Gerstner, Lea, Ärnlöv, Johan, Bakker, Stephan JL, Baptista, Daniela, Biggs, Mary L, Boerwinkle, Eric, Brenner, Hermann, Burkhardt, Ralph, Carroll, Robert J, Chee, Miao-Li, Chee, Miao-Ling, Chen, Mengmeng, Cheng, Ching-Yu, Cook, James P, Coresh, Josef, Corre, Tanguy, Danesh, John, de Borst, Martin H, De Grandi, Alessandro, de Mutsert, Renée, de Vries, Aiko PJ, Degenhardt, Frauke, Dittrich, Katalin, Divers, Jasmin, Eckardt, Kai-Uwe, Ehret, Georg, Endlich, Karlhans, Felix, Janine F, Franco, Oscar H, Franke, Andre, Freedman, Barry I, Freitag-Wolf, Sandra, Gansevoort, Ron T, Giedraitis, Vilmantas, Gögele, Martin, Grundner-Culemann, Franziska, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Hamet, Pavel, Harris, Tamara B, Hicks, Andrew A, Holm, Hilma, Foo, Valencia Hui Xian, Hwang, Shih-Jen, Ikram, M Arfan, Ingelsson, Erik, Jaddoe, Vincent WV, Jakobsdottir, Johanna, Josyula, Navya Shilpa, Jung, Bettina, Kähönen, Mika, Khor, Chiea-Chuen, Kiess, Wieland, Koenig, Wolfgang, Körner, Antje, Kovacs, Peter, Kramer, Holly, Krämer, Bernhard K, Kronenberg, Florian, Lange, Leslie A, Langefeld, Carl D, Lee, Jeannette Jen-Mai, Lehtimäki, Terho, Lieb, Wolfgang, Lim, Su-Chi, Lind, Lars, Lindgren, Cecilia M, Liu, Jianjun, and Loeffler, Markus
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Animals ,Humans ,Drosophila melanogaster ,Albuminuria ,Diabetes Mellitus ,Genetic Predisposition to Disease ,Creatinine ,Risk Factors ,Chromosome Mapping ,Gene Expression Regulation ,Meta-Analysis as Topic ,Genome-Wide Association Study ,Genetic Loci ,Phenomics - Abstract
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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- 2019
26. Genome‐Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium
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Young, Kendra A, Palmer, Nicholette D, Fingerlin, Tasha E, Langefeld, Carl D, Norris, Jill M, Wang, Nan, Xiang, Anny H, Guo, Xiuqing, Williams, Adrienne H, Chen, Yii‐Der I, Taylor, Kent D, Rotter, Jerome I, Raffel, Leslie J, Goodarzi, Mark O, Watanabe, Richard M, and Wagenknecht, Lynne E
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Human Genome ,Clinical Research ,Digestive Diseases ,Prevention ,Liver Disease ,Genetics ,Chronic Liver Disease and Cirrhosis ,Adult ,Alanine Transaminase ,Aspartate Aminotransferases ,Female ,Genetic Loci ,Genome-Wide Association Study ,Humans ,Linear Models ,Lipase ,Liver ,Male ,Membrane Proteins ,Mexican Americans ,Middle Aged ,Non-alcoholic Fatty Liver Disease ,Polymorphism ,Single Nucleotide ,gamma-Glutamyltransferase ,Endocrinology & Metabolism - Abstract
ObjectivePopulations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry.MethodsLevels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis.ResultsIn the PNPLA3 gene, rs4823173 (P = 3.44 × 10-10 ), rs2896019 (P = 7.29 × 10-9 ), and rs2281135 (P = 8.73 × 10-9 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10-8 , P = 1.98 × 10-7 , and P = 1.81 × 10-7 , respectively). The strong correlation (r2 = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT.ConclusionsPNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry.
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- 2019
27. The African Descent and Glaucoma Evaluation Study (ADAGES) III Contribution of Genotype to Glaucoma Phenotype in African Americans: Study Design and Baseline Data
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Zangwill, Linda M, Ayyagari, Radha, Liebmann, Jeffrey M, Girkin, Christopher A, Feldman, Robert, Dubiner, Harvey, Dirkes, Keri A, Holmann, Matthew, Williams-Steppe, Eunice, Hammel, Naama, Saunders, Luke J, Vega, Suzanne, Sandow, Kevin, Roll, Kathryn, Slight, Rigby, Auerbach, Daniel, Samuels, Brian C, Panarelli, Joseph F, Mitchell, John P, Al-Aswad, A, Park, Sung Chul, Tello, Celso, Cotliar, Jeremy, Bansal, Rajendra, Sidoti, Paul A, Cioffi, George A, Blumberg, Dana, Ritch, Robert, Bell, Nicholas P, Blieden, Lauren S, Davis, Garvin, Medeiros, Felipe A, Ng, Maggie CY, Das, Swapan K, Palmer, Nicholette D, Divers, Jasmin, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, Christopher, Mark A, Chen, Yii-der I, Guo, Xiuqing, Taylor, Kent D, Rotter, Jerome I, Weinreb, Robert N, and Group, African Descent and Glaucoma Evaluation Study III Genomics Study
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Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Neurosciences ,Aging ,Neurodegenerative ,Clinical Research ,Eye Disease and Disorders of Vision ,Eye ,Black or African American ,Aged ,Body Constitution ,Case-Control Studies ,Cross-Sectional Studies ,Female ,Gene-Environment Interaction ,Genome-Wide Association Study ,Genotype ,Glaucoma ,Open-Angle ,Humans ,Intraocular Pressure ,Male ,Middle Aged ,Phenotype ,Polymorphism ,Single Nucleotide ,Research Design ,Visual Acuity ,Visual Fields ,White People ,African Descent and Glaucoma Evaluation Study III Genomics Study Group ,Clinical Sciences ,Opthalmology and Optometry ,Public Health and Health Services ,Ophthalmology & Optometry ,Ophthalmology and optometry - Abstract
PurposeTo describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III.DesignCross-sectional, case-control study.ParticipantsThree thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States.MethodsIndividuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review.Main outcome measuresParticipant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded.ResultsThe 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients.ConclusionsWith its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.
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- 2019
28. Genetic Architecture of Primary Open-Angle Glaucoma in Individuals of African Descent The African Descent and Glaucoma Evaluation Study III
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Taylor, Kent D, Guo, Xiuqing, Zangwill, Linda M, Liebmann, Jeffrey M, Girkin, Christopher A, Feldman, Robert M, Dubiner, Harvey, Hai, Yang, Samuels, Brian C, Panarelli, Joseph F, Mitchell, John P, Al-Aswad, A, Park, Sung Chul, Tello, Celso, Cotliar, Jeremy, Bansal, Rajendra, Sidoti, Paul A, Cioffi, George A, Blumberg, Dana, Ritch, Robert, Bell, Nicholas P, Blieden, Lauren S, Davis, Garvin, Medeiros, Felipe A, Das, Swapan K, Divers, Jasmin, Langefeld, Carl D, Palmer, Nicholette D, Freedman, Barry I, Bowden, Donald W, Ng, Maggie CY, Chen, Yii-Der Ida, Ayyagari, Radha, Rotter, Jerome I, Weinreb, Robert N, and Group, African Descent and Glaucoma Evaluation Study III Genomics Study
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Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Neurosciences ,Eye Disease and Disorders of Vision ,Prevention ,Genetics ,Aging ,Neurodegenerative ,Human Genome ,Black or African American ,Aged ,Case-Control Studies ,Cross-Sectional Studies ,Female ,Gene Frequency ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Glaucoma ,Open-Angle ,Humans ,Intraocular Pressure ,Male ,Middle Aged ,Phosphopyruvate Hydratase ,Polymorphism ,Single Nucleotide ,ROC Curve ,African Descent and Glaucoma Evaluation Study III Genomics Study Group ,Clinical Sciences ,Opthalmology and Optometry ,Public Health and Health Services ,Ophthalmology & Optometry ,Ophthalmology and optometry - Abstract
PurposeTo find genetic contributions to glaucoma in African Americans.DesignCross-sectional, case-control study.ParticipantsOne thousand eight hundred seventy-five primary open-angle glaucoma (POAG) patients and 1709 controls, self-identified as being of African descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGES) III and Wake Forest School of Medicine.MethodsMegaChip genotypes were imputed to Thousand Genomes data. Association of single nucleotide polymorphisms (SNPs) with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by receiver operator characteristic curves (ROC-AUCs).Main outcome measuresPrimary open-angle glaucoma defined by visual field loss without other nonocular conditions (n = 1875). Advanced POAG was defined by age-based mean deviation of visual field (n = 946).ResultsEighteen million two hundred eighty-one thousand nine hundred twenty SNPs met imputation quality of r2 > 0.7 and minor allele frequency > 0.005. Association of a novel locus, EN04, was observed for advanced POAG (rs185815146 β, 0.36; standard error, 0.065; P < 3×10-8). For POAG, an AD signal was observed at the 9p21 European descent (ED) POAG signal (rs79721419; P < 6.5×10-5) independent of the previously observed 9p21 ED signal (rs2383204; P < 2.3×10-5) by conditional analyses. An association with POAG in FNDC3B (rs111698934; P < 3.9×10-5) was observed, not in linkage disequilibrium (LD) with the previously reported ED SNP. Additional previously identified loci associated with POAG in persons of AD were: 8q22, AFAP1, and TMC01. An AUC of 0.62 was observed with an unweighted genetic risk score comprising 11 SNPs in candidate genes. Two additional risk scores were studied by using a penalized matrix decomposition with cross-validation; risk scores of 50 and 400 SNPs were identified with ROC of AUC = 0.74 and AUC = 0.94, respectively.ConclusionsA novel association with advanced POAG in the EN04 locus was identified putatively in persons of AD. In addition to this finding, this genome-wide association study in POAG patients of AD contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine mapping of regions because of shorter average LD (FNDC3B). Although not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.
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- 2019
29. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.
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Franceschini, Nora, Giambartolomei, Claudia, de Vries, Paul S, Finan, Chris, Bis, Joshua C, Huntley, Rachael P, Lovering, Ruth C, Tajuddin, Salman M, Winkler, Thomas W, Graff, Misa, Kavousi, Maryam, Dale, Caroline, Smith, Albert V, Hofer, Edith, van Leeuwen, Elisabeth M, Nolte, Ilja M, Lu, Lingyi, Scholz, Markus, Sargurupremraj, Muralidharan, Pitkänen, Niina, Franzén, Oscar, Joshi, Peter K, Noordam, Raymond, Marioni, Riccardo E, Hwang, Shih-Jen, Musani, Solomon K, Schminke, Ulf, Palmas, Walter, Isaacs, Aaron, Correa, Adolfo, Zonderman, Alan B, Hofman, Albert, Teumer, Alexander, Cox, Amanda J, Uitterlinden, André G, Wong, Andrew, Smit, Andries J, Newman, Anne B, Britton, Annie, Ruusalepp, Arno, Sennblad, Bengt, Hedblad, Bo, Pasaniuc, Bogdan, Penninx, Brenda W, Langefeld, Carl D, Wassel, Christina L, Tzourio, Christophe, Fava, Cristiano, Baldassarre, Damiano, O'Leary, Daniel H, Teupser, Daniel, Kuh, Diana, Tremoli, Elena, Mannarino, Elmo, Grossi, Enzo, Boerwinkle, Eric, Schadt, Eric E, Ingelsson, Erik, Veglia, Fabrizio, Rivadeneira, Fernando, Beutner, Frank, Chauhan, Ganesh, Heiss, Gerardo, Snieder, Harold, Campbell, Harry, Völzke, Henry, Markus, Hugh S, Deary, Ian J, Jukema, J Wouter, de Graaf, Jacqueline, Price, Jacqueline, Pott, Janne, Hopewell, Jemma C, Liang, Jingjing, Thiery, Joachim, Engmann, Jorgen, Gertow, Karl, Rice, Kenneth, Taylor, Kent D, Dhana, Klodian, Kiemeney, Lambertus ALM, Lind, Lars, Raffield, Laura M, Launer, Lenore J, Holdt, Lesca M, Dörr, Marcus, Dichgans, Martin, Traylor, Matthew, Sitzer, Matthias, Kumari, Meena, Kivimaki, Mika, Nalls, Mike A, Melander, Olle, Raitakari, Olli, Franco, Oscar H, Rueda-Ochoa, Oscar L, Roussos, Panos, Whincup, Peter H, Amouyel, Philippe, and Giral, Philippe
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MEGASTROKE Consortium ,Humans ,Coronary Disease ,Genetic Predisposition to Disease ,Amino Acid Oxidoreductases ,Protein-Lysine 6-Oxidase ,Risk Factors ,Lod Score ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Genome-Wide Association Study ,Plaque ,Atherosclerotic ,Carotid Intima-Media Thickness ,ADAMTS9 Protein ,Plaque ,Atherosclerotic ,Polymorphism ,Single Nucleotide - Abstract
Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
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- 2018
30. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations
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Temprano‐Sagrera, Gerard, Sitlani, Colleen M., Bone, William P., Martin‐Bornez, Miguel, Voight, Benjamin F., Morrison, Alanna C., Damrauer, Scott M., de Vries, Paul S., Smith, Nicholas L., Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank W.G., Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L, Peyser, Patricia A, Elliot, Paul, de Vries, Paul S, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Turman, Constance, Germain, Marine, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean‐François, O’Donnell, Chris J, Kim, Jihye, Kraft, Peter, Hansen, John‐Bjarne, Heit, John A, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre‐Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David‐Alexandre, Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten‐Jacobs, Loes, Giese, Anne‐Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chen, Wei‐Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Holliday, Elizabeth G, Howard, George, Hsu, Fang‐Chi, Hyacinth, Hyacinth I, Arfan Ikram, M, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez‐Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin‐Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei‐Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Pulit, Sara L, Rannikmäe, Kristiina, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Rost, Natalia S, Rothwell, Peter M, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil‐Smoller, Sylvia, Wilson, James G, Yusuf, Salim, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu‐Ching, Hoan Choi, Seung, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean‐François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Mei Liu, Yong, Lopez, Oscar L, Makoto, Hirata, Martinez‐Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller‐Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Reddy Peddareddygari, Leema, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba‐Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti‐Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano‐Tárraga, Carolina, Stanne, Tara, Colin Stine, O, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres‐Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez‐Cadenas, Israel, Longstreth, W T, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin
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- 2022
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31. TGFBR1*6A as a modifier of breast cancer risk and progression: advances and future prospects
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Agyemang, Kojo, Johansen, Allan M., Barker, Grayson W., Pennison, Michael J., Sheffield, Kimberly, Jimenez, Hugo, Blackman, Carl, Sharma, Sambad, Fordjour, Patrick A., Singh, Ravi, Cook, Katherine L., Lin, Hui-Kuan, Zhang, Wei, Lo, Hui-Wen, Watabe, Kounosuke, Sun, Peiqing, Langefeld, Carl D., and Pasche, Boris
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- 2022
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32. Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
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Winkler, Thomas W., Rasheed, Humaira, Teumer, Alexander, Gorski, Mathias, Rowan, Bryce X., Stanzick, Kira J., Thomas, Laurent F., Tin, Adrienne, Hoppmann, Anselm, Chu, Audrey Y., Tayo, Bamidele, Thio, Chris H. L., Cusi, Daniele, Chai, Jin-Fang, Sieber, Karsten B., Horn, Katrin, Li, Man, Scholz, Markus, Cocca, Massimiliano, Wuttke, Matthias, van der Most, Peter J., Yang, Qiong, Ghasemi, Sahar, Nutile, Teresa, Li, Yong, Pontali, Giulia, Günther, Felix, Dehghan, Abbas, Correa, Adolfo, Parsa, Afshin, Feresin, Agnese, de Vries, Aiko P. J., Zonderman, Alan B., Smith, Albert V., Oldehinkel, Albertine J., De Grandi, Alessandro, Rosenkranz, Alexander R., Franke, Andre, Teren, Andrej, Metspalu, Andres, Hicks, Andrew A., Morris, Andrew P., Tönjes, Anke, Morgan, Anna, Podgornaia, Anna I., Peters, Annette, Körner, Antje, Mahajan, Anubha, Campbell, Archie, Freedman, Barry I., Spedicati, Beatrice, Ponte, Belen, Schöttker, Ben, Brumpton, Ben, Banas, Bernhard, Krämer, Bernhard K., Jung, Bettina, Åsvold, Bjørn Olav, Smith, Blair H., Ning, Boting, Penninx, Brenda W. J. H., Vanderwerff, Brett R., Psaty, Bruce M., Kammerer, Candace M., Langefeld, Carl D., Hayward, Caroline, Spracklen, Cassandra N., Robinson-Cohen, Cassianne, Hartman, Catharina A., Lindgren, Cecilia M., Wang, Chaolong, Sabanayagam, Charumathi, Heng, Chew-Kiat, Lanzani, Chiara, Khor, Chiea-Chuen, Cheng, Ching-Yu, Fuchsberger, Christian, Gieger, Christian, Shaffer, Christian M., Schulz, Christina-Alexandra, Willer, Cristen J., Chasman, Daniel I., Gudbjartsson, Daniel F., Ruggiero, Daniela, Toniolo, Daniela, Czamara, Darina, Porteous, David J., Waterworth, Dawn M., Mascalzoni, Deborah, Mook-Kanamori, Dennis O., Reilly, Dermot F., Daw, E. Warwick, Hofer, Edith, Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Tai, E-Shyong, Catamo, Eulalia, Rizzi, Federica, Guo, Feng, Rivadeneira, Fernando, Guilianini, Franco, Sveinbjornsson, Gardar, Ehret, Georg, Waeber, Gerard, Biino, Ginevra, Girotto, Giorgia, Pistis, Giorgio, Nadkarni, Girish N., Delgado, Graciela E., Montgomery, Grant W., Snieder, Harold, Campbell, Harry, White, Harvey D., Gao, He, Stringham, Heather M., Schmidt, Helena, Li, Hengtong, Brenner, Hermann, Holm, Hilma, Kirsten, Holgen, Kramer, Holly, Rudan, Igor, Nolte, Ilja M., Tzoulaki, Ioanna, Olafsson, Isleifur, Martins, Jade, Cook, James P., Wilson, James F., Halbritter, Jan, Felix, Janine F., Divers, Jasmin, Kooner, Jaspal S., Lee, Jeannette Jen-Mai, O’Connell, Jeffrey, Rotter, Jerome I., Liu, Jianjun, Xu, Jie, Thiery, Joachim, Ärnlöv, Johan, Kuusisto, Johanna, Jakobsdottir, Johanna, Tremblay, Johanne, Chambers, John C., Whitfield, John B., Gaziano, John M., Marten, Jonathan, Coresh, Josef, Jonas, Jost B., Mychaleckyj, Josyf C., Christensen, Kaare, Eckardt, Kai-Uwe, Mohlke, Karen L., Endlich, Karlhans, Dittrich, Katalin, Ryan, Kathleen A., Rice, Kenneth M., Taylor, Kent D., Ho, Kevin, Nikus, Kjell, Matsuda, Koichi, Strauch, Konstantin, Miliku, Kozeta, Hveem, Kristian, Lind, Lars, Wallentin, Lars, Yerges-Armstrong, Laura M., Raffield, Laura M., Phillips, Lawrence S., Launer, Lenore J., Lyytikäinen, Leo-Pekka, Lange, Leslie A., Citterio, Lorena, Klaric, Lucija, Ikram, M. Arfan, Ising, Marcus, Kleber, Marcus E., Francescatto, Margherita, Concas, Maria Pina, Ciullo, Marina, Piratsu, Mario, Orho-Melander, Marju, Laakso, Markku, Loeffler, Markus, Perola, Markus, de Borst, Martin H., Gögele, Martin, Bianca, Martina La, Lukas, Mary Ann, Feitosa, Mary F., Biggs, Mary L., Wojczynski, Mary K., Kavousi, Maryam, Kanai, Masahiro, Akiyama, Masato, Yasuda, Masayuki, Nauck, Matthias, Waldenberger, Melanie, Chee, Miao-Li, Chee, Miao-Ling, Boehnke, Michael, Preuss, Michael H., Stumvoll, Michael, Province, Michael A., Evans, Michele K., O’Donoghue, Michelle L., Kubo, Michiaki, Kähönen, Mika, Kastarinen, Mika, Nalls, Mike A., Kuokkanen, Mikko, Ghanbari, Mohsen, Bochud, Murielle, Josyula, Navya Shilpa, Martin, Nicholas G., Tan, Nicholas Y. Q., Palmer, Nicholette D., Pirastu, Nicola, Schupf, Nicole, Verweij, Niek, Hutri-Kähönen, Nina, Mononen, Nina, Bansal, Nisha, Devuyst, Olivier, Melander, Olle, Raitakari, Olli T., Polasek, Ozren, Manunta, Paolo, Gasparini, Paolo, Mishra, Pashupati P., Sulem, Patrick, Magnusson, Patrik K. E., Elliott, Paul, Ridker, Paul M., Hamet, Pavel, Svensson, Per O., Joshi, Peter K., Kovacs, Peter, Pramstaller, Peter P., Rossing, Peter, Vollenweider, Peter, van der Harst, Pim, Dorajoo, Rajkumar, Sim, Ralene Z. H., Burkhardt, Ralph, Tao, Ran, Noordam, Raymond, Mägi, Reedik, Schmidt, Reinhold, de Mutsert, Renée, Rueedi, Rico, van Dam, Rob M., Carroll, Robert J., Gansevoort, Ron T., Loos, Ruth J. F., Felicita, Sala Cinzia, Sedaghat, Sanaz, Padmanabhan, Sandosh, Freitag-Wolf, Sandra, Pendergrass, Sarah A., Graham, Sarah E., Gordon, Scott D., Hwang, Shih-Jen, Kerr, Shona M., Vaccargiu, Simona, Patil, Snehal B., Hallan, Stein, Bakker, Stephan J. L., Lim, Su-Chi, Lucae, Susanne, Vogelezang, Suzanne, Bergmann, Sven, Corre, Tanguy, Ahluwalia, Tarunveer S., Lehtimäki, Terho, Boutin, Thibaud S., Meitinger, Thomas, Wong, Tien-Yin, Bergler, Tobias, Rabelink, Ton J., Esko, Tõnu, Haller, Toomas, Thorsteinsdottir, Unnur, Völker, Uwe, Foo, Valencia Hui Xian, Salomaa, Veikko, Vitart, Veronique, Giedraitis, Vilmantas, Gudnason, Vilmundur, Jaddoe, Vincent W. V., Huang, Wei, Zhang, Weihua, Wei, Wen Bin, Kiess, Wieland, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Gao, Xin, Sim, Xueling, Wang, Ya Xing, Friedlander, Yechiel, Tham, Yih-Chung, Kamatani, Yoichiro, Okada, Yukinori, Milaneschi, Yuri, Yu, Zhi, Stark, Klaus J., Stefansson, Kari, Böger, Carsten A., Hung, Adriana M., Kronenberg, Florian, Köttgen, Anna, Pattaro, Cristian, and Heid, Iris M.
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- 2022
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33. Reply to: A balanced measure shows superior performance of pseudobulk methods in single-cell RNA-sequencing analysis
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Zimmerman, Kip D., Evans, Ciaran, and Langefeld, Carl D.
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- 2022
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34. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes
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Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten-Jacobs, Loes, Giese, Anne-Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chasman, Daniel I, Chen, Wei-Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Haessler, Jeffrey, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Heckbert, Susan R, Holliday, Elizabeth G, Howard, George, Hsu, Fang-Chi, Hyacinth, Hyacinth I, Ikram, M Arfan, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez-Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kooperberg, Charles, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin-Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei-Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Psaty, Bruce M, Pulit, Sara L, Rannikmäe, Kristiina, Reiner, Alexander P, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Ridker, Paul M, Rost, Natalia S, Rothwell, Peter M, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, and Sale, Michele M
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Biological Sciences ,Genetics ,Human Genome ,Stroke ,Clinical Research ,Brain Disorders ,Aetiology ,2.1 Biological and endogenous factors ,Cardiovascular ,Computational Biology ,Databases ,Genetic ,Epigenesis ,Genetic ,Female ,Gene Regulatory Networks ,Genetic Loci ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,INDEL Mutation ,Linkage Disequilibrium ,Male ,Models ,Genetic ,Polymorphism ,Single Nucleotide ,Risk Factors ,AFGen Consortium ,Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium ,International Genomics of Blood Pressure (iGEN-BP) Consortium ,INVENT Consortium ,STARNET ,BioBank Japan Cooperative Hospital Group ,COMPASS Consortium ,EPIC-CVD Consortium ,EPIC-InterAct Consortium ,International Stroke Genetics Consortium ,METASTROKE Consortium ,Neurology Working Group of the CHARGE Consortium ,NINDS Stroke Genetics Network ,UK Young Lacunar DNA Study ,MEGASTROKE Consortium ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
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- 2018
35. Genome‐Wide Study of Subcutaneous and Visceral Adipose Tissue Reveals Novel Sex‐Specific Adiposity Loci in Mexican Americans
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Gao, Chuan, Langefeld, Carl D, Ziegler, Julie T, Taylor, Kent D, Norris, Jill M, Chen, Yii‐Der I, Hellwege, Jacklyn N, Guo, Xiuqing, Allison, Matthew A, Speliotes, Elizabeth K, Rotter, Jerome I, Bowden, Donald W, Wagenknecht, Lynne E, and Palmer, Nicholette D
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Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Obesity ,Nutrition ,Prevention ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Adipose Tissue ,Adiposity ,Body Mass Index ,Female ,Genome-Wide Association Study ,Genotype ,Humans ,Male ,Mexican Americans ,Middle Aged ,Phenotype ,Polymorphism ,Single Nucleotide ,Risk Factors ,Endocrinology & Metabolism - Abstract
ObjectiveThis study aimed to explore the genetic mechanisms of regional fat deposition, which is a strong risk factor for metabolic diseases beyond total adiposity.MethodsA genome-wide association study of 7,757,139 single-nucleotide polymorphisms (SNPs) in 983 Mexican Americans (nmale = 403; nfemale = 580) from the Insulin Resistance Atherosclerosis Family Study was performed. Association analyses were performed with and without sex stratification for subcutaneous adipose tissue, visceral adipose tissue (VAT), and visceral-subcutaneous ratio (VSR) obtained from computed tomography.ResultsThe strongest signal identified was SNP rs2185405 (minor allele frequencies [MAF] = 40%; PVAT = 1.98 × 10-8 ) with VAT. It is an intronic variant of the GLIS family zinc finger 3 gene (GLIS3). In addition, SNP rs12657394 (MAF = 19%) was associated with VAT in males (Pmale = 2.39×10-8 ; Pfemale = 2.5 × 10-3 ). It is located intronically in the serum response factor binding protein 1 gene (SRFBP1). On average, male carriers of the variant had 24.6 cm2 increased VAT compared with noncarriers. Subsequently, genome-wide SNP-sex interaction analysis was performed. SNP rs10913233 (MAF = 14%; Pint = 3.07 × 10-8 ) in PAPPA2 and rs10923724 (MAF = 38%; Pint = 2.89 × 10-8 ) upstream of TBX15 were strongly associated with the interaction effect for VSR.ConclusionsSix loci were identified with genome-wide significant associations with fat deposition and interactive effects. These results provided genetic evidence for a differential basis of fat deposition between genders.
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- 2018
36. Metabolomic architecture of obesity implicates metabolonic lactone sulfate in cardiometabolic disease
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Das, Swapan K., Ainsworth, Hannah C., Dimitrov, Latchezar, Okut, Hayrettin, Comeau, Mary E., Sharma, Neeraj, Ng, Maggie C.Y., Norris, Jill M., Chen, Yii-der I., Wagenknecht, Lynne E., Bowden, Donald W., Hsu, Fang-Chi, Taylor, Kent D., Langefeld, Carl D., and Palmer, Nicholette D.
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- 2021
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37. Abstract 147: Novel Inflammatory and Pro-Thrombotic mRNA Pathways Associated With Worse 3-month Outcome After Intracerebral Hemorrhage
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Wright, W. S, primary, Langefeld, Carl D., additional, Comeau, Mary, additional, Hawkins, Greg, additional, Flaherty, Matthew, additional, Gilkerson, Lee, additional, Howard, Tim D., additional, James, Michael L, additional, Kittner, Steven J, additional, Mehndiratta, Prachi, additional, Roh, David, additional, Vahidy, Farhaan, additional, Testai, Fernando, additional, Bagga, Ranjit, additional, Thornton, James B., additional, Cortes, Juan Camilo, additional, Menzies, Lauren, additional, Nobel, Lisa, additional, Wechsler, Paul, additional, Xia, Christina, additional, Woo, Daniel, additional, and Demel, Stacie, additional
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- 2024
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38. Identification of Influential Variants in Significant Aggregate Rare Variant Tests
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Blumhagen, Rachel Z., Schwartz, David A., Langefeld, Carl D., and Fingerlin, Tasha E.
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- 2020
39. miR-181a Mediates Inflammatory Gene Expression After Intracerebral Hemorrhage: An Integrated Analysis of miRNA-seq and mRNA-seq in a Swine ICH Model
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Walsh, Kyle B., Zimmerman, Kip D., Zhang, Xiang, Demel, Stacie L., Luo, Yu, Langefeld, Carl D., Wohleb, Eric, Schulert, Grant, Woo, Daniel, and Adeoye, Opeolu
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- 2021
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40. Transancestral mapping and genetic load in systemic lupus erythematosus.
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Langefeld, Carl D, Ainsworth, Hannah C, Cunninghame Graham, Deborah S, Kelly, Jennifer A, Comeau, Mary E, Marion, Miranda C, Howard, Timothy D, Ramos, Paula S, Croker, Jennifer A, Morris, David L, Sandling, Johanna K, Almlöf, Jonas Carlsson, Acevedo-Vásquez, Eduardo M, Alarcón, Graciela S, Babini, Alejandra M, Baca, Vicente, Bengtsson, Anders A, Berbotto, Guillermo A, Bijl, Marc, Brown, Elizabeth E, Brunner, Hermine I, Cardiel, Mario H, Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M, Dahlqvist, Solbritt Rantapää, D'Alfonso, Sandra, Da Silva, Berta Martins, de la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C, Endreffy, Emőke, Esquivel-Valerio, Jorge A, Fortin, Paul R, Freedman, Barry I, Frostegård, Johan, García, Mercedes A, de la Torre, Ignacio García, Gilkeson, Gary S, Gladman, Dafna D, Gunnarsson, Iva, Guthridge, Joel M, Huggins, Jennifer L, James, Judith A, Kallenberg, Cees GM, Kamen, Diane L, Karp, David R, Kaufman, Kenneth M, Kottyan, Leah C, Kovács, László, Laustrup, Helle, Lauwerys, Bernard R, Li, Quan-Zhen, Maradiaga-Ceceña, Marco A, Martín, Javier, McCune, Joseph M, McWilliams, David R, Merrill, Joan T, Miranda, Pedro, Moctezuma, José F, Nath, Swapan K, Niewold, Timothy B, Orozco, Lorena, Ortego-Centeno, Norberto, Petri, Michelle, Pineau, Christian A, Pons-Estel, Bernardo A, Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D, Russell, Laurie P, Sabio, José M, Aguilar-Salinas, Carlos A, Scherbarth, Hugo R, Scorza, Raffaella, Seldin, Michael F, Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D, Toloza, Sergio MA, Truedsson, Lennart, Tusié-Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M, Wallace, Daniel J, Weisman, Michael H, Wither, Joan E, Bhangale, Tushar, Oksenberg, Jorge R, Rioux, John D, Gregersen, Peter K, Syvänen, Ann-Christine, Rönnblom, Lars, Criswell, Lindsey A, Jacob, Chaim O, Sivils, Kathy L, Tsao, Betty P, Schanberg, Laura E, and Behrens, Timothy W
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Humans ,Lupus Erythematosus ,Systemic ,HLA Antigens ,Logistic Models ,Case-Control Studies ,Mutagenesis ,Insertional ,Age of Onset ,Sequence Deletion ,Genetic Load ,Multifactorial Inheritance ,Polymorphism ,Single Nucleotide ,African Continental Ancestry Group ,American Native Continental Ancestry Group ,European Continental Ancestry Group ,Hispanic Americans ,Lupus Erythematosus ,Systemic ,Mutagenesis ,Insertional ,Polymorphism ,Single Nucleotide - Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P
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- 2017
41. Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms
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Rusu, Victor, Hoch, Eitan, Mercader, Josep M, Tenen, Danielle E, Gymrek, Melissa, Hartigan, Christina R, DeRan, Michael, von Grotthuss, Marcin, Fontanillas, Pierre, Spooner, Alexandra, Guzman, Gaelen, Deik, Amy A, Pierce, Kerry A, Dennis, Courtney, Clish, Clary B, Carr, Steven A, Wagner, Bridget K, Schenone, Monica, Ng, Maggie CY, Chen, Brian H, Consortium, MEDIA, Shriner, Daniel, Li, Jiang, Chen, Wei-Min, Guo, Xiuqing, Liu, Jiankang, Bielinski, Suzette J, Yanek, Lisa R, Nalls, Michael A, Comeau, Mary E, Rasmussen-Torvik, Laura J, Jensen, Richard A, Evans, Daniel S, Sun, Yan V, An, Ping, Patel, Sanjay R, Lu, Yingchang, Long, Jirong, Armstrong, Loren L, Wagenknecht, Lynne, Yang, Lingyao, Snively, Beverly M, Palmer, Nicholette D, Mudgal, Poorva, Langefeld, Carl D, Keene, Keith L, Freedman, Barry I, Mychaleckyj, Josyf C, Nayak, Uma, Raffel, Leslie J, Goodarzi, Mark O, Chen, Y-D Ida, Taylor, Herman A, Correa, Adolfo, Sims, Mario, Couper, David, Pankow, James S, Boerwinkle, Eric, Adeyemo, Adebowale, Doumatey, Ayo, Chen, Guanjie, Mathias, Rasika A, Vaidya, Dhananjay, Singleton, Andrew B, Zonderman, Alan B, Igo, Robert P, Sedor, John R, Consortium, the FIND, Kabagambe, Edmond K, Siscovick, David S, McKnight, Barbara, Rice, Kenneth, Liu, Yongmei, Hsueh, Wen-Chi, Zhao, Wei, Bielak, Lawrence F, Kraja, Aldi, Province, Michael A, Bottinger, Erwin P, Gottesman, Omri, Cai, Qiuyin, Zheng, Wei, Blot, William J, Lowe, William L, Pacheco, Jennifer A, Crawford, Dana C, Consortium, the eMERGE, Consortium, the DIAGRAM, Grundberg, Elin, Consortium, the MuTHER, Rich, Stephen S, Hayes, M Geoffrey, Shu, Xiao-Ou, Loos, Ruth JF, Borecki, Ingrid B, Peyser, Patricia A, Cummings, Steven R, and Psaty, Bruce M
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Biological Sciences ,Genetics ,Clinical Research ,Diabetes ,Digestive Diseases ,Liver Disease ,Aetiology ,2.1 Biological and endogenous factors ,Metabolic and endocrine ,Basigin ,Cell Membrane ,Chromosomes ,Human ,Pair 17 ,Diabetes Mellitus ,Type 2 ,Gene Knockdown Techniques ,Haplotypes ,Hepatocytes ,Heterozygote ,Histone Code ,Humans ,Liver ,Models ,Molecular ,Monocarboxylic Acid Transporters ,MEDIA Consortium ,SIGMA T2D Consortium ,MCT11 ,SLC16A11 ,disease mechanism ,fatty acid metabolism ,genetics ,lipid metabolism ,monocarboxylates ,precision medicine ,solute carrier ,type 2 diabetes ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.
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- 2017
42. A genome‐wide linkage and association analysis of imputed insertions and deletions with cardiometabolic phenotypes in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study
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Gao, Chuan, Hsu, Fang‐Chi, Dimitrov, Latchezar M, Okut, Hayrettin, Chen, Yii‐Der I, Taylor, Kent D, Rotter, Jerome I, Langefeld, Carl D, Bowden, Donald W, and Palmer, Nicholette D
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Epidemiology ,Biological Sciences ,Health Sciences ,Genetics ,Atherosclerosis ,Human Genome ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Adult ,Demography ,Family ,Female ,Gene Frequency ,Genetic Linkage ,Genome ,Human ,Genome-Wide Association Study ,Humans ,INDEL Mutation ,Insulin Resistance ,Male ,Mexican Americans ,Phenotype ,Polymorphism ,Single Nucleotide ,cardiometabolic disease ,genome-wide association analysis ,imputation ,insertion ,deletions ,linkage analysis ,insertion/deletions ,Public Health and Health Services - Abstract
Insertions and deletions (INDELs) represent a significant fraction of interindividual variation in the human genome yet their contribution to phenotypes is poorly understood. To confirm the quality of imputed INDELs and investigate their roles in mediating cardiometabolic phenotypes, genome-wide association and linkage analyses were performed for 15 phenotypes with 1,273,952 imputed INDELs in 1,024 Mexican-origin Americans. Imputation quality was validated using whole exome sequencing with an average kappa of 0.93 in common INDELs (minor allele frequencies [MAFs] ≥ 5%). Association analysis revealed one genome-wide significant association signal for the cholesterylester transfer protein gene (CETP) with high-density lipoprotein levels (rs36229491, P = 3.06 × 10-12 ); linkage analysis identified two peaks with logarithm of the odds (LOD) > 5 (rs60560566, LOD = 5.36 with insulin sensitivity (SI ) and rs5825825, LOD = 5.11 with adiponectin levels). Suggestive overlapping signals between linkage and association were observed: rs59849892 in the WSC domain containing 2 gene (WSCD2) was associated and nominally linked with SI (P = 1.17 × 10-7 , LOD = 1.99). This gene has been implicated in glucose metabolism in human islet cell expression studies. In addition, rs201606363 was linked and nominally associated with low-density lipoprotein (P = 4.73 × 10-4 , LOD = 3.67), apolipoprotein B (P = 1.39 × 10-3 , LOD = 4.64), and total cholesterol (P = 1.35 × 10-2 , LOD = 3.80) levels. rs201606363 is an intronic variant of the UBE2F-SCLY (where UBE2F is ubiquitin-conjugating enzyme E2F and SCLY is selenocysteine lyase) fusion gene that may regulate cholesterol through selenium metabolism. In conclusion, these results confirm the feasibility of imputing INDELs from array-based single nucleotide polymorphism (SNP) genotypes. Analysis of these variants using association and linkage replicated previously identified SNP signals and identified multiple novel INDEL signals. These results support the inclusion of INDELs into genetic studies to more fully interrogate the spectrum of genetic variation.
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- 2017
43. Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family‐Based Linkage and Association in the IRAS Family Study
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Tabb, Keri L, Hellwege, Jacklyn N, Palmer, Nicholette D, Dimitrov, Latchezar, Sajuthi, Satria, Taylor, Kent D, Ng, Maggie CY, Hawkins, Gregory A, Chen, Yii‐der Ida, Brown, W Mark, McWilliams, David, Williams, Adrienne, Lorenzo, Carlos, Norris, Jill M, Long, Jirong, Rotter, Jerome I, Curran, Joanne E, Blangero, John, Wagenknecht, Lynne E, Langefeld, Carl D, and Bowden, Donald W
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Biological Sciences ,Genetics ,Human Genome ,Clinical Research ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Adiponectin ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Atherosclerosis ,Exome ,Female ,Gene Frequency ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Insulin Resistance ,Lipids ,Lod Score ,Male ,Middle Aged ,Polymorphism ,Single Nucleotide ,Sequence Analysis ,DNA ,Young Adult ,Cohort study ,genetic variance ,Hispanic ,novel variants ,Clinical Sciences ,Genetics & Heredity - Abstract
Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 logarithm of the odds (LOD) scores with 1148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (P T in APOA5 and triglyceride levels (P = 3.67 × 10-10 ). Overall, there was a 5.2-fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to the Database of Single Nucleotide Polymorphisms (dbSNP) build 138. Thus, integration of results from two-point linkage and single-variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits.
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- 2017
44. Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans
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Hellwege, Jacklyn N, Palmer, Nicholette D, Dimitrov, Latchezar, Keaton, Jacob M, Tabb, Keri L, Sajuthi, Satria, Taylor, Kent D, Ng, Maggie CY, Speliotes, Elizabeth K, Hawkins, Gregory A, Long, Jirong, Ida Chen, Yii-Der, Lorenzo, Carlos, Norris, Jill M, Rotter, Jerome I, Langefeld, Carl D, Wagenknecht, Lynne E, and Bowden, Donald W
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Biological Sciences ,Genetics ,Biotechnology ,Diabetes ,Clinical Research ,Atherosclerosis ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Diabetes Mellitus ,Type 2 ,Female ,Genetic Linkage ,Genome-Wide Association Study ,Genotype ,Hispanic or Latino ,Humans ,Insulin Resistance ,Laminin ,Lod Score ,Male ,Middle Aged ,NFI Transcription Factors ,Polymorphism ,Single Nucleotide ,Tumor Necrosis Factor-alpha ,Young Adult ,Clinical Sciences ,Genetics & Heredity ,Clinical sciences - Abstract
Linkage studies of complex genetic diseases have been largely replaced by genome-wide association studies, due in part to limited success in complex trait discovery. However, recent interest in rare and low-frequency variants motivates re-examination of family-based methods. In this study, we investigated the performance of two-point linkage analysis for over 1.6 million single-nucleotide polymorphisms (SNPs) combined with single variant association analysis to identify high impact variants, which are both strongly linked and associated with cardiometabolic traits in up to 1414 Hispanics from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of all 50 phenotypes yielded 83 557 000 LOD (logarithm of the odds) scores, with 9214 LOD scores ⩾3.0, 845 ⩾4.0 and 89 ⩾5.0, with a maximal LOD score of 6.49 (rs12956744 in the LAMA1 gene for tumor necrosis factor-α (TNFα) receptor 2). Twenty-seven variants were associated with P4, including variants in the NFIB gene under a linkage peak with TNFα receptor 2 levels on chromosome 9. Linkage regions of interest included a broad peak (31 Mb) on chromosome 1q with acute insulin response (max LOD=5.37). This region was previously documented with type 2 diabetes in family-based studies, providing support for the validity of these results. Overall, we have demonstrated the utility of two-point linkage and association in comprehensive genome-wide array-based SNP genotypes.
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- 2017
45. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation
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Chu, Audrey Y, Deng, Xuan, Fisher, Virginia A, Drong, Alexander, Zhang, Yang, Feitosa, Mary F, Liu, Ching-Ti, Weeks, Olivia, Choh, Audrey C, Duan, Qing, Dyer, Thomas D, Eicher, John D, Guo, Xiuqing, Heard-Costa, Nancy L, Kacprowski, Tim, Kent, Jack W, Lange, Leslie A, Liu, Xinggang, Lohman, Kurt, Lu, Lingyi, Mahajan, Anubha, O'Connell, Jeffrey R, Parihar, Ankita, Peralta, Juan M, Smith, Albert V, Zhang, Yi, Homuth, Georg, Kissebah, Ahmed H, Kullberg, Joel, Laqua, René, Launer, Lenore J, Nauck, Matthias, Olivier, Michael, Peyser, Patricia A, Terry, James G, Wojczynski, Mary K, Yao, Jie, Bielak, Lawrence F, Blangero, John, Borecki, Ingrid B, Bowden, Donald W, Carr, John Jeffrey, Czerwinski, Stefan A, Ding, Jingzhong, Friedrich, Nele, Gudnason, Vilmunder, Harris, Tamara B, Ingelsson, Erik, Johnson, Andrew D, Kardia, Sharon LR, Langefeld, Carl D, Lind, Lars, Liu, Yongmei, Mitchell, Braxton D, Morris, Andrew P, Mosley, Thomas H, Rotter, Jerome I, Shuldiner, Alan R, Towne, Bradford, Völzke, Henry, Wallaschofski, Henri, Wilson, James G, Allison, Matthew, Lindgren, Cecilia M, Goessling, Wolfram, Cupples, L Adrienne, Steinhauser, Matthew L, and Fox, Caroline S
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Nutrition ,Human Genome ,Genetics ,Adipocytes ,Animals ,Body Fat Distribution ,Cell Differentiation ,Cohort Studies ,Ethnicity ,Female ,Genetic Loci ,Genetic Markers ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Male ,Mice ,Mice ,Inbred C57BL ,Obesity ,Phenotype ,Polymorphism ,Single Nucleotide ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.
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- 2017
46. Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND)
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Williams, Robert C, Elston, Robert C, Kumar, Pankaj, Knowler, William C, Abboud, Hanna E, Adler, Sharon, Bowden, Donald W, Divers, Jasmin, Freedman, Barry I, Igo, Robert P, Ipp, Eli, Iyengar, Sudha K, Kimmel, Paul L, Klag, Michael J, Kohn, Orly, Langefeld, Carl D, Leehey, David J, Nelson, Robert G, Nicholas, Susanne B, Pahl, Madeleine V, Parekh, Rulan S, Rotter, Jerome I, Schelling, Jeffrey R, Sedor, John R, Shah, Vallabh O, Smith, Michael W, Taylor, Kent D, Thameem, Farook, Thornley-Brown, Denyse, Winkler, Cheryl A, Guo, Xiuqing, Zager, Phillip, Hanson, Robert L, and the FIND Research Group
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Biological Sciences ,Genetics ,American Indian or Alaska Native ,Diabetes ,Health Disparities ,Minority Health ,Human Genome ,Metabolic and endocrine ,Black or African American ,Algorithms ,Chromosome Mapping ,Diabetic Nephropathies ,Genetic Markers ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Indians ,North American ,Likelihood Functions ,Mexican Americans ,Models ,Genetic ,Oligonucleotide Array Sequence Analysis ,Polymorphism ,Single Nucleotide ,Principal Component Analysis ,United States ,White People ,Individual genetic ancestry ,Population structure ,SNP ,Diabetic nephropathy ,FIND Research Group ,Information and Computing Sciences ,Medical and Health Sciences ,Bioinformatics ,Biological sciences ,Biomedical and clinical sciences - Abstract
BackgroundThe presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample.ResultsA fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy.ConclusionsThe identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.
- Published
- 2016
47. A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs
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Oogheelkunde Onderzoek, CTI Research, Immuno/reuma onderzoek 3 (Loosdregt), Child Health, Infection & Immunity, MS Oogheelkunde, CTI Lab support, Genetica Sectie Genoomdiagnostiek, Cancer, CMM Groep Burgering, Genetica, Hubrecht Institute with UMC, Venema, Wouter J, Hiddingh, Sanne, van Loosdregt, Jorg, Bowes, John, Balliu, Brunilda, de Boer, Joke H, Ossewaarde-van Norel, Jeannette, Thompson, Susan D, Langefeld, Carl D, de Ligt, Aafke, van der Veken, Lars T, Krijger, Peter H L, de Laat, Wouter, Kuiper, Jonas J W, Oogheelkunde Onderzoek, CTI Research, Immuno/reuma onderzoek 3 (Loosdregt), Child Health, Infection & Immunity, MS Oogheelkunde, CTI Lab support, Genetica Sectie Genoomdiagnostiek, Cancer, CMM Groep Burgering, Genetica, Hubrecht Institute with UMC, Venema, Wouter J, Hiddingh, Sanne, van Loosdregt, Jorg, Bowes, John, Balliu, Brunilda, de Boer, Joke H, Ossewaarde-van Norel, Jeannette, Thompson, Susan D, Langefeld, Carl D, de Ligt, Aafke, van der Veken, Lars T, Krijger, Peter H L, de Laat, Wouter, and Kuiper, Jonas J W
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- 2024
48. Asymmetric Independence Model for Detecting Interactions between Variables
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Yu, Guoqiang, Miller, David J., Langefeld, Carl D., Herrington, David M., and Wang, Yue
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Statistics - Methodology - Abstract
Detecting complex interactions among risk factors in case-control studies is a fundamental task in clinical and population research. However, though hypothesis testing using logistic regression (LR) is a convenient solution, the LR framework is poorly powered and ill-suited under several common circumstances in practice including missing or unmeasured risk factors, imperfectly correlated "surrogates", and multiple disease sub-types. The weakness of LR in these settings is related to the way in which the null hypothesis is defined. Here we propose the Asymmetric Independence Model (AIM) as a biologically-inspired alternative to LR, based on the key observation that the mechanisms associated with acquiring a "disease" versus maintaining "health" are asymmetric. We prove mathematically that, unlike LR, AIM is a robust model under the abovementioned confounding scenarios. Further, we provide a mathematical definition of a "synergistic" interaction, and prove that theoretically AIM has better power than LR for such interactions. We then experimentally show the superior performance of AIM as compared to LR on both simulations and four real datasets. While the principal application here involves genetic or environmental variables in the life sciences, our methodology is readily applied to other types of measurements and inferences, e.g. in the social sciences.
- Published
- 2015
49. Factors Associated With Participation in Clinical Trials Among Patients With Lupus
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Harry, Onengiya, Langefeld, Carl D., Crosby, Lori E., and Modi, Avani C.
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- 2022
- Full Text
- View/download PDF
50. Comparative study of prostate cancer biophysical and migratory characteristics via iterative mechanoelectrical properties (iMEP) and standard migration assays
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Ghassemi, Parham, Harris, Koran S., Ren, Xiang, Foster, Brittni M., Langefeld, Carl D., Kerr, Bethany A., and Agah, Masoud
- Published
- 2020
- Full Text
- View/download PDF
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