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2. Embryonic alcohol exposure in zebrafish predisposes adults to cardiomyopathy and diastolic dysfunction.

Author

Weeks, Olivia, Gao, Xinlei, Basu, Sandeep, Galdieri, Jennifer, Chen, Kaifu, Burns, C Geoffrey, and Burns, Caroline E

Subjects
*PRENATAL alcohol exposure, *FETAL alcohol syndrome, *CONGENITAL heart disease, *GENE expression, *HEART diseases
Abstract

Aims Fetal alcohol spectrum disorders (FASDs) impact up to 0.8% of the global population. However, cardiovascular health outcomes in adult patients, along with predictive biomarkers for cardiac risk stratification, remain unknown. Our aim was to utilize a longitudinal cohort study in an animal model to evaluate the impact of embryonic alcohol exposure (EAE) on cardiac structure, function, and transcriptional profile across the lifespan. Methods and results Using zebrafish, we characterized the aftereffects of EAE in adults binned by congenital heart defect (CHD) severity. Chamber sizes were quantified on dissected adult hearts to identify structural changes indicative of cardiomyopathy. Using echocardiography, we quantified systolic function based on ejection fraction and longitudinal strain, and diastolic function based on ventricular filling dynamics, ventricular wall movement, and estimated atrial pressures. Finally, we performed RNA-sequencing on EAE ventricles and assessed how differentially expressed genes (DEGs) correlated with cardiac function. Here, we demonstrate that EAE causes cardiomyopathy and diastolic dysfunction through persistent alterations to ventricular wall structure and gene expression. Following abnormal ventricular morphogenesis, >30% of all EAE adults developed increased atrial-to-ventricular size ratios, abnormal ventricular filling dynamics, and reduced myocardial wall relaxation during early diastole despite preserved systolic function. RNA-sequencing of the EAE ventricle revealed novel and heart failure-associated genes (slc25a33, ankrd9, dusp2, dusp4, spry4, eya4, and edn1) whose expression levels were altered across the animal's lifespan or correlated with the degree of diastolic dysfunction detected in adulthood. Conclusion Our study identifies EAE as a risk factor for adult-onset cardiomyopathy and diastolic dysfunction, regardless of CHD status, and suggests novel molecular indicators of adult EAE-induced heart disease. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation

Author

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

Subjects
Biological Sciences, Genetics, Prevention, Human Genome, 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, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational 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.

Published
2017

4. Fetal alcohol spectrum disorder predisposes to metabolic abnormalities in adulthood

Author

Weeks, Olivia, Bosse, Gabriel D., Oderberg, Isaac M., Aide, Sebastian, Houvras, Yariv, Wrighton, Paul J., LaBella, Kyle, Iversen, Isabelle, Tavakoli, Sahar, Adatto, Isaac, Schwartz, Arkadi, Kloosterman, Daan, Tsomides, Allison, Charness, Michael E., Peterson, Randall T., Steinhauser, Matthew L., Fazeli, Pouneh K., and Goessling, Wolfram

Subjects
Harvard University. Harvard Stem Cell Institute, Diseases, Analysis, Usage, Obesity -- Analysis -- Usage, Type 2 diabetes -- Usage -- Analysis, Medical research -- Analysis -- Usage, Pregnant women -- Usage -- Analysis, Fetal alcohol syndrome -- Analysis -- Usage, Hyperglycemia, Adipose tissue, Fasting, Newborn infants, Triglycerides, Phenotypes
Abstract

Introduction Alcohol and its primary metabolite, acetaldehyde, are teratogens, and exposure during gestation detrimentally affects fetal development (1-3). More than 10% of pregnant women worldwide consume alcohol, and recent estimates [...], Prenatal alcohol exposure (PAE) affects at least 10% of newborns globally and leads to the development of fetal alcohol spectrum disorders (FASDs). Despite its high incidence, there is no consensus on the implications of PAE on metabolic disease risk in adults. Here, we describe a cohort of adults with FASDs that had an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity. Using a zebrafish model for PAE, we performed population studies to elucidate the metabolic disease seen in the clinical cohort. Embryonic alcohol exposure (EAE) in male zebrafish increased the propensity for diet-induced obesity and fasting hyperglycemia in adulthood. We identified several consequences of EAE that may contribute to these phenotypes, including a reduction in adult locomotor activity, alterations in visceral adipose tissue and hepatic development, and persistent diet-responsive transcriptional changes. Taken together, our findings define metabolic vulnerabilities due to EAE and provide evidence that behavioral changes and primary organ dysfunction contribute to resultant metabolic abnormalities.

Published
2020
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11. SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function

Author

Li, Man, Li, Yong, Weeks, Olivia, Mijatovic, Vladan, Teumer, Alexander, Huffman, Jennifer E., Tromp, Gerard, Fuchsberger, Christian, Gorski, Mathias, Lyytikainen, Leo-Pekka, Nutile, Teresa, Sedaghat, Sanaz, Sorice, Rossella, Tin, Adrienne, Yang, Qiong, Ahluwalia, Tarunveer S., Arking, Dan E., Bihlmeyer, Nathan A., Boeger, Carsten A., Carroll, Robert J., Chasman, Daniel I., Comelis, Marilyn C., Dehghan, Abbas, Faul, Jessica D., Feitosa, Mary F., Gambaro, Giovanni, Gasparini, Paolo, Giulianini, Franco, Heid, Iris, Huang, Jinyan, Imboden, Medea, Jackson, Anne U., Jeff, Janina, Jhun, Min A., Katz, Ronit, Kifley, Annette, Kilpelainen, Tuomas, Kumar, Ashish, Laakso, Markku, Li-Gao, Ruifang, Lohman, Kurt, Lu, Yingchang, Maegi, Reedik, Malerba, Giovanni, Mihailov, Evelin, Mohlke, Karen L., Mook-Kanamori, Dennis O., Robino, Antonietta, Ruderfer, Douglas, Salvi, Erika, Schick, Ursula M., Schulz, Christina-Alexandra, Smith, Albert V., Smith, Jennifer A., Traglia, Michela, Yerges-Armstrong, Laura M., Zhao, Wei, Goodarzi, Mark O., Kraja, Aldi T., Liu, Chunyu, Wessel, Jennifer, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bottinger, Erwin P., Braga, Daniele, Brandslund, Ivan, Brody, Jennifer A., Campbell, Archie, Carey, David J., Christensen, Cramer, Coresh, Josef, Crook, Errol, Curhan, Gary C., Cusi, Daniele, de Boer, Ian H., de Vries, Aiko P. J., Denny, Joshua C., Devuyst, Olivier, Dreisbach, Albert W., Endlich, Karlhans, Esko, Tonu, Franco, Oscar H., Fulop, Tibor, Gerhard, Glenn S., Gluemer, Charlotte, Gottesman, Omri, Grarup, Niels, Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hocking, Lynne, Hofman, Albert, Hu, Frank B., Husemoen, Lise Lotte N., Jackson, Rebecca D., Jorgensen, Torben, Jorgensen, Marit E., Kaehoenen, Mika, Kardia, Sharon L. R., Koenig, Wolfgang, Kooperberg, Charles, Kriebel, Jennifer, Launer, Lenore J., Lauritzen, Torsten, Lehtimaki, Terho, Levy, Daniel, Linksted, Pamela, Linneberg, Allan, Liu, Yongmei, Loos, Ruth J. F., Lupo, Antonio, Meisinger, Christine, Melander, Olle, Metspalu, Andres, Mitchell, Paul, Nauck, Matthias, Nuernberg, Peter, Orho-Melander, Marju, Parsa, Afshin, Pedersen, Oluf, Peters, Annette, Peters, Ulrike, Polasek, Ozren, Porteous, David, Probst-Hensch, Nicole M., Psaty, Bruce M., Qi, Lu, Raitakari, Olli T., Reiner, Alex P., Rettig, Rainer, Ridker, Paul M., Rivadeneira, Fernando, Rossouw, Jacques E., Schmidt, Frank, Siscovick, David, Soranzo, Nicole, Strauch, Konstantin, Toniolo, Daniela, Turner, Stephen T., Uitterlinden, Andre G., Ulivi, Sheila, Velayutham, Dinesh, Voelker, Uwe, Volzke, Henry, Waldenberger, Melanie, Wang, Jie Jin, Weir, David R., Witte, Daniel, Kuivaniemi, Helena, Fox, Caroline S., Franceschini, Nora, Goessling, Wolfram, Koettgen, Anna, Chu, Audrey Y., Li, Man, Li, Yong, Weeks, Olivia, Mijatovic, Vladan, Teumer, Alexander, Huffman, Jennifer E., Tromp, Gerard, Fuchsberger, Christian, Gorski, Mathias, Lyytikainen, Leo-Pekka, Nutile, Teresa, Sedaghat, Sanaz, Sorice, Rossella, Tin, Adrienne, Yang, Qiong, Ahluwalia, Tarunveer S., Arking, Dan E., Bihlmeyer, Nathan A., Boeger, Carsten A., Carroll, Robert J., Chasman, Daniel I., Comelis, Marilyn C., Dehghan, Abbas, Faul, Jessica D., Feitosa, Mary F., Gambaro, Giovanni, Gasparini, Paolo, Giulianini, Franco, Heid, Iris, Huang, Jinyan, Imboden, Medea, Jackson, Anne U., Jeff, Janina, Jhun, Min A., Katz, Ronit, Kifley, Annette, Kilpelainen, Tuomas, Kumar, Ashish, Laakso, Markku, Li-Gao, Ruifang, Lohman, Kurt, Lu, Yingchang, Maegi, Reedik, Malerba, Giovanni, Mihailov, Evelin, Mohlke, Karen L., Mook-Kanamori, Dennis O., Robino, Antonietta, Ruderfer, Douglas, Salvi, Erika, Schick, Ursula M., Schulz, Christina-Alexandra, Smith, Albert V., Smith, Jennifer A., Traglia, Michela, Yerges-Armstrong, Laura M., Zhao, Wei, Goodarzi, Mark O., Kraja, Aldi T., Liu, Chunyu, Wessel, Jennifer, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bottinger, Erwin P., Braga, Daniele, Brandslund, Ivan, Brody, Jennifer A., Campbell, Archie, Carey, David J., Christensen, Cramer, Coresh, Josef, Crook, Errol, Curhan, Gary C., Cusi, Daniele, de Boer, Ian H., de Vries, Aiko P. J., Denny, Joshua C., Devuyst, Olivier, Dreisbach, Albert W., Endlich, Karlhans, Esko, Tonu, Franco, Oscar H., Fulop, Tibor, Gerhard, Glenn S., Gluemer, Charlotte, Gottesman, Omri, Grarup, Niels, Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hocking, Lynne, Hofman, Albert, Hu, Frank B., Husemoen, Lise Lotte N., Jackson, Rebecca D., Jorgensen, Torben, Jorgensen, Marit E., Kaehoenen, Mika, Kardia, Sharon L. R., Koenig, Wolfgang, Kooperberg, Charles, Kriebel, Jennifer, Launer, Lenore J., Lauritzen, Torsten, Lehtimaki, Terho, Levy, Daniel, Linksted, Pamela, Linneberg, Allan, Liu, Yongmei, Loos, Ruth J. F., Lupo, Antonio, Meisinger, Christine, Melander, Olle, Metspalu, Andres, Mitchell, Paul, Nauck, Matthias, Nuernberg, Peter, Orho-Melander, Marju, Parsa, Afshin, Pedersen, Oluf, Peters, Annette, Peters, Ulrike, Polasek, Ozren, Porteous, David, Probst-Hensch, Nicole M., Psaty, Bruce M., Qi, Lu, Raitakari, Olli T., Reiner, Alex P., Rettig, Rainer, Ridker, Paul M., Rivadeneira, Fernando, Rossouw, Jacques E., Schmidt, Frank, Siscovick, David, Soranzo, Nicole, Strauch, Konstantin, Toniolo, Daniela, Turner, Stephen T., Uitterlinden, Andre G., Ulivi, Sheila, Velayutham, Dinesh, Voelker, Uwe, Volzke, Henry, Waldenberger, Melanie, Wang, Jie Jin, Weir, David R., Witte, Daniel, Kuivaniemi, Helena, Fox, Caroline S., Franceschini, Nora, Goessling, Wolfram, Koettgen, Anna, and Chu, Audrey Y.

Abstract

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (n(stage1);111,666;n(stage2): 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; P-stage1<3.7 x10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4x 10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

Published
2017

12. SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function

Author

Li, Man, Li, Yong, Weeks, Olivia, Mijatovic, Vladan, Teumer, Alexander, Huffman, Jennifer E, Tromp, Gerard, Fuchsberger, Christian, Gorski, Mathia, Lyytikäinen, Leo Pekka, Nutile, Teresa, Sedaghat, Sanaz, Sorice, Rossella, Tin, Adrienne, Yang, Qiong, Ahluwalia, Tarunveer S, Arking, Dan E, Bihlmeyer, Nathan A, Böger, Carsten A, Carroll, Robert J, Chasman, Daniel I, Cornelis, Marilyn C, Dehghan, Abba, Faul, Jessica D, Feitosa, Mary F, Gambaro, Giovanni, Gasparini, Paolo, Giulianini, Franco, Heid, Iri, Huang, Jinyan, Imboden, Medea, Jackson, Anne U, Jeff, Janina, Jhun, Min A, Katz, Ronit, Kifley, Annette, Kilpeläinen, Tuomas O, Kumar, Ashish, Laakso, Markku, Li Gao, Ruifang, Lohman, Kurt, Lu, Yingchang, Mägi, Reedik, Malerba, Giovanni, Mihailov, Evelin, Mohlke, Karen L, Mook Kanamori, Dennis O, Robino, Antonietta, Ruderfer, Dougla, Salvi, Erika, Schick, Ursula M, Schulz, Christina Alexandra, Smith, Albert V, Smith, Jennifer A, Traglia, Michela, Yerges Armstrong, Laura M, Zhao, Wei, Goodarzi, Mark O, Kraja, Aldi T, Liu, Chunyu, Wessel, Jennifer, Boerwinkle, Eric, Borecki, Ingrid B, Bork Jensen, Jette, Bottinger, Erwin P, Braga, Daniele, Brandslund, Ivan, Brody, Jennifer A, Campbell, Archie, Carey, David J, Christensen, Cramer, Coresh, Josef, Crook, Errol, Curhan, Gary C, Cusi, Daniele, de Boer, Ian H, de Vries, Aiko P. J, Denny, Joshua C, Devuyst, Olivier, Dreisbach, Albert W, Endlich, Karlhan, Esko, Tõnu, Franco, Oscar H, Fulop, Tibor, Gerhard, Glenn S, Glümer, Charlotte, Gottesman, Omri, Grarup, Niel, Gudnason, Vilmundur, Harris, Tamara B, Hayward, Caroline, Hocking, Lynne, Hofman, Albert, Hu, Frank B, Husemoen, Lise Lotte N, Jackson, Rebecca D, Jørgensen, Torben, Jørgensen, Marit E, Kähönen, Mika, Kardia, Sharon L. R, König, Wolfgang, Kooperberg, Charle, Kriebel, Jennifer, Launer, Lenore J, Lauritzen, Torsten, Lehtimäki, Terho, Levy, Daniel, Linksted, Pamela, Linneberg, Allan, Liu, Yongmei, Loos, Ruth J. F, Lupo, Antonio, Meisinger, Christine, Melander, Olle, Metspalu, Andre, Mitchell, Paul, Nauck, Matthia, Nürnberg, Peter, Orho Melander, Marju, Parsa, Afshin, Pedersen, Oluf, Peters, Annette, Peters, Ulrike, Polasek, Ozren, Porteous, David, Probst Hensch, Nicole M, Psaty, Bruce M, Qi, Lu, Raitakari, Olli T, Reiner, Alex P, Rettig, Rainer, Ridker, Paul M, Rivadeneira, Fernando, Rossouw, Jacques E, Schmidt, Frank, Siscovick, David, Soranzo, Nicole, Strauch, Konstantin, Toniolo, Daniela, Turner, Stephen T, Uitterlinden, André G, Ulivi, Sheila, Velayutham, Dinesh, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Wang, Jie Jin, Weir, David R, Witte, Daniel, Kuivaniemi, Helena, Fox, Caroline S, Franceschini, Nora, Goessling, Wolfram, Köttgen, Anna, Chu, Audrey Y., Gambaro, Giovanni (ORCID:0000-0001-5733-2370), Li, Man, Li, Yong, Weeks, Olivia, Mijatovic, Vladan, Teumer, Alexander, Huffman, Jennifer E, Tromp, Gerard, Fuchsberger, Christian, Gorski, Mathia, Lyytikäinen, Leo Pekka, Nutile, Teresa, Sedaghat, Sanaz, Sorice, Rossella, Tin, Adrienne, Yang, Qiong, Ahluwalia, Tarunveer S, Arking, Dan E, Bihlmeyer, Nathan A, Böger, Carsten A, Carroll, Robert J, Chasman, Daniel I, Cornelis, Marilyn C, Dehghan, Abba, Faul, Jessica D, Feitosa, Mary F, Gambaro, Giovanni, Gasparini, Paolo, Giulianini, Franco, Heid, Iri, Huang, Jinyan, Imboden, Medea, Jackson, Anne U, Jeff, Janina, Jhun, Min A, Katz, Ronit, Kifley, Annette, Kilpeläinen, Tuomas O, Kumar, Ashish, Laakso, Markku, Li Gao, Ruifang, Lohman, Kurt, Lu, Yingchang, Mägi, Reedik, Malerba, Giovanni, Mihailov, Evelin, Mohlke, Karen L, Mook Kanamori, Dennis O, Robino, Antonietta, Ruderfer, Dougla, Salvi, Erika, Schick, Ursula M, Schulz, Christina Alexandra, Smith, Albert V, Smith, Jennifer A, Traglia, Michela, Yerges Armstrong, Laura M, Zhao, Wei, Goodarzi, Mark O, Kraja, Aldi T, Liu, Chunyu, Wessel, Jennifer, Boerwinkle, Eric, Borecki, Ingrid B, Bork Jensen, Jette, Bottinger, Erwin P, Braga, Daniele, Brandslund, Ivan, Brody, Jennifer A, Campbell, Archie, Carey, David J, Christensen, Cramer, Coresh, Josef, Crook, Errol, Curhan, Gary C, Cusi, Daniele, de Boer, Ian H, de Vries, Aiko P. J, Denny, Joshua C, Devuyst, Olivier, Dreisbach, Albert W, Endlich, Karlhan, Esko, Tõnu, Franco, Oscar H, Fulop, Tibor, Gerhard, Glenn S, Glümer, Charlotte, Gottesman, Omri, Grarup, Niel, Gudnason, Vilmundur, Harris, Tamara B, Hayward, Caroline, Hocking, Lynne, Hofman, Albert, Hu, Frank B, Husemoen, Lise Lotte N, Jackson, Rebecca D, Jørgensen, Torben, Jørgensen, Marit E, Kähönen, Mika, Kardia, Sharon L. R, König, Wolfgang, Kooperberg, Charle, Kriebel, Jennifer, Launer, Lenore J, Lauritzen, Torsten, Lehtimäki, Terho, Levy, Daniel, Linksted, Pamela, Linneberg, Allan, Liu, Yongmei, Loos, Ruth J. F, Lupo, Antonio, Meisinger, Christine, Melander, Olle, Metspalu, Andre, Mitchell, Paul, Nauck, Matthia, Nürnberg, Peter, Orho Melander, Marju, Parsa, Afshin, Pedersen, Oluf, Peters, Annette, Peters, Ulrike, Polasek, Ozren, Porteous, David, Probst Hensch, Nicole M, Psaty, Bruce M, Qi, Lu, Raitakari, Olli T, Reiner, Alex P, Rettig, Rainer, Ridker, Paul M, Rivadeneira, Fernando, Rossouw, Jacques E, Schmidt, Frank, Siscovick, David, Soranzo, Nicole, Strauch, Konstantin, Toniolo, Daniela, Turner, Stephen T, Uitterlinden, André G, Ulivi, Sheila, Velayutham, Dinesh, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Wang, Jie Jin, Weir, David R, Witte, Daniel, Kuivaniemi, Helena, Fox, Caroline S, Franceschini, Nora, Goessling, Wolfram, Köttgen, Anna, Chu, Audrey Y., and Gambaro, Giovanni (ORCID:0000-0001-5733-2370)

Abstract

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

Published
2016

13. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation

Author

Chu, Audrey Y, primary, Deng, Xuan, additional, Fisher, Virginia A, additional, Drong, Alexander, additional, Zhang, Yang, additional, Feitosa, Mary F, additional, Liu, Ching-Ti, additional, Weeks, Olivia, additional, Choh, Audrey C, additional, Duan, Qing, additional, Dyer, Thomas D, additional, Eicher, John D, additional, Guo, Xiuqing, additional, Heard-Costa, Nancy L, additional, Kacprowski, Tim, additional, Kent, Jack W, additional, Lange, Leslie A, additional, Liu, Xinggang, additional, Lohman, Kurt, additional, Lu, Lingyi, additional, Mahajan, Anubha, additional, O'Connell, Jeffrey R, additional, Parihar, Ankita, additional, Peralta, Juan M, additional, Smith, Albert V, additional, Zhang, Yi, additional, Homuth, Georg, additional, Kissebah, Ahmed H, additional, Kullberg, Joel, additional, Laqua, René, additional, Launer, Lenore J, additional, Nauck, Matthias, additional, Olivier, Michael, additional, Peyser, Patricia A, additional, Terry, James G, additional, Wojczynski, Mary K, additional, Yao, Jie, additional, Bielak, Lawrence F, additional, Blangero, John, additional, Borecki, Ingrid B, additional, Bowden, Donald W, additional, Carr, John Jeffrey, additional, Czerwinski, Stefan A, additional, Ding, Jingzhong, additional, Friedrich, Nele, additional, Gudnason, Vilmunder, additional, Harris, Tamara B, additional, Ingelsson, Erik, additional, Johnson, Andrew D, additional, Kardia, Sharon L R, additional, Langefeld, Carl D, additional, Lind, Lars, additional, Liu, Yongmei, additional, Mitchell, Braxton D, additional, Morris, Andrew P, additional, Mosley, Thomas H, additional, Rotter, Jerome I, additional, Shuldiner, Alan R, additional, Towne, Bradford, additional, Völzke, Henry, additional, Wallaschofski, Henri, additional, Wilson, James G, additional, Allison, Matthew, additional, Lindgren, Cecilia M, additional, Goessling, Wolfram, additional, Cupples, L Adrienne, additional, Steinhauser, Matthew L, additional, and Fox, Caroline S, additional

Published
2016
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15. The Law Is What It Is, but Is It Equitable? The Law of Encroachments Where the Innocent, Negligent, and Willful Are Treated the Same.

Author

WEEKS, OLIVIA L.

Subjects
ENCROACHMENTS (Real property), PROPERTY, LEGAL status of landowners, EXTORTION, ACTIONS & defenses (Law), GOVERNMENT policy
Abstract

A landowner builds a house that encroaches two feet on his neighbor's property. The encroachment involves very little land, but it creates many issues for the respective landowners. In today's society, where subdivisions are developed daily, there is an increasing potential for encroachments due to innocent mistakes, negligence, or willfulness. When an encroachment occurs, it would be terrific if the parties could negotiate a fair solution, but this rarely happens. This is because the law automatically places an encroaching landowner in an inferior bargaining position. In North Carolina, courts will order the encroaching landowner to remove the encroachment regardless of his intent. Therefore, the encroaching landowner must meet the neighbor's demands for waiving a mandatory injunction to compel removal or prepare to move the encroaching portion of the structure. This Article addresses the public policy and equitable issues sparked by the encroachment of a permanent structure on an adjoining landowner's property. It focuses on the equitable hardship doctrine, which is commonly invoked by many jurisdictions in encroachment cases and applied when the circumstances of a given case justif superseding the landowner's ordinary remedy to an injunction-a doctrine which North Carolina has paid lip service to but does not apply. The analysis in this Article leads to the conclusion that in determining whether to grant an injunction, a court must balance the equities by assessing the relative hardship of each party. Application of the equitable hardship doctrine in encroachment cases will prevent economic waste, the potential for extortion, and unnecessary litigation, and create a just result for both parties. [ABSTRACT FROM AUTHOR]

Published
2017

18. Restructure and Reform: Products-Liability Law in North Carolina.

Author

MCQUADE, J. STANLEY and WEEKS, OLIVIA L.

Subjects
PRODUCT liability, LEGAL liability, NEGLIGENCE, TORTS, NEGLIGENT enablement (Law), U.S. states
Abstract

The article offers information on products-liability law in North Carolina. Topics discussed include introduction of the Model Uniform Product Liability Act; early development of products liability law; tort-law influences in products liability; and improvements to North Carolina's products-liability act.

Published
2015

19. Molecular characterization of dental development in a toothed archosaur, the American alligator Alligator mississippiensis.

Author

Weeks, Olivia, Bhullar, Bhart‐Anjan S., and Abzhanov, Arhat

Subjects
*DENTAL anthropology, *ARCHOSAURIA, *NATURAL history, *CROCODILIANS, *TETRAPODS, *AMNIOTES
Abstract

SUMMARY Few skeletal structures are as informative of the adaptive natural history of vertebrate animals as their teeth. Understanding principles of tooth development is key to understanding evolution of the vertebrate dentition in general and emergence of multiple specialized tooth types in particular. Morphological and phylogenetic considerations suggest that crocodilians have the most primitive mode of dentition within extant tetrapods, displaying simple, conical, socketed, and continuously replaced teeth. Previous histological studies revealed several dental fates, including functional and non-functional teeth (rudiments) in the developing alligator embryos. We analyze expression of key odontogenic regulators and markers to better characterize the molecular patterning of crocodilian dentition. Importantly, we demonstrate that the morphologically distinct tooth types in Alligator mississippiensis are distinguishable by differences in their developmental programs. We also present evidence showing that tooth maturation is accompanied by dynamic gene expression in the epithelial and mesenchymal cells involved in tooth development. Our data reveal a significant morphological and genetic variation in early dental fates. We believe that this underlying developmental variation reflects modularity, or the ability of teeth to develop semi-autonomously along the alligator jaw. We propose that such modularity may have been a crucial for adaptive evolution within Amniota, allowing for the progressive modifications to tooth replacement, number, and shape. [ABSTRACT FROM AUTHOR]

Published
2013
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20. Environmental and Genetic Perturbations During Development Shape Multi-Organ Health Outcomes

Author

Weeks, Olivia

Subjects
DOHaD, fetal alcohol spectrum disorder, metabolic syndrome, prenatal alcohol exposure, teratogen, Developmental biology
Abstract

The developmental origin of health and disease hypothesis (DOHaD) postulates that environmental and genetic factors present during prenatal and perinatal stages alter development and fundamentally influence adolescent and adult health. Adverse or stressful intrauterine events repeatedly associate with poor health outcomes, including psychiatric disease, neurobehavioral abnormalities, metabolic disease, and cardiovascular disorders. Prenatal alcohol exposure (PAE) is a common developmental stressor that can result in fetal alcohol spectrum disorder (FASD). At least 10% of pregnancies involve alcohol exposure, and recent estimates suggest that 2.5 - 5% of babies born from North America and Europe, and greater than 10% of those from South Africa, have FASD. Affected patients can present with behavioral and cognitive alterations, nerve and brain abnormalities, birth defects in organs such as the heart and kidney, and craniofacial anomalies. The teratogenic effects of EtOH are thought to have a lifelong impact on affected individuals; however, the consequences of PAE on adult metabolic health outcomes have yet to be characterized. Furthermore, the cellular and molecular mechanisms underlying EtOH’s teratogenicity are poorly understood. In Chapter 2, I investigate metabolic health outcomes in FASD. I demonstrate that adults with FASD have an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity, and recapitulate these findings in zebrafish model of embryonic alcohol exposure (EAE). Furthermore, I identify several consequences of EAE that may contribute to these phenotypes, including a reduction in adult swimming activity, diet-responsive transcriptional changes, and alterations in visceral adipocyte and hepatic development. In Chapter 3, I identify the proteasome as a critical target of EAE and demonstrate that EtOH-induced disruptions to the ubiquitin proteasome system (UPS) may contribute to neurodevelopmental disorder, craniofacial malformation, and endoderm defects following EAE. Finally, in Chapter 4, I interrogate the role of nuclear receptor nr5a2 in endoderm formation and demonstrate that it is required for hepatopancreas development. Taken together, this dissertation demonstrates the life-long impact of environmental and genetic perturbations during development, and provides clinically relevant insight into the metabolic health outcomes and molecular underpinnings of FASD.

Published
2020

21. SOS2 and ACP1 loci identified through large-scale exome chip analysis regulate kidney development and function

Author

Jacques E. Rossouw, Aldi T. Kraja, Daniel I. Chasman, Jennifer Wessel, Paul Mitchell, Erika Salvi, Adrienne Tin, Paul M. Ridker, David J. Carey, Daniele Braga, Sharon L.R. Kardia, Wolfgang König, Medea Imboden, Antonio Lupo, Paolo Gasparini, Glenn S. Gerhard, David J. Porteous, Karlhans Endlich, Mathias Gorski, Tuomas O. Kilpeläinen, Ivan Brandslund, Jinyan Huang, Min A. Jhun, Alexander P. Reiner, Christine Meisinger, Yong Li, Karen L. Mohlke, Anne U. Jackson, Janina M. Jeff, Iris M. Heid, Gary C. Curhan, Uwe Völker, Marju Orho-Melander, Allan Linneberg, Olli T. Raitakari, Caroline S. Fox, Vilmundur Gudnason, Charlotte Glümer, Ozren Polasek, Annette Kifley, David R. Weir, Konstantin Strauch, Albert V. Smith, Archie Campbell, Annette Peters, Nicole Probst-Hensch, Lu Qi, Rebecca D. Jackson, Eric Boerwinkle, Daniela Toniolo, Laura M. Yerges-Armstrong, Ruifang Li-Gao, Ian H. De Boer, Qiong Yang, Mika Kähönen, Carsten A. Böger, Dan E. Arking, Albert W. Dreisbach, Man Li, Mary F. Feitosa, Stephen T. Turner, Afshin Parsa, Charles Kooperberg, Jennifer E. Huffman, Sanaz Sedaghat, Omri Gottesman, Fernando Rivadeneira, Marit E. Jørgensen, Joshua C. Denny, Olivier Devuyst, Giovanni Malerba, Frank Schmidt, Robert J. Carroll, Michela Traglia, Chunyu Liu, Ruth J. F. Loos, Franco Giulianini, Daniel Levy, Terho Lehtimäki, Tarunveer S. Ahluwalia, Helena Kuivaniemi, Kurt Lohman, Vladan Mijatovic, Matthias Nauck, Henry Völzke, Aiko P. J. de Vries, Torben Hansen, Wolfram Goessling, Lenore J. Launer, Frank B. Hu, Tibor Fülöp, Nathan A. Bihlmeyer, Reedik Mägi, Gerard Tromp, Yingchang Lu, Jessica D. Faul, Nora Franceschini, Lise Lotte N. Husemoen, Leo Pekka Lyytikäinen, Markku Laakso, Dennis O. Mook-Kanamori, Ronit Katz, Dinesh Velayutham, Jennifer A. Smith, Teresa Nutile, David S. Siscovick, Ulrike Peters, Jie Jin Wang, Tamara B. Harris, Christina-Alexandra Schulz, Douglas Ruderfer, Mark O. Goodarzi, Oscar H. Franco, Yongmei Liu, Cramer Christensen, Nicole Soranzo, Audrey Y. Chu, Melanie Waldenberger, Oluf Pedersen, Ingrid B. Borecki, Peter Nürnberg, D. Cusi, Abbas Dehghan, Daniel R. Witte, Niels Grarup, Christian Fuchsberger, Sheila Ulivi, Josef Coresh, Evelin Mihailov, Ashok Kumar, Jennifer Kriebel, Jennifer A. Brody, Erwin P. Bottinger, Marilyn C. Cornelis, Torsten Lauritzen, Albert Hofman, Olivia Weeks, Rainer Rettig, Lynne J. Hocking, Giovanni Gambaro, André G. Uitterlinden, Anna Köttgen, Caroline Hayward, Alexander Teumer, Tõnu Esko, Antonietta Robino, Torben Jørgensen, Bruce M. Psaty, Ursula M. Schick, Rossella Sorice, Wei Zhao, Andres Metspalu, Pamela Linksted, Olle Melander, Jette Bork-Jensen, Errol D. Crook, Li, Man, Li, Yong, Weeks, Olivia, Mijatovic, Vladan, Teumer, Alexander, Huffman, Jennifer E., Tromp, Gerard, Fuchsberger, Christian, Gorski, Mathia, Lyytikäinen, Leo-Pekka, Nutile, Teresa, Sedaghat, Sanaz, Sorice, Rossella, Tin, Adrienne, Yang, Qiong, Ahluwalia, Tarunveer S., Arking, Dan E., Bihlmeyer, Nathan A., Böger, Carsten A., Carroll, Robert J., Chasman, Daniel I., Cornelis, Marilyn C., Dehghan, Abba, Faul, Jessica D., Feitosa, Mary F., Gambaro, Giovanni, Gasparini, Paolo, Giulianini, Franco, Heid, Iri, Huang, Jinyan, Imboden, Medea, Jackson, Anne U., Jeff, Janina, Jhun, Min A., Katz, Ronit, Kifley, Annette, Kilpeläinen, Tuomas O., Kumar, Ashish, Laakso, Markku, Li-Gao, Ruifang, Lohman, Kurt, Lu, Yingchang, Mägi, Reedik, Malerba, Giovanni, Mihailov, Evelin, Mohlke, Karen L., Mook-Kanamori, Dennis O., Robino, Antonietta, Ruderfer, Dougla, Salvi, Erika, Schick, Ursula M., Schulz, Christina-Alexandra, Smith, Albert V., Smith, Jennifer A., Traglia, Michela, Yerges-Armstrong, Laura M., Zhao, Wei, Goodarzi, Mark O., Kraja, Aldi T., Liu, Chunyu, Wessel, Jennifer, Boerwinkle, Eric, Borecki, Ingrid B., Bork-Jensen, Jette, Bottinger, Erwin P., Braga, Daniele, Brandslund, Ivan, Brody, Jennifer A., Campbell, Archie, Carey, David J., Christensen, Cramer, Coresh, Josef, Crook, Errol, Curhan, Gary C., Cusi, Daniele, De Boer, Ian H., De Vries, Aiko P. J., Denny, Joshua C., Devuyst, Olivier, Dreisbach, Albert W., Endlich, Karlhan, Esko, Tõnu, Franco, Oscar H., Fulop, Tibor, Gerhard, Glenn S., Glümer, Charlotte, Gottesman, Omri, Grarup, Niel, Gudnason, Vilmundur, Hansen, Torben, Harris, Tamara B., Hayward, Caroline, Hocking, Lynne, Hofman, Albert, Hu, Frank B., Husemoen, Lise Lotte N., Jackson, Rebecca D., Jørgensen, Torben, Jørgensen, Marit E., Kähönen, Mika, Kardia, Sharon L. R., König, Wolfgang, Kooperberg, Charle, Kriebel, Jennifer, Launer, Lenore J., Lauritzen, Torsten, Lehtimäki, Terho, Levy, Daniel, Linksted, Pamela, Linneberg, Allan, Liu, Yongmei, Loos, Ruth J. F., Lupo, Antonio, Meisinger, Christine, Melander, Olle, Metspalu, Andre, Mitchell, Paul, Nauck, Matthia, Nürnberg, Peter, Orho-Melander, Marju, Parsa, Afshin, Pedersen, Oluf, Peters, Annette, Peters, Ulrike, Polasek, Ozren, Porteous, David, Probst-Hensch, Nicole M., Psaty, Bruce M., Qi, Lu, Raitakari, Olli T., Reiner, Alex P., Rettig, Rainer, Ridker, Paul M., Rivadeneira, Fernando, Rossouw, Jacques E., Schmidt, Frank, Siscovick, David, Soranzo, Nicole, Strauch, Konstantin, Toniolo, Daniela, Turner, Stephen T., Uitterlinden, André G., Ulivi, Sheila, Velayutham, Dinesh, Völker, Uwe, Völzke, Henry, Waldenberger, Melanie, Wang, Jie Jin, Weir, David R., Witte, Daniel, Kuivaniemi, Helena, Fox, Caroline S., Franceschini, Nora, Goessling, Wolfram, Köttgen, Anna, Chu, Audrey Y., Epidemiology, Erasmus MC other, and Internal Medicine

Subjects
0301 basic medicine, Nonsynonymous substitution, Nephrology, medicine.medical_specialty, human genetics, Renal function, Genome-wide association study, Single-nucleotide polymorphism, Biology, Kidney, 03 medical and health sciences, 0302 clinical medicine, kidney development, renal function, Clinical Research, Proto-Oncogene Proteins, Internal medicine, Animals, Exome, Genetic Loci, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Protein Tyrosine Phosphatases, Son of Sevenless Proteins, Zebrafish, Journal Article, medicine, Settore MED/14 - NEFROLOGIA, human genetic, Gene, Genetic association, Genetics, Proto-Oncogene Protein, Animal, Son of Sevenless Protein, General Medicine, ta3121, 030104 developmental biology, Human Genetics, Kidney Development, Renal Function, Protein Tyrosine Phosphatase, genome, nephron, 030217 neurology & neurosurgery, Meta-Analysis, Human
Abstract

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1

Published
2017
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