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1. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.

Author

Wyss, Annah B, Sofer, Tamar, Lee, Mi Kyeong, Terzikhan, Natalie, Nguyen, Jennifer N, Lahousse, Lies, Latourelle, Jeanne C, Smith, Albert Vernon, Bartz, Traci M, Feitosa, Mary F, Gao, Wei, Ahluwalia, Tarunveer S, Tang, Wenbo, Oldmeadow, Christopher, Duan, Qing, de Jong, Kim, Wojczynski, Mary K, Wang, Xin-Qun, Noordam, Raymond, Hartwig, Fernando Pires, Jackson, Victoria E, Wang, Tianyuan, Obeidat, Ma'en, Hobbs, Brian D, Huan, Tianxiao, Gui, Hongsheng, Parker, Margaret M, Hu, Donglei, Mogil, Lauren S, Kichaev, Gleb, Jin, Jianping, Graff, Mariaelisa, Harris, Tamara B, Kalhan, Ravi, Heckbert, Susan R, Paternoster, Lavinia, Burkart, Kristin M, Liu, Yongmei, Holliday, Elizabeth G, Wilson, James G, Vonk, Judith M, Sanders, Jason L, Barr, R Graham, de Mutsert, Renée, Menezes, Ana Maria Baptista, Adams, Hieab HH, van den Berge, Maarten, Joehanes, Roby, Levin, Albert M, Liberto, Jennifer, Launer, Lenore J, Morrison, Alanna C, Sitlani, Colleen M, Celedón, Juan C, Kritchevsky, Stephen B, Scott, Rodney J, Christensen, Kaare, Rotter, Jerome I, Bonten, Tobias N, Wehrmeister, Fernando César, Bossé, Yohan, Xiao, Shujie, Oh, Sam, Franceschini, Nora, Brody, Jennifer A, Kaplan, Robert C, Lohman, Kurt, McEvoy, Mark, Province, Michael A, Rosendaal, Frits R, Taylor, Kent D, Nickle, David C, Williams, L Keoki, Burchard, Esteban G, Wheeler, Heather E, Sin, Don D, Gudnason, Vilmundur, North, Kari E, Fornage, Myriam, Psaty, Bruce M, Myers, Richard H, O'Connor, George, Hansen, Torben, Laurie, Cathy C, Cassano, Patricia A, Sung, Joohon, Kim, Woo Jin, Attia, John R, Lange, Leslie, Boezen, H Marike, Thyagarajan, Bharat, Rich, Stephen S, Mook-Kanamori, Dennis O, Horta, Bernardo Lessa, Uitterlinden, André G, Im, Hae Kyung, Cho, Michael H, Brusselle, Guy G, and Gharib, Sina A

Subjects
Lung, Humans, Lung Diseases, Pulmonary Disease, Chronic Obstructive, Genetic Predisposition to Disease, Vital Capacity, Forced Expiratory Volume, Regression Analysis, Sample Size, Smoking, Genomics, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, African Continental Ancestry Group, Asian Americans, European Continental Ancestry Group, Hispanic Americans, Female, Male, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive
Abstract

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

Published
2018

2. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author

Hobbs, Brian D, de Jong, Kim, Lamontagne, Maxime, Bossé, Yohan, Shrine, Nick, Artigas, María Soler, Wain, Louise V, Hall, Ian P, Jackson, Victoria E, Wyss, Annah B, London, Stephanie J, North, Kari E, Franceschini, Nora, Strachan, David P, Beaty, Terri H, Hokanson, John E, Crapo, James D, Castaldi, Peter J, Chase, Robert P, Bartz, Traci M, Heckbert, Susan R, Psaty, Bruce M, Gharib, Sina A, Zanen, Pieter, Lammers, Jan W, Oudkerk, Matthijs, Groen, HJ, Locantore, Nicholas, Tal-Singer, Ruth, Rennard, Stephen I, Vestbo, Jørgen, Timens, Wim, Paré, Peter D, Latourelle, Jeanne C, Dupuis, Josée, O'Connor, George T, Wilk, Jemma B, Kim, Woo Jin, Lee, Mi Kyeong, Oh, Yeon-Mok, Vonk, Judith M, de Koning, Harry J, Leng, Shuguang, Belinsky, Steven A, Tesfaigzi, Yohannes, Manichaikul, Ani, Wang, Xin-Qun, Rich, Stephen S, Barr, R Graham, Sparrow, David, Litonjua, Augusto A, Bakke, Per, Gulsvik, Amund, Lahousse, Lies, Brusselle, Guy G, Stricker, Bruno H, Uitterlinden, André G, Ampleford, Elizabeth J, Bleecker, Eugene R, Woodruff, Prescott G, Meyers, Deborah A, Qiao, Dandi, Lomas, David A, Yim, Jae-Joon, Kim, Deog Kyeom, Hawrylkiewicz, Iwona, Sliwinski, Pawel, Hardin, Megan, Fingerlin, Tasha E, Schwartz, David A, Postma, Dirkje S, MacNee, William, Tobin, Martin D, Silverman, Edwin K, Boezen, H Marike, and Cho, Michael H

Subjects
Biological Sciences, Genetics, Chronic Obstructive Pulmonary Disease, Lung, Human Genome, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Respiratory, Adult, Aged, Aged, 80 and over, Alleles, Asthma, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Pulmonary Fibrosis, Risk Factors, Smoking, COPDGene Investigators, ECLIPSE Investigators, LifeLines Investigators, SPIROMICS Research Group, International COPD Genetics Network Investigators, UK BiLEVE Investigators, International COPD Genetics Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Published
2017

3. Association Between Interstitial Lung Abnormalities and All-Cause Mortality

Author

Putman, Rachel K, Hatabu, Hiroto, Araki, Tetsuro, Gudmundsson, Gunnar, Gao, Wei, Nishino, Mizuki, Okajima, Yuka, Dupuis, Josée, Latourelle, Jeanne C, Cho, Michael H, El-Chemaly, Souheil, Coxson, Harvey O, Celli, Bartolome R, Fernandez, Isis E, Zazueta, Oscar E, Ross, James C, Harmouche, Rola, San José Estépar, Raúl, Diaz, Alejandro A, Sigurdsson, Sigurdur, Gudmundsson, Elías F, Eiríksdottír, Gudny, Aspelund, Thor, Budoff, Matthew J, Kinney, Gregory L, Hokanson, John E, Williams, Michelle C, Murchison, John T, MacNee, William, Hoffmann, Udo, O’Donnell, Christopher J, Launer, Lenore J, Harrris, Tamara B, Gudnason, Vilmundur, Silverman, Edwin K, O’Connor, George T, Washko, George R, Rosas, Ivan O, and Hunninghake, Gary M

Subjects
Epidemiology, Health Sciences, Chronic Obstructive Pulmonary Disease, Lung, Human Genome, Clinical Research, Genetics, Aetiology, 2.4 Surveillance and distribution, Respiratory, Cause of Death, Cohort Studies, Coronary Artery Disease, Female, Humans, Male, Neoplasms, Prevalence, Proportional Hazards Models, Prospective Studies, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Radiography, Smoking, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators, COPDGene Investigators, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceInterstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated.ObjectiveTo investigate whether interstitial lung abnormalities are associated with increased mortality.Design, setting, and populationProspective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006).ExposuresInterstitial lung abnormality status as determined by chest CT evaluation.Main outcomes and measuresAll-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.ResultsInterstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P

Published
2016

4. Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations

Author

Sakornsakolpat, Phuwanat, Prokopenko, Dmitry, Lamontagne, Maxime, Reeve, Nicola F., Guyatt, Anna L., Jackson, Victoria E., Shrine, Nick, Qiao, Dandi, Bartz, Traci M., Kim, Deog Kyeom, Lee, Mi Kyeong, Latourelle, Jeanne C., Li, Xingnan, Morrow, Jarrett D., Obeidat, Ma’en, Wyss, Annah B., Bakke, Per, Barr, R. Graham, Beaty, Terri H., Belinsky, Steven A., Brusselle, Guy G., Crapo, James D., de Jong, Kim, DeMeo, Dawn L., Fingerlin, Tasha E., Gharib, Sina A., Gulsvik, Amund, Hall, Ian P., Hokanson, John E., Kim, Woo Jin, Lomas, David A., London, Stephanie J., Meyers, Deborah A., O’Connor, George T., Rennard, Stephen I., Schwartz, David A., Sliwinski, Pawel, Sparrow, David, Strachan, David P., Tal-Singer, Ruth, Tesfaigzi, Yohannes, Vestbo, Jørgen, Vonk, Judith M., Yim, Jae-Joon, Zhou, Xiaobo, Bossé, Yohan, Manichaikul, Ani, Lahousse, Lies, Silverman, Edwin K., Boezen, H. Marike, Wain, Louise V., Tobin, Martin D., Hobbs, Brian D., and Cho, Michael H.

Published
2019
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5. The Gly2019Ser mutation in LRRK2is not fully penetrant in familial Parkinson's disease: the GenePD study

Author

Latourelle, Jeanne C, Sun, Mei, Lew, Mark F, Suchowersky, Oksana, Klein, Christine, Golbe, Lawrence I, Mark, Margery H, Growdon, John H, Wooten, G Frederick, Watts, Ray L, Guttman, Mark, Racette, Brad A, Perlmutter, Joel S, Ahmed, Anwar, Shill, Holly A, Singer, Carlos, Goldwurm, Stefano, Pezzoli, Gianni, Zini, Michela, Saint-Hilaire, Marie H, Hendricks, Audrey E, Williamson, Sally, Nagle, Michael W, Wilk, Jemma B, Massood, Tiffany, Huskey, Karen W, Laramie, Jason M, DeStefano, Anita L, Baker, Kenneth B, Itin, Ilia, Litvan, Irene, Nicholson, Garth, Corbett, Alastair, Nance, Martha, Drasby, Edward, Isaacson, Stuart, Burn, David J, Chinnery, Patrick F, Pramstaller, Peter P, Al-hinti, Jomana, Moller, Anette T, Ostergaard, Karen, Sherman, Scott J, Roxburgh, Richard, Snow, Barry, Slevin, John T, Cambi, Franca, Gusella, James F, and Myers, Richard H

Subjects
Biomedical and Clinical Sciences, Health Sciences, Neurodegenerative, Parkinson's Disease, Brain Disorders, Clinical Research, Genetics, Aging, Neurosciences, Genetic Testing, Aetiology, 2.1 Biological and endogenous factors, Neurological, Age Factors, Aged, Aged, 80 and over, Female, Glycine, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Mutation, Parkinson Disease, Penetrance, Protein Serine-Threonine Kinases, Random Allocation, Serine, Sex Factors, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundWe report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.MethodsA sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.ResultsThirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.ConclusionLifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Published
2008

6. The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study.

Author

Latourelle, Jeanne C, Sun, Mei, Lew, Mark F, Suchowersky, Oksana, Klein, Christine, Golbe, Lawrence I, Mark, Margery H, Growdon, John H, Wooten, G Frederick, Watts, Ray L, Guttman, Mark, Racette, Brad A, Perlmutter, Joel S, Ahmed, Anwar, Shill, Holly A, Singer, Carlos, Goldwurm, Stefano, Pezzoli, Gianni, Zini, Michela, Saint-Hilaire, Marie H, Hendricks, Audrey E, Williamson, Sally, Nagle, Michael W, Wilk, Jemma B, Massood, Tiffany, Huskey, Karen W, Laramie, Jason M, DeStefano, Anita L, Baker, Kenneth B, Itin, Ilia, Litvan, Irene, Nicholson, Garth, Corbett, Alastair, Nance, Martha, Drasby, Edward, Isaacson, Stuart, Burn, David J, Chinnery, Patrick F, Pramstaller, Peter P, Al-hinti, Jomana, Moller, Anette T, Ostergaard, Karen, Sherman, Scott J, Roxburgh, Richard, Snow, Barry, Slevin, John T, Cambi, Franca, Gusella, James F, and Myers, Richard H

Subjects
Humans, Parkinson Disease, Protein-Serine-Threonine Kinases, Serine, Glycine, Random Allocation, Age Factors, Sex Factors, Penetrance, Mutation, Aged, Aged, 80 and over, Middle Aged, Female, Male, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, and over, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundWe report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.MethodsA sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.ResultsThirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.ConclusionLifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Published
2008

11. Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington’s disease motor onset

Author

Ramos, Eliana Marisa, Latourelle, Jeanne C., Gillis, Tammy, Mysore, Jayalakshmi S., Squitieri, Ferdinando, Di Pardo, Alba, Di Donato, Stefano, Gellera, Cinzia, Hayden, Michael R., Morrison, Patrick J., Nance, Martha, Ross, Christopher A., Margolis, Russell L., Gomez-Tortosa, Estrella, Ayuso, Carmen, Suchowersky, Oksana, Trent, Ronald J., McCusker, Elizabeth, Novelletto, Andrea, Frontali, Marina, Jones, Randi, Ashizawa, Tetsuo, Frank, Samuel, Saint-Hilaire, Marie-Helene, Hersch, Steven M., Rosas, Herminia D., Lucente, Diane, Harrison, Madaline B., Zanko, Andrea, Abramson, Ruth K., Marder, Karen, Gusella, James F., Lee, Jong-Min, Alonso, Isabel, Sequeiros, Jorge, Myers, Richard H., and MacDonald, Marcy E.

Published
2013
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12. Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset

Author

Ramos, Eliana Marisa, Latourelle, Jeanne C., Lee, Ji-Hyun, Gillis, Tammy, Mysore, Jayalakshmi S., Squitieri, Ferdinando, Di Pardo, Alba, Di Donato, Stefano, Hayden, Michael R., Morrison, Patrick J., Nance, Martha, Ross, Christopher A., Margolis, Russell L., Gomez-Tortosa, Estrella, Ayuso, Carmen, Suchowersky, Oksana, Trent, Ronald J., McCusker, Elizabeth, Novelletto, Andrea, Frontali, Marina, Jones, Randi, Ashizawa, Tetsuo, Frank, Samuel, Saint-Hilaire, Marie-Helene, Hersch, Steven M., Rosas, Herminia D., Lucente, Diane, Harrison, Madaline B., Zanko, Andrea, Marder, Karen, Gusella, James F., Lee, Jong-Min, Alonso, Isabel, Sequeiros, Jorge, Myers, Richard H., and MacDonald, Marcy E.

Published
2012
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13. Supplement to: MUC5B promoter polymorphism and interstitial lung abnormalities.

Author

Hunninghake, Gary M., Hatabu, Hiroto, Okajima, Yuka, Gao, Wei, Dupuis, Josée, Latourelle, Jeanne C., Nishino, Mizuki, Araki, Tetsuro, Zazueta, Oscar E., Kurugol, Sila, Ross, James C., José Estépar, Raúl San, Murphy, Elissa, Steele, Mark P., Loyd, James E., Schwarz, Marvin I., Fingerlin, Tasha E., Rosas, Ivan O., Washko, George R., OʼConnor, George T., and Schwartz, David A.

Published
2013

15. MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities

Author

Hunninghake, Gary M., Hatabu, Hiroto, Okajima, Yuka, Gao, Wei, Dupuis, Josée, Latourelle, Jeanne C., Nishino, Mizuki, Araki, Tetsuro, Zazueta, Oscar E., Kurugol, Sila, Ross, James C., San José Estépar, Raúl, Murphy, Elissa, Steele, Mark P., Loyd, James E., Schwarz, Marvin I., Fingerlin, Tasha E., Rosas, Ivan O., Washko, George R., OʼConnor, George T., and Schwartz, David A.

Published
2013
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16. Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

Author

Wilk, Jemma B., Shrine, Nick R. G., Loehr, Laura R., Zhao, Jing Hua, Manichaikul, Ani, Lopez, Lorna M., Smith, Albert Vernon, Heckbert, Susan R., Smolonska, Joanna, Tang, Wenbo, Loth, Daan W., Curjuric, Ivan, Hui, Jennie, Cho, Michael H., Latourelle, Jeanne C., Henry, Amanda P., Aldrich, Melinda, Bakke, Per, Beaty, Terri H., Bentley, Amy R., Borecki, Ingrid B., Brusselle, Guy G., Burkart, Kristin M., Chen, Ting-hsu, Couper, David, Crapo, James D., Davies, Gail, Dupuis, Josée, Franceschini, Nora, Gulsvik, Amund, Hancock, Dana B., Harris, Tamara B., Hofman, Albert, Imboden, Medea, James, Alan L., Khaw, Kay-Tee, Lahousse, Lies, Launer, Lenore J., Litonjua, Augusto, Liu, Yongmei, Lohman, Kurt K., Lomas, David A., Lumley, Thomas, Marciante, Kristin D., McArdle, Wendy L., Meibohm, Bernd, Morrison, Alanna C., Musk, Arthur W., Myers, Richard H., North, Kari E., Postma, Dirkje S., Psaty, Bruce M., Rich, Stephen S., Rivadeneira, Fernando, Rochat, Thierry, Rotter, Jerome I., Artigas, María Soler, Starr, John M., Uitterlinden, André G., Wareham, Nicholas J., Wijmenga, Cisca, Zanen, Pieter, Province, Michael A., Silverman, Edwin K., Deary, Ian J., Palmer, Lyle J., Cassano, Patricia A., Gudnason, Vilmundur, Barr, Graham R., Loos, Ruth J. F., Strachan, David P., London, Stephanie J., Boezen, Marike H., Probst-Hensch, Nicole, Gharib, Sina A., Hall, Ian P., O’Connor, George T., Tobin, Martin D., and Stricker, Bruno H.

Published
2012
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17. Meta-analysis of Parkinsonʼs Disease:: Identification of a novel locus, RIT2

Author

Pankratz, Nathan, Beecham, Gary W., DeStefano, Anita L., Dawson, Ted M., Doheny, Kimberly F., Factor, Stewart A., Hamza, Taye H., Hung, Albert Y., Hyman, Bradley T., Ivinson, Adrian J., Krainc, Dmitri, Latourelle, Jeanne C., Clark, Lorraine N., Marder, Karen, Martin, Eden R., Mayeux, Richard, Ross, Owen A., Scherzer, Clemens R., Simon, David K., Tanner, Caroline, Vance, Jeffery M., Wszolek, Zbigniew K., Zabetian, Cyrus P., Myers, Richard H., Payami, Haydeh, Scott, William K., and Foroud, Tatiana

Published
2012
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21. Huntington CAG repeat size does not modify onset age in familial Parkinsonʼs disease:: TheGenePD study

Author

McNicoll, Christopher F., Latourelle, Jeanne C., MacDonald, Marcy E., Lew, Mark F., Suchowersky, Oksana, Klein, Christine, Golbe, Lawrence I., Mark, Margery H., Growdon, John H., Wooten, Frederick G., Watts, Ray L., Guttman, Mark, Racette, Brad A., Perlmutter, Joel S., Ahmed, Anwar, Shill, Holly A., Singer, Carlos, Saint-Hilaire, Marie H., Massood, Tiffany, Huskey, Karen W., DeStefano, Anita L., Gillis, Tammy, Mysore, Jayalakshmi, Goldwurm, Stefano, Pezzoli, Gianni, Baker, Kenneth B., Itin, Ilia, Litvan, Irene, Nicholson, Garth, Corbett, Alastair, Nance, Martha, Drasby, Edward, Isaacson, Stuart, Burn, David J., Chinnery, Patrick F., Pramstaller, Peter P., Al-Hinti, Jomana, Moller, Anette T., Ostergaard, Karen, Sherman, Scott J., Roxburgh, Richard, Snow, Barry, Slevin, John T., Cambi, Franca, Gusella, James F., and Myers, Richard H.

Published
2008
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22. Influence of Heterozygosity for Parkin Mutation on Onset Age in Familial Parkinson Disease: The GenePD Study

Author

Sun, Mei, Latourelle, Jeanne C., Wooten, G. Frederick, Lew, Mark F., Klein, Christine, Shill, Holly A., Golbe, Lawrence I., Mark, Margery H., Racette, Brad A., Perlmutter, Joel S., Parsian, Abbas, Guttman, Mark, Nicholson, Garth, Xu, Gang, Wilk, Jemma B., Saint-Hilaire, Marie H., DeStefano, Anita L., Prakash, Ranjana, Williamson, Sally, Suchowersky, Oksana, Labelle, Nancy, Growdon, John H., Singer, Carlos, Watts, Ray L., Goldwurm, Stefano, Pezzoli, Gianni, Baker, Kenneth B., Pramstaller, Peter P., Burn, David J., Chinnery, Patrick F., Sherman, Scott, Vieregge, Peter, Litvan, Irene, Gillis, Tammy, MacDonald, Marcy E., Myers, Richard H., and Gusella, James F.

Published
2006

23. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 1; peer review: 1 approved, 1 approved with reservations]

Author

Jackson, Victoria E., Latourelle, Jeanne C., Wain, Louise V., Smith, Albert V., Grove, Megan L., Bartz, Traci M., Obeidat, Ma’En, Province, Michael A., Gao, Wei, Qaiser, Beenish, Porteous, David J., Cassano, Patricia A., Ahluwalia, Tarunveer S., Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E., Manichaikul, Ani, Pottinger, Tess D., Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M., Brody, Jennifer A., Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M., Linneberg, Allan, Lange, Leslie A., Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E., Brusselle, Guy G., Hansen, Torben, Uitterlinden, André G., Ikram, M. Arfan, Dupuis, Josée, Epidemiology, Erasmus School of Economics, Department of Finance, Internal Medicine, and Radiology & Nuclear Medicine

Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P

Published
2018

24. Risk of Parkinson's disease after tamoxifen treatment

Author

Destefano Anita L, Dybdahl Merete, Latourelle Jeanne C, Myers Richard H, and Lash Timothy L

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Women have a reduced risk of developing Parkinson's disease (PD) compared with age-matched men. Neuro-protective effects of estrogen potentially explain this difference. Tamoxifen, commonly used in breast cancer treatment, may interfere with the protective effects of estrogen and increase risk of PD. We compared the rate of PD in Danish breast cancer patients treated with tamoxifen to the rate among those not treated with tamoxifen. Methods A cohort of 15,419 breast cancer patients identified from the Danish Breast Cancer Collaborative Group database was linked to the National Registry of Patients to identify PD diagnoses. Overall risk and rate of PD following identification into the study was compared between patients treated with tamoxifen as adjuvant hormonal therapy and patients not receiving tamoxifen. Time-dependent effects of tamoxifen treatment on PD rate were examined to estimate the likely induction period for tamoxifen. Results In total, 35 cases of PD were identified among the 15,419 breast cancer patients. No overall effect of tamoxifen on rate of PD was observed (HR = 1.3, 95% CI: 0.64-2.5), but a PD hazard ratio of 5.1 (95% CI: 1.0-25) was seen four to six years following initiation of tamoxifen treatment. Conclusions These results provide evidence that the neuro-protective properties of estrogen against PD occurrence may be disrupted by tamoxifen therapy. Tamoxifen treatments may be associated with an increased rate of PD; however these effects act after four years, are of limited duration, and the adverse effect is overwhelmed by the protection against breast recurrence conferred by tamoxifen therapy.

Published
2010
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25. Genomewide association study for onset age in Parkinson disease

Author

Halter Cheryl, DeStefano Anita L, Mariani Claudio B, Pezzoli Gianni, Goldwurm Stefano, Wilk Jemma B, Dumitriu Alexandra, Pankratz Nathan, Latourelle Jeanne C, Gusella James F, Nichols William C, Myers Richard H, and Foroud Tatiana

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Age at onset in Parkinson disease (PD) is a highly heritable quantitative trait for which a significant genetic influence is supported by multiple segregation analyses. Because genes associated with onset age may represent invaluable therapeutic targets to delay the disease, we sought to identify such genetic modifiers using a genomewide association study in familial PD. There have been previous genomewide association studies (GWAS) to identify genes influencing PD susceptibility, but this is the first to identify genes contributing to the variation in onset age. Methods Initial analyses were performed using genotypes generated with the Illumina HumanCNV370Duo array in a sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of imputed SNPs was performed combining the familial PD data with that from a previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with the lowest p-values and consistency in the direction of effect for onset age were then genotyped in a replication sample of 747 idiopathic PD cases from the Parkinson Institute Biobank of Milan, Italy. Results Meta-analysis across the three studies detected consistent association (p < 1 × 10-5) with five SNPs, none of which reached genomewide significance. On chromosome 11, the SNP with the lowest p-value (rs10767971; p = 5.4 × 10-7) lies between the genes QSER1 and PRRG4. Near the PARK3 linkage region on chromosome 2p13, association was observed with a SNP (rs7577851; p = 8.7 × 10-6) which lies in an intron of the AAK1 gene. This gene is closely related to GAK, identified as a possible PD susceptibility gene in the GWAS of the familial PD cases. Conclusion Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis.

Published
2009
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26. The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study

Author

Corbett Alastair, Nicholson Garth, Litvan Irene, Itin Ilia, Baker Kenneth B, DeStefano Anita L, Laramie Jason M, Huskey Karen W, Massood Tiffany, Wilk Jemma B, Nagle Michael W, Williamson Sally, Hendricks Audrey E, Saint-Hilaire Marie H, Zini Michela, Pezzoli Gianni, Goldwurm Stefano, Singer Carlos, Shill Holly A, Ahmed Anwar, Perlmutter Joel S, Guttman Mark, Racette Brad A, Watts Ray L, Wooten G Frederick, Growdon John H, Mark Margery H, Golbe Lawrence I, Klein Christine, Suchowersky Oksana, Lew Mark F, Sun Mei, Latourelle Jeanne C, Nance Martha, Drasby Edward, Isaacson Stuart, Burn David J, Chinnery Patrick F, Pramstaller Peter P, Al-hinti Jomana, Moller Anette T, Ostergaard Karen, Sherman Scott J, Roxburgh Richard, Snow Barry, Slevin John T, Cambi Franca, Gusella James F, and Myers Richard H

Subjects
Medicine
Abstract

Abstract Background We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD. Methods A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample. Results Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families. Conclusion Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Published
2008
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27. Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; The NHLBI Family Heart Study

Author

Tobin Jennifer E, Latourelle Jeanne C, Nagle Michael W, Williamson Sally L, Wilk Jemma B, Laramie Jason M, Province Michael A, Borecki Ingrid B, and Myers Richard H

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background The chromosome 7q32 region is linked to metabolic syndrome and obesity related traits in the Family Heart Study. As part of a fine mapping study of the region, we evaluated the relationship of polymorphisms to fasting glucose levels and Type 2 diabetes. Methods Thirty-nine HapMap defined tag SNPs in a 1.08 Mb region and a novel deletion polymorphism were genotyped in 2,603 participants of the NHLBI Family Heart Study (FHS). Regression modeling, adjusting for BMI, age, sex, smoking and the TCF7L2 polymorphism, was used to evaluate the association of these polymorphisms with T2D and fasting glucoses levels. Results The deletion polymorphism confers a protective effect for T2D, with homozygous deletion carriers having a 53% reduced risk compared to non-deleted carriers. Among non-diabetics, the deletion was significantly associated with lower fasting glucose levels in men (p = 0.038) but not women (p = 0.118). In addition, seven SNPs near the deletion were significantly associated (p < 0.01) to diabetes. Conclusion Chromosome 7q32 contains both SNPs and a deletion that were associated to T2D. Although the deletion region contains several islands of strongly conserved sequence, it is not known to contain a transcribed gene. The closest nearby gene, EXOC4, is involved in insulin-stimulated glucose transport and may be a candidate for this association. Further work is needed to determine if the deletion represents a functional variant or may be in linkage disequilibrium with a functional mutation influencing EXOC4 or another nearby gene.

Published
2008
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28. Meta-analysis of exome array data identifies six novel genetic loci for lung function.

Author

Jackson, Victoria E, Latourelle, Jeanne C, Wain, Louise V, Smith, Albert V, Grove, Megan L, Bartz, Traci M, Obeidat, Ma'en, Province, Michael A, Gao, Wei, Qaiser, Beenish, Porteous, David J, Cassano, Patricia A, Ahluwalia, Tarunveer S, Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E, Manichaikul, Ani, Pottinger, Tess D, Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo-Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M, Brody, Jennifer A, Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M, Linneberg, Allan, Lange, Leslie A, Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E, Smith, Blair H, Davies, Gail, Burkart, Kristin M, Mychaleckyj, Josyf C, Bonten, Tobias N, Enroth, Stefan, Lind, Lars, Brusselle, Guy G, Kumar, Ashish, Stubbe, Beate, Kähönen, Mika, Wyss, Annah B, Psaty, Bruce M, Heckbert, Susan R, Hao, Ke, Rantanen, Taina, Kritchevsky, Stephen B, Lohman, Kurt, Skaaby, Tea, Pisinger, Charlotta, Hansen, Torben, Schulz, Holger, Polasek, Ozren, Campbell, Archie, Starr, John M, Rich, Stephen S, Mook-Kanamori, Dennis O, Johansson, Åsa, Ingelsson, Erik, Uitterlinden, André G, Weiss, Stefan, Raitakari, Olli T, Gudnason, Vilmundur, North, Kari E, Gharib, Sina A, Sin, Don D, Taylor, Kent D, O'Connor, George T, Kaprio, Jaakko, Harris, Tamara B, Pederson, Oluf, Vestergaard, Henrik, Wilson, James G, Strauch, Konstantin, Hayward, Caroline, Kerr, Shona, Deary, Ian J, Barr, R Graham, de Mutsert, Renée, Gyllensten, Ulf, Morris, Andrew P, Ikram, M Arfan, Probst-Hensch, Nicole, Gläser, Sven, Zeggini, Eleftheria, Lehtimäki, Terho, Strachan, David P, Dupuis, Josée, Morrison, Alanna C, Hall, Ian P, Tobin, Martin D, London, Stephanie J, Jackson, Victoria E, Latourelle, Jeanne C, Wain, Louise V, Smith, Albert V, Grove, Megan L, Bartz, Traci M, Obeidat, Ma'en, Province, Michael A, Gao, Wei, Qaiser, Beenish, Porteous, David J, Cassano, Patricia A, Ahluwalia, Tarunveer S, Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E, Manichaikul, Ani, Pottinger, Tess D, Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo-Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M, Brody, Jennifer A, Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M, Linneberg, Allan, Lange, Leslie A, Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E, Smith, Blair H, Davies, Gail, Burkart, Kristin M, Mychaleckyj, Josyf C, Bonten, Tobias N, Enroth, Stefan, Lind, Lars, Brusselle, Guy G, Kumar, Ashish, Stubbe, Beate, Kähönen, Mika, Wyss, Annah B, Psaty, Bruce M, Heckbert, Susan R, Hao, Ke, Rantanen, Taina, Kritchevsky, Stephen B, Lohman, Kurt, Skaaby, Tea, Pisinger, Charlotta, Hansen, Torben, Schulz, Holger, Polasek, Ozren, Campbell, Archie, Starr, John M, Rich, Stephen S, Mook-Kanamori, Dennis O, Johansson, Åsa, Ingelsson, Erik, Uitterlinden, André G, Weiss, Stefan, Raitakari, Olli T, Gudnason, Vilmundur, North, Kari E, Gharib, Sina A, Sin, Don D, Taylor, Kent D, O'Connor, George T, Kaprio, Jaakko, Harris, Tamara B, Pederson, Oluf, Vestergaard, Henrik, Wilson, James G, Strauch, Konstantin, Hayward, Caroline, Kerr, Shona, Deary, Ian J, Barr, R Graham, de Mutsert, Renée, Gyllensten, Ulf, Morris, Andrew P, Ikram, M Arfan, Probst-Hensch, Nicole, Gläser, Sven, Zeggini, Eleftheria, Lehtimäki, Terho, Strachan, David P, Dupuis, Josée, Morrison, Alanna C, Hall, Ian P, Tobin, Martin D, and London, Stephanie J

Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

Published
2018
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29. Meta-analysis of exome array data identifies six novel genetic loci for lung function [version 1; peer review:1 approved, 1 approved with reservations]

Author

Jackson, Victoria E., Latourelle, Jeanne C., Wain, Louise V., Smith, Albert V., Grove, Megan L., Bartz, Traci M., Obeidat, Ma’En, Province, Michael A., Gao, Wei, Qaiser, Beenish, Porteous, David J., Cassano, Patricia A., Ahluwalia, Tarunveer S., Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E., Manichaikul, Ani, Pottinger, Tess D., Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M., Brody, Jennifer A., Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M., Linneberg, Allan, Lange, Leslie A., Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E., Brusselle, Guy G., Hansen, Torben, Uitterlinden, André G., Ikram, M. Arfan, Dupuis, Josée, Jackson, Victoria E., Latourelle, Jeanne C., Wain, Louise V., Smith, Albert V., Grove, Megan L., Bartz, Traci M., Obeidat, Ma’En, Province, Michael A., Gao, Wei, Qaiser, Beenish, Porteous, David J., Cassano, Patricia A., Ahluwalia, Tarunveer S., Grarup, Niels, Li, Jin, Altmaier, Elisabeth, Marten, Jonathan, Harris, Sarah E., Manichaikul, Ani, Pottinger, Tess D., Li-Gao, Ruifang, Lind-Thomsen, Allan, Mahajan, Anubha, Lahousse, Lies, Imboden, Medea, Teumer, Alexander, Prins, Bram, Lyytikäinen, Leo Pekka, Eiriksdottir, Gudny, Franceschini, Nora, Sitlani, Colleen M., Brody, Jennifer A., Bossé, Yohan, Timens, Wim, Kraja, Aldi, Loukola, Anu, Tang, Wenbo, Liu, Yongmei, Bork-Jensen, Jette, Justesen, Johanne M., Linneberg, Allan, Lange, Leslie A., Rawal, Rajesh, Karrasch, Stefan, Huffman, Jennifer E., Brusselle, Guy G., Hansen, Torben, Uitterlinden, André G., Ikram, M. Arfan, and Dupuis, Josée

Abstract

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2•8x10 -7 ) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

Published
2018

30. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Author

Wyss, Annah B., Sofer, Tamar, Lee, Mi Kyeong, Terzikhan, Natalie, Nguyen, Jennifer N., Lahousse, Lies, Latourelle, Jeanne C., Smith, Albert Vernon, Bartz, Traci M., Feitosa, Mary F., Gao, Wei, Ahluwalia, Tarunveer S., Tang, Wenbo, Oldmeadow, Christopher, Duan, Qing, de Jong, Kim, Wojczynski, Mary K., Wang, Xin-Qun, Noordam, Raymond, Hartwig, Fernando Pires, Jackson, Victoria E., Wang, Tianyuan, Obeidat, Ma'en, Hobbs, Brian D., Huan, Tianxiao, Gui, Hongsheng, Parker, Margaret M., Hu, Donglei, Mogil, Lauren S., Kichaev, Gleb, Jin, Jianping, Graff, Mariaelisa, Harris, Tamara B., Kalhan, Ravi, Heckbert, Susan R., Paternoster, Lavinia, Burkart, Kristin M., Liu, Yongmei, Holliday, Elizabeth G., Wilson, James G., Vonk, Judith M., Sanders, Jason L., Barr, R. Graham, de Mutsert, Renee, Baptista Menezes, Ana Maria, Adams, Hieab H. H., van den Berge, Maarten, Joehanes, Roby, Levin, Albert M., Liberto, Jennifer, Launer, Lenore J., Morrison, Alanna C., Sitlani, Colleen M., Celedon, Juan C., Kritchevsky, Stephen B., Scott, Rodney J., Christensen, Kaare, Rotter, Jerome I., Bonten, Tobias N., Wehrmeister, Fernando Cesar, Bosse, Yohan, Xiao, Shujie, Oh, Sam, Franceschini, Nora, Brody, Jennifer A., Kaplan, Robert C., Lohman, Kurt, McEvoy, Mark, Province, Michael A., Rosendaal, Frits R., Taylor, Kent D., Nickle, David C., Williams, L. Keoki, Burchard, Esteban G., Wheeler, Heather E., Sin, Don D., Gudnason, Vilmundur, North, Kari E., Fornage, Myriam, Psaty, Bruce M., Myers, Richard H., O'Connor, George, Hansen, Torben, Laurie, Cathy C., Cassano, Patricia A., Sung, Joohon, Kim, Woo Jin, Attia, John R., Lange, Leslie, Boezen, H. Marike, Thyagarajan, Bharat, Rich, Stephen S., Mook-Kanamori, Dennis O., Horta, Bernardo Lessa, Uitterlinden, Andre G., Im, Hae Kyung, Cho, Michael H., Brusselle, Guy G., Gharib, Sina A., Dupuis, Josee, Manichaikul, Ani, London, Stephanie J., Wyss, Annah B., Sofer, Tamar, Lee, Mi Kyeong, Terzikhan, Natalie, Nguyen, Jennifer N., Lahousse, Lies, Latourelle, Jeanne C., Smith, Albert Vernon, Bartz, Traci M., Feitosa, Mary F., Gao, Wei, Ahluwalia, Tarunveer S., Tang, Wenbo, Oldmeadow, Christopher, Duan, Qing, de Jong, Kim, Wojczynski, Mary K., Wang, Xin-Qun, Noordam, Raymond, Hartwig, Fernando Pires, Jackson, Victoria E., Wang, Tianyuan, Obeidat, Ma'en, Hobbs, Brian D., Huan, Tianxiao, Gui, Hongsheng, Parker, Margaret M., Hu, Donglei, Mogil, Lauren S., Kichaev, Gleb, Jin, Jianping, Graff, Mariaelisa, Harris, Tamara B., Kalhan, Ravi, Heckbert, Susan R., Paternoster, Lavinia, Burkart, Kristin M., Liu, Yongmei, Holliday, Elizabeth G., Wilson, James G., Vonk, Judith M., Sanders, Jason L., Barr, R. Graham, de Mutsert, Renee, Baptista Menezes, Ana Maria, Adams, Hieab H. H., van den Berge, Maarten, Joehanes, Roby, Levin, Albert M., Liberto, Jennifer, Launer, Lenore J., Morrison, Alanna C., Sitlani, Colleen M., Celedon, Juan C., Kritchevsky, Stephen B., Scott, Rodney J., Christensen, Kaare, Rotter, Jerome I., Bonten, Tobias N., Wehrmeister, Fernando Cesar, Bosse, Yohan, Xiao, Shujie, Oh, Sam, Franceschini, Nora, Brody, Jennifer A., Kaplan, Robert C., Lohman, Kurt, McEvoy, Mark, Province, Michael A., Rosendaal, Frits R., Taylor, Kent D., Nickle, David C., Williams, L. Keoki, Burchard, Esteban G., Wheeler, Heather E., Sin, Don D., Gudnason, Vilmundur, North, Kari E., Fornage, Myriam, Psaty, Bruce M., Myers, Richard H., O'Connor, George, Hansen, Torben, Laurie, Cathy C., Cassano, Patricia A., Sung, Joohon, Kim, Woo Jin, Attia, John R., Lange, Leslie, Boezen, H. Marike, Thyagarajan, Bharat, Rich, Stephen S., Mook-Kanamori, Dennis O., Horta, Bernardo Lessa, Uitterlinden, Andre G., Im, Hae Kyung, Cho, Michael H., Brusselle, Guy G., Gharib, Sina A., Dupuis, Josee, Manichaikul, Ani, and London, Stephanie J.

Published
2018

32. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author

Infection & Immunity, Afdeling Longfunctie, Longziekten, Hobbs, Brian D, de Jong, Kim, Lamontagne, Maxime, Bossé, Yohan, Shrine, Nick, Artigas, María Soler, Wain, Louise V, Hall, Ian P, Jackson, Victoria E, Wyss, Annah B, London, Stephanie J, North, Kari E, Franceschini, Nora, Strachan, David P, Beaty, Terri H, Hokanson, John E, Crapo, James D, Castaldi, Peter J, Chase, Robert P, Bartz, Traci M, Heckbert, Susan R, Psaty, Bruce M, Gharib, Sina A, Zanen, Pieter, Lammers, Jan W, Oudkerk, Matthijs, Groen, H J, Locantore, Nicholas, Tal-Singer, Ruth, Rennard, Stephen I, Vestbo, Jørgen, Timens, Wim, Paré, Peter D, Latourelle, Jeanne C, Dupuis, Josée, O'Connor, George T, Wilk, Jemma B, Kim, Woo Jin, Lee, Mi Kyeong, Oh, Yeon-Mok, Vonk, Judith M, de Koning, Harry J, Leng, Shuguang, Belinsky, Steven A, Tesfaigzi, Yohannes, Manichaikul, Ani, Wang, Xin-Qun, Rich, Stephen S, Barr, R Graham, Sparrow, David, COPDGene Investigators, Infection & Immunity, Afdeling Longfunctie, Longziekten, Hobbs, Brian D, de Jong, Kim, Lamontagne, Maxime, Bossé, Yohan, Shrine, Nick, Artigas, María Soler, Wain, Louise V, Hall, Ian P, Jackson, Victoria E, Wyss, Annah B, London, Stephanie J, North, Kari E, Franceschini, Nora, Strachan, David P, Beaty, Terri H, Hokanson, John E, Crapo, James D, Castaldi, Peter J, Chase, Robert P, Bartz, Traci M, Heckbert, Susan R, Psaty, Bruce M, Gharib, Sina A, Zanen, Pieter, Lammers, Jan W, Oudkerk, Matthijs, Groen, H J, Locantore, Nicholas, Tal-Singer, Ruth, Rennard, Stephen I, Vestbo, Jørgen, Timens, Wim, Paré, Peter D, Latourelle, Jeanne C, Dupuis, Josée, O'Connor, George T, Wilk, Jemma B, Kim, Woo Jin, Lee, Mi Kyeong, Oh, Yeon-Mok, Vonk, Judith M, de Koning, Harry J, Leng, Shuguang, Belinsky, Steven A, Tesfaigzi, Yohannes, Manichaikul, Ani, Wang, Xin-Qun, Rich, Stephen S, Barr, R Graham, Sparrow, David, and COPDGene Investigators

Published
2017

33. Large-scale identification of clinical and genetic predictors of motor progression in patients with newly diagnosed Parkinson's disease: a longitudinal cohort study and validation

Author

Latourelle, Jeanne C, primary, Beste, Michael T, additional, Hadzi, Tiffany C, additional, Miller, Robert E, additional, Oppenheim, Jacob N, additional, Valko, Matthew P, additional, Wuest, Diane M, additional, Church, Bruce W, additional, Khalil, Iya G, additional, Hayete, Boris, additional, and Venuto, Charles S, additional

Published
2017
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34. Multiethnic meta-analysis identifies new loci for pulmonary function

Author

Wyss, Annah B., primary, Sofer, Tamar, additional, Lee, Mi Kyeong, additional, Terzikhan, Natalie, additional, Nguyen, Jennifer N., additional, Lahousse, Lies, additional, Latourelle, Jeanne C., additional, Smith, Albert Vernon, additional, Bartz, Traci M., additional, Feitosa, Mary F., additional, Gao, Wei, additional, Ahluwalia, Tarunveer S., additional, Tang, Wenbo, additional, Oldmeadow, Christopher, additional, Duan, Qing, additional, Jong, Kim de, additional, Wojczynski, Mary K., additional, Wang, Xin-Qun, additional, Noordam, Raymond, additional, Hartwig, Fernando Pires, additional, Jackson, Victoria E., additional, Wang, Tianyuan, additional, Obeidat, Ma’en, additional, Hobbs, Brian D., additional, Huan, Tianxiao, additional, Kichaev, Gleb, additional, Jin, Jianping, additional, Graff, Mariaelisa, additional, Harris, Tamara B., additional, Kalhan, Ravi, additional, Heckbert, Susan R., additional, Paternoster, Lavinia, additional, Burkart, Kristin M., additional, Liu, Yongmei, additional, Holliday, Elizabeth G., additional, Wilson, James G., additional, Vonk, Judith M., additional, Sanders, Jason, additional, Barr, R. Graham, additional, Mutsert, Renée de, additional, Menezes, Ana Maria Baptista, additional, Adams, Hieab H. H., additional, Berge, Maarten van den, additional, Joehanes, Roby, additional, Launer, Lenore J., additional, Morrison, Alanna C., additional, Sitlani, Colleen M., additional, Celedón, Juan C., additional, Kritchevsky, Stephen B., additional, Scott, Rodney J., additional, Christensen, Kaare, additional, Rotter, Jerome I., additional, Bonten, Tobias N., additional, César Wehrmeister, Fernando, additional, Bossé, Yohan, additional, Franceschini, Nora, additional, Brody, Jennifer A., additional, Kaplan, Robert C., additional, Lohman, Kurt, additional, McEvoy, Mark, additional, Province, Michael A., additional, Rosendaal, Frits R., additional, Taylor, Kent D., additional, Nickle, David C., additional, North, Kari E., additional, Fornage, Myriam, additional, Psaty, Bruce M., additional, Myers, Richard H., additional, O’Connor, George, additional, Hansen, Torben, additional, Laurie, Cathy C., additional, Cassano, Pat, additional, Sung, Joohon, additional, Kim, Woo Jin, additional, Attia, John R., additional, Lange, Leslie, additional, Boezen, H. Marike, additional, Thyagarajan, Bharat, additional, Rich, Stephen S., additional, Mook-Kanamori, Dennis O., additional, Horta, Bernardo Lessa, additional, Uitterlinden, André G, additional, Sin, Don D., additional, Im, Hae Kyung, additional, Cho, Michael H., additional, Brusselle, Guy G., additional, Gharib, Sina A., additional, Dupuis, Josée, additional, Manichaikul, Ani, additional, and London, Stephanie J., additional

Published
2017
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35. Meta-analysis of exome array data identifies six novel genetic loci for lung function

Author

Jackson, Victoria E, primary, Latourelle, Jeanne C, additional, Wain, Louise V, additional, Smith, Albert V., additional, Grove, Megan L., additional, Bartz, Traci M, additional, Obeidat, Maen, additional, Province, Michael A, additional, Gao, Wei, additional, Qaiser, Beenish, additional, Porteous, David J, additional, Cassano, Patricia A, additional, Ahluwalia, Tarunveer S., additional, Grarup, Niels, additional, Li, Jin, additional, Altmaier, Elisabeth, additional, Marten, Jonathan, additional, Harris, Sarah E, additional, Manichaikul, Ani, additional, Pottinger, Tess D, additional, Li-Gao, Ruifang, additional, Lind-Thomsen, Allan, additional, Mahajan, Anubha, additional, Lahousse, Lies, additional, Imboden, Medea, additional, Teumer, Alexander, additional, Prins, Bram, additional, Lyytikäinen, Leo-Pekka, additional, Eiriksdottir, Gudny, additional, Franceschini, Nora, additional, Sitlani, Colleen M, additional, Brody, Jennifer A, additional, Bossé, Yohan, additional, Timens, Wim, additional, Kraja, Aldi, additional, Loukola, Anu, additional, Tang, Wenbo, additional, Liu, Yongmei, additional, Bork-Jensen, Jette, additional, Justesen, Johanne M., additional, Linneberg, Allan, additional, Lange, Leslie A., additional, Rawal, Rajesh, additional, Karrasch, Stefan, additional, Huffman, Jennifer E, additional, Smith, Blair H, additional, Davies, Gail, additional, Burkart, Kristin M, additional, Mychaleckyj, Josyf C, additional, Bonten, Tobias N., additional, Enroth, Stefan, additional, Lind, Lars, additional, Brusselle, Guy G, additional, Kumar, Ashish, additional, Stubbe, Beate, additional, Kähönen, Mika, additional, Wyss, Annah B., additional, Psaty, Bruce M, additional, Heckbert, Susan R, additional, Hao, Ke, additional, Rantanen, Taina, additional, Kritchevsky, Stephen B, additional, Lohman, Kurt, additional, Skaaby, Tea, additional, Pisinger, Charlotta, additional, Hansen, Torben, additional, Schulz, Holger, additional, Polasek, Ozren, additional, Campbell, Archie, additional, Starr, John M, additional, Rich, Stephen S, additional, Mook-Kanamori, Dennis O., additional, Johansson, Åsa, additional, Ingelsson, Erik, additional, Uitterlinden, André G, additional, Weiss, Stefan, additional, Raitakari, Olli T., additional, Gudnason, Vilmundur, additional, North, Kari E., additional, Gharib, Sina A, additional, Sin, Don D, additional, Taylor, Kent D, additional, O’Connor, George T, additional, Kaprio, Jaakko, additional, Harris, Tamara B, additional, Pedersen, Oluf, additional, Vestergaard, Henrik, additional, Wilson, James G., additional, Strauch, Konstantin, additional, Hayward, Caroline, additional, Kerr, Shona, additional, Deary, Ian J, additional, Barr, R Graham, additional, de Mutsert, Renée, additional, Gyllensten, Ulf, additional, Morris, Andrew P, additional, Ikram, M. Arfan, additional, Probst-Hensch, Nicole M, additional, Gläser, Sven, additional, Zeggini, Eleftheria, additional, Lehtimäki, Terho, additional, Strachan, David P, additional, Dupuis, Josee, additional, Morrison, Alanna C., additional, Hall, Ian P, additional, Tobin, Martin D, additional, and London, Stephanie J, additional

Published
2017
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36. miR‐149 and miR‐29c as candidates for bipolar disorder biomarkers

Author

Choi, Jason L., primary, Kao, Patricia F., additional, Itriago, Elena, additional, Zhan, Yougen, additional, Kozubek, James A., additional, Hoss, Andrew G., additional, Banigan, Meredith G., additional, Vanderburg, Charles R., additional, Rezvani, Amir H., additional, Latourelle, Jeanne C., additional, Cabral, Howard, additional, and Delalle, Ivana, additional

Published
2017
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37. Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study

Author

Araki, Tetsuro, primary, Putman, Rachel K., additional, Hatabu, Hiroto, additional, Gao, Wei, additional, Dupuis, Josée, additional, Latourelle, Jeanne C., additional, Nishino, Mizuki, additional, Zazueta, Oscar E., additional, Kurugol, Sila, additional, Ross, James C., additional, San José Estépar, Raúl, additional, Schwartz, David A., additional, Rosas, Ivan O., additional, Washko, George R., additional, O’Connor, George T., additional, and Hunninghake, Gary M., additional

Published
2016
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39. Correction: RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression

Author

Labadorf, Adam, primary, Hoss, Andrew G., additional, Lagomarsino, Valentina, additional, Latourelle, Jeanne C., additional, Hadzi, Tiffany C., additional, Bregu, Joli, additional, MacDonald, Marcy E., additional, Gusella, James F., additional, Chen, Jiang-Fan, additional, Akbarian, Schahram, additional, Weng, Zhiping, additional, and Myers, Richard H., additional

Published
2016
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40. Galectin-3 Is Associated with Restrictive Lung Disease and Interstitial Lung Abnormalities

Author

Ho, Jennifer E., primary, Gao, Wei, additional, Levy, Daniel, additional, Santhanakrishnan, Rajalakshmi, additional, Araki, Tetsuro, additional, Rosas, Ivan O., additional, Hatabu, Hiroto, additional, Latourelle, Jeanne C., additional, Nishino, Mizuki, additional, Dupuis, Josée, additional, Washko, George R., additional, O’Connor, George T., additional, and Hunninghake, Gary M., additional

Published
2016
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42. RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression

Author

Labadorf, Adam, primary, Hoss, Andrew G., additional, Lagomarsino, Valentina, additional, Latourelle, Jeanne C., additional, Hadzi, Tiffany C., additional, Bregu, Joli, additional, MacDonald, Marcy E., additional, Gusella, James F., additional, Chen, Jiang-Fan, additional, Akbarian, Schahram, additional, Weng, Zhiping, additional, and Myers, Richard H., additional

Published
2015
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44. Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

Author

Franceschini, Nora, Bentley, Amy R., Lopez, Lorna M., Gulsvik, Amund, Curjuric, Ivan, Harris, Tamara B., Manichaikul, Ani, Loehr, Laura R., Loth, Daan W., Shrine, Nick R. G., Cho, Michael H., Bakke, Per, Wilk, Jemma B., Davies, Gail, Tang, Wenbo, Heckbert, Susan R., Chen, Ting-hsu, Beaty, Terri H., Crapo, James D., Aldrich, Melinda, Henry, Amanda P., Zhao, Jing Hua, Borecki, Ingrid B., Couper, David, Latourelle, Jeanne C., Brusselle, Guy G., Smith, Albert Vernon, Hui, Jennie, Dupuis, Josée, Burkart, Kristin M., Hancock, Dana B., and Smolonska, Joanna

Subjects
respiratory tract diseases
Abstract

Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.

Published
2012
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45. A comparison of visual and quantitative methods to identify interstitial lung abnormalities

Author

Kliment, Corrine R., primary, Araki, Tetsuro, additional, Doyle, Tracy J., additional, Gao, Wei, additional, Dupuis, Josée, additional, Latourelle, Jeanne C., additional, Zazueta, Oscar E., additional, Fernandez, Isis E., additional, Nishino, Mizuki, additional, Okajima, Yuka, additional, Ross, James C., additional, Estépar, Raúl San José, additional, Diaz, Alejandro A., additional, Lederer, David J., additional, Schwartz, David A., additional, Silverman, Edwin K., additional, Rosas, Ivan O., additional, Washko, George R., additional, O’Connor, George T., additional, Hatabu, Hiroto, additional, and Hunninghake, Gary M., additional

Published
2015
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46. miR-10b-5p expression in Huntington’s disease brain relates to age of onset and the extent of striatal involvement

Author

Hoss, Andrew G, primary, Labadorf, Adam, additional, Latourelle, Jeanne C, additional, Kartha, Vinay K, additional, Hadzi, Tiffany C, additional, Gusella, James F, additional, MacDonald, Marcy E, additional, Chen, Jiang-Fan, additional, Akbarian, Schahram, additional, Weng, Zhiping, additional, Vonsattel, Jean Paul, additional, and Myers, Richard H, additional

Published
2015
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47. Estrogen-related and other disease diagnoses preceding Parkinson's disease

Author

Latourelle, Jeanne C, Dybdal, Merete, Destefano, Anita L, Myers, Richard H, and Lash, Timothy L

Subjects
hormones, hormone substitutes, and hormone antagonists
Abstract

Estrogen exposure has been associated with the occurrence of Parkinson's disease (PD), as well as many other disorders, and yet the mechanisms underlying these relations are often unknown. While it is likely that estrogen exposure modifies the risk of various diseases through many different mechanisms, some estrogen-related disease processes might work in similar manners and result in association between the diseases. Indeed, the association between diseases need not be due only to estrogen-related factors, but due to similar disease processes from a variety of mechanisms.

Published
2010

48. MicroRNAs Located in the Hox Gene Clusters Are Implicated in Huntington's Disease Pathogenesis

Author

Hoss, Andrew G., primary, Kartha, Vinay K., additional, Dong, Xianjun, additional, Latourelle, Jeanne C., additional, Dumitriu, Alexandra, additional, Hadzi, Tiffany C., additional, MacDonald, Marcy E., additional, Gusella, James F., additional, Akbarian, Schahram, additional, Chen, Jiang-Fan, additional, Weng, Zhiping, additional, and Myers, Richard H., additional

Published
2014
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49. MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities

Author

Hunninghake, Gary M., primary, Hatabu, Hiroto, additional, Okajima, Yuka, additional, Gao, Wei, additional, Dupuis, Josée, additional, Latourelle, Jeanne C., additional, Nishino, Mizuki, additional, Araki, Tetsuro, additional, Zazueta, Oscar E., additional, Kurugol, Sila, additional, Ross, James C., additional, Estépar, Raúl San José, additional, Murphy, Elissa, additional, Steele, Mark P., additional, Loyd, James E., additional, Schwarz, Marvin I., additional, Fingerlin, Tasha E., additional, Rosas, Ivan O., additional, Washko, George R., additional, O’Connor, George T., additional, and Schwartz, David A., additional

Published
2013
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50. Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study

Author

move to dc.description.sponsorship, Massachusetts Institute of Technology. Department of Biology, Lindquist, Susan, Dumitriu, Alexandra, Pacheco, Chris D., Wilk, Jemma B., Strathearn, Katherine E., Latourelle, Jeanne C., Goldwurm, Stefano, Pezzoli, Gianni, Rochet, Jean-Christophe, Myers, Richard H., move to dc.description.sponsorship, Massachusetts Institute of Technology. Department of Biology, Lindquist, Susan, Dumitriu, Alexandra, Pacheco, Chris D., Wilk, Jemma B., Strathearn, Katherine E., Latourelle, Jeanne C., Goldwurm, Stefano, Pezzoli, Gianni, Rochet, Jean-Christophe, and Myers, Richard H.

Abstract

Although family history is a well-established risk factor for Parkinson's disease (PD), fewer than 5% of PD cases can be attributed to known genetic mutations. The etiology for the remainder of PD cases is unclear; however, neuronal accumulation of the protein α-synuclein is common to nearly all patients, implicating pathways that influence α-synuclein in PD pathogenesis. We report a genome-wide significant association (P = 3.97 × 10−8) between a polymorphism, rs1564282, in the cyclin-G-associated kinase (GAK) gene and increased PD risk, with a meta-analysis odds ratio of 1.48. This association result is based on the meta-analysis of three publicly available PD case–control genome-wide association study and genotyping from a new, independent Italian cohort. Microarray expression analysis of post-mortem frontal cortex from PD and control brains demonstrates a significant association between rs1564282 and higher α-synuclein expression, a known cause of early onset PD. Functional knockdown of GAK in cell culture causes a significant increase in toxicity when α-synuclein is over-expressed. Furthermore, knockdown of GAK in rat primary neurons expressing the A53T mutation of α-synuclein, a well-established model for PD, decreases cell viability. These observations provide evidence that GAK is associated with PD risk and suggest that GAK and α-synuclein interact in a pathway involved in PD pathogenesis. The GAK protein, a serine/threonine kinase, belongs to a family of proteins commonly targeted for drug development. This, combined with GAK's observed relationship to the levels of α-synuclein expression and toxicity, suggests that the protein is an attractive therapeutic target for the treatment of PD., Robert P. & Judith N. Goldberg Foundation, William N. & Bernice E. Bumpus Foundation, Howard Hughes Medical Institute (Collaborative Innovation Award), National Science Foundation (U.S.) (R01-NS036711)

Published
2011

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