Search

Your search keyword '"Hauser, Michael"' showing total 1,689 results
Start Over Author "Hauser, Michael"

Refine your results

1,689 results on '"Hauser, Michael"'

1. Ontologie Egona Bondyho jako anticipace současné filosofie

Author

Hauser, Michael

Subjects
egon bondy, insubstantial ontology, slavoj žižek, artificial intelligence, Philosophy (General), B1-5802
Abstract

This discussion study addresses the ontological and ethical questions that can be found in Myšlení a tvorba Egona Bondyho (The Thought and Creative Work of Egon Bondy), edited by Petr Kužel. This is the first monograph dedicated to the work of this original thinker. In the introductory part, I deal with the reasons that led to Bondy’s work being neglected up to this point in time by those who interpret philosophy. In the second part, I summarize the axiological and logical arguments put forward by the authors of the section of the book concerned with ontology, which should show that Bondy’s abandonment of the category of substance was justified. Then I explore two possible objections to the axiological justification of a non-substantial ontology and an objection to its logical justification. Nonetheless, in all parts of the study I show that Bondy anticipated a number of the principal themes of contemporary ontology and the theory of artificial intelligence, which have figured, for example, in the work of Slavoj Žižek or Nick Bostrom. In the closing part, I formulate some topics that, I believe, further research on Bondy should focus on.

Published
2021
Full Text
View/download PDF

3. Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder

Author

Nievergelt, Caroline M., Maihofer, Adam X., Atkinson, Elizabeth G., Chen, Chia-Yen, Choi, Karmel W., Coleman, Jonathan R. I., Daskalakis, Nikolaos P., Duncan, Laramie E., Polimanti, Renato, Aaronson, Cindy, Amstadter, Ananda B., Andersen, Soren B., Andreassen, Ole A., Arbisi, Paul A., Ashley-Koch, Allison E., Austin, S. Bryn, Avdibegoviç, Esmina, Babić, Dragan, Bacanu, Silviu-Alin, Baker, Dewleen G., Batzler, Anthony, Beckham, Jean C., Belangero, Sintia, Benjet, Corina, Bergner, Carisa, Bierer, Linda M., Biernacka, Joanna M., Bierut, Laura J., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Brandolino, Amber, Breen, Gerome, Bressan, Rodrigo Affonseca, Bryant, Richard A., Bustamante, Angela C., Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Børglum, Anders D., Børte, Sigrid, Cahn, Leah, Calabrese, Joseph R., Caldas-de-Almeida, Jose Miguel, Chatzinakos, Chris, Cheema, Sheraz, Clouston, Sean A. P., Colodro-Conde, Lucía, Coombes, Brandon J., Cruz-Fuentes, Carlos S., Dale, Anders M., Dalvie, Shareefa, Davis, Lea K., Deckert, Jürgen, Delahanty, Douglas L., Dennis, Michelle F., Desarnaud, Frank, DiPietro, Christopher P., Disner, Seth G., Docherty, Anna R., Domschke, Katharina, Dyb, Grete, Kulenović, Alma Džubur, Edenberg, Howard J., Evans, Alexandra, Fabbri, Chiara, Fani, Negar, Farrer, Lindsay A., Feder, Adriana, Feeny, Norah C., Flory, Janine D., Forbes, David, Franz, Carol E., Galea, Sandro, Garrett, Melanie E., Gelaye, Bizu, Gelernter, Joel, Geuze, Elbert, Gillespie, Charles F., Goleva, Slavina B., Gordon, Scott D., Goçi, Aferdita, Grasser, Lana Ruvolo, Guindalini, Camila, Haas, Magali, Hagenaars, Saskia, Hauser, Michael A., Heath, Andrew C., Hemmings, Sian M. J., Hesselbrock, Victor, Hickie, Ian B., Hogan, Kelleigh, Hougaard, David Michael, Huang, Hailiang, Huckins, Laura M., Hveem, Kristian, Jakovljević, Miro, Javanbakht, Arash, Jenkins, Gregory D., Johnson, Jessica, Jones, Ian, Jovanovic, Tanja, Karstoft, Karen-Inge, Kaufman, Milissa L., Kennedy, James L., Kessler, Ronald C., Khan, Alaptagin, Kimbrel, Nathan A., King, Anthony P., Koen, Nastassja, Kotov, Roman, Kranzler, Henry R., Krebs, Kristi, Kremen, William S., Kuan, Pei-Fen, Lawford, Bruce R., Lebois, Lauren A. M., Lehto, Kelli, Levey, Daniel F., Lewis, Catrin, Liberzon, Israel, Linnstaedt, Sarah D., Logue, Mark W., Lori, Adriana, Lu, Yi, Luft, Benjamin J., Lupton, Michelle K., Luykx, Jurjen J., Makotkine, Iouri, Maples-Keller, Jessica L., Marchese, Shelby, Marmar, Charles, Martin, Nicholas G., Martínez-Levy, Gabriela A., McAloney, Kerrie, McFarlane, Alexander, McLaughlin, Katie A., McLean, Samuel A., Medland, Sarah E., Mehta, Divya, Meyers, Jacquelyn, Michopoulos, Vasiliki, Mikita, Elizabeth A., Milani, Lili, Milberg, William, Miller, Mark W., Morey, Rajendra A., Morris, Charles Phillip, Mors, Ole, Mortensen, Preben Bo, Mufford, Mary S., Nelson, Elliot C., Nordentoft, Merete, Norman, Sonya B., Nugent, Nicole R., O’Donnell, Meaghan, Orcutt, Holly K., Pan, Pedro M., Panizzon, Matthew S., Pathak, Gita A., Peters, Edward S., Peterson, Alan L., Peverill, Matthew, Pietrzak, Robert H., Polusny, Melissa A., Porjesz, Bernice, Powers, Abigail, Qin, Xue-Jun, Ratanatharathorn, Andrew, Risbrough, Victoria B., Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Kenneth J., Rung, Ariane, Runz, Heiko, Rutten, Bart P. F., de Viteri, Stacey Saenz, Salum, Giovanni Abrahão, Sampson, Laura, Sanchez, Sixto E., Santoro, Marcos, Seah, Carina, Seedat, Soraya, Seng, Julia S., Shabalin, Andrey, Sheerin, Christina M., Silove, Derrick, Smith, Alicia K., Smoller, Jordan W., Sponheim, Scott R., Stein, Dan J., Stensland, Synne, Stevens, Jennifer S., Sumner, Jennifer A., Teicher, Martin H., Thompson, Wesley K., Tiwari, Arun K., Trapido, Edward, Uddin, Monica, Ursano, Robert J., Valdimarsdóttir, Unnur, Van Hooff, Miranda, Vermetten, Eric, Vinkers, Christiaan H., Voisey, Joanne, Wang, Yunpeng, Wang, Zhewu, Waszczuk, Monika, Weber, Heike, Wendt, Frank R., Werge, Thomas, Williams, Michelle A., Williamson, Douglas E., Winsvold, Bendik S., Winternitz, Sherry, Wolf, Christiane, Wolf, Erika J., Xia, Yan, Xiong, Ying, Yehuda, Rachel, Young, Keith A., Young, Ross McD, Zai, Clement C., Zai, Gwyneth C., Zervas, Mark, Zhao, Hongyu, Zoellner, Lori A., Zwart, John-Anker, deRoon-Cassini, Terri, van Rooij, Sanne J. H., van den Heuvel, Leigh L., Stein, Murray B., Ressler, Kerry J., and Koenen, Karestan C.

Published
2024
Full Text
View/download PDF

4. GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

Author

Docherty, Anna, Mullins, Niamh, Ashley-Koch, Allison, Qin, Xuejun, Coleman, Jonathan, Shabalin, Andrey, Kang, JooEun, Murnyak, Balasz, Wendt, Frank, Adams, Mark, Campos, Adrian, DiBlasi, Emily, Fullerton, Janice, Kranzler, Henry, Bakian, Amanda, Monson, Eric, Rentería, Miguel, Walss-Bass, Consuelo, Andreassen, Ole, Behera, Chittaranjan, Bulik, Cynthia, Edenberg, Howard, Kessler, Ronald, Mann, J, Nurnberger, John, Pistis, Giorgio, Streit, Fabian, Ursano, Robert, Polimanti, Renato, Dennis, Michelle, Garrett, Melanie, Hair, Lauren, Harvey, Philip, Hauser, Elizabeth, Hauser, Michael, Huffman, Jennifer, Jacobson, Daniel, Madduri, Ravi, McMahon, Benjamin, Oslin, David, Trafton, Jodie, Awasthi, Swapnil, Berrettini, Wade, Bohus, Martin, Chang, Xiao, Chen, Hsi-Chung, Chen, Wei, Christensen, Erik, Crow, Scott, Duriez, Philibert, Edwards, Alexis, Fernández-Aranda, Fernando, Galfalvy, Hanga, Gandal, Michael, Gorwood, Philip, Guo, Yiran, Hafferty, Jonathan, Hakonarson, Hakon, Halmi, Katherine, Hishimoto, Akitoyo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan, Kaye, Walter, Keel, Pamela, Kennedy, James, Kim, Minsoo, Klump, Kelly, Levey, Daniel, Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Marshall, Christian, Mitchell, James, Okazaki, Satoshi, Otsuka, Ikuo, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Ripke, Stephan, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen, Schmahl, Christian, Sokolowski, Marcus, Starnawska, Anna, Strober, Michael, Su, Mei-Hsin, Thornton, Laura, Treasure, Janet, Ware, Erin, Watson, Hunna, Witt, Stephanie, Woodside, D, Yilmaz, Zeynep, Zillich, Lea, and Adolfsson, Rolf

Subjects
Biological Markers, Depressive Disorders, Genetics, Schizophrenia Spectrum and Other Psychotic Disorders, Self-Harm, Suicide, Humans, Genome-Wide Association Study, Suicide, Attempted, Depressive Disorder, Major, Risk Factors, Suicidal Ideation, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Genetic Loci
Abstract

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values

Published
2023

9. Psychological trauma and the genetic overlap between posttraumatic stress disorder and major depressive disorder

Author

Mundy, Jessica, Hübel, Christopher, Gelernter, Joel, Levey, Daniel, Murray, Robin M, Skelton, Megan, Stein, Murray B, Maihofer, Adam X, Nievergelt, Caroline M, Baker, Dewlen G, Risborough, Victoria B, Calabrese, Joseph R, Galea, Sandro, Stein, Dan J, Koen, Nastassja, Dalvie, Shareefa, Aiello, Allison E, Roberts, Andrea L, Koenen, KC, Solovieff, Nadia, Kranzler, Henry R, Zhao, Hongyu, Farrer, Lindsay A, Johnson, Eric Otto, Rice, John P, Bierut, Laura J, Saccone, Nancy L, McFarlane, Alexander, Forbes, David, Silove, Derrick, O'Donnell, Meaghan, Bryant, Richard A, van Hooff, Miranda, Sponheim, Scott R, Disner, Seth G, Pietrzak, Robert H, Chen, Chia-Yen, Smoller, Jordan W, Ursano, Robert J, Kessler, Ronald C, Junglen, Angela G, Delahanty, Douglas L, Amstadter, Ananda B, Sheerin, Christina M, Ruggiero, Ken, McLaughlin, Katie A, Peverill, Matthew, Caldas-de-Almeida, JM, Austin, S Bryn, Gelaye, Bizu, Williams, Michelle A, Sanchez, Sixto E, Franz, Carol E, Panizzon, Matthew S, Lyons, Michael J, Kremen, William S, Andreassen, Ole A, Dale, Anders M, Rutten, Bart PF, Vinkers, Christiaan, Schijven, Dick, Geuze, Elbert, Vermetten, Eric, Luykx, Jurjen J, Boks, Marco P, Ashley-Koch, Allison E, Beckham, Jean C, Garrett, Melanie E, Hauser, Michael A, Dennis, Michelle F, Kimbrel, Nathan A, Qin, Xue-Jun, Karstoft, Karen-Inge, Andersen, Soren B, Borglum, Anders D, Hougaard, David Michael, Bybjerg-Grauholm, Jonas, Duncan, Laramie E, Bµkvad-Hansen, Marie, Nordentoft, Merete, Mors, Ole, Mortensen, PB, Werge, Thomas, Thompson, Wesley K, Wang, Yunpeng, Heath, Andrew C, Nelson, Elliot C, Martin, Nicholas G, Gordon, Scott D, Wolf, Erika J, Logue, Mark W, Miller, Mark W, McGlinchey, Regina E, Milberg, William, Erbes, Christopher R, Polusny, Melissa A, Arbisi, Paul A, and Peterson, Alan L

Subjects
Prevention, Clinical Research, Genetics, Serious Mental Illness, Depression, Post-Traumatic Stress Disorder (PTSD), Mental Health, Brain Disorders, Anxiety Disorders, Major Depressive Disorder, Human Genome, 2.3 Psychological, social and economic factors, Aetiology, Mental health, Good Health and Well Being, Posttraumatic stress disorder, major depressive disorder, psychological trauma, genetics, genetic correlations, polygenic risk scores, Million Veteran Program, Post Traumatic Stress Disorder Working Group of the Psychiatric Genomics Consortium, Neurosciences, Public Health and Health Services, Psychology, Psychiatry
Abstract

BackgroundPosttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are commonly reported co-occurring mental health consequences of psychological trauma exposure. The disorders have high genetic overlap. Trauma is a complex phenotype but research suggests that trauma sensitivity has a heritable basis. We investigated whether sensitivity to trauma in those with MDD reflects a similar genetic component in those with PTSD.MethodsGenetic correlations between PTSD and MDD in individuals reporting trauma and MDD in individuals not reporting trauma were estimated, as well as with recurrent MDD and single-episode MDD, using genome-wide association study (GWAS) summary statistics. Genetic correlations were replicated using PTSD data from the Psychiatric Genomics Consortium and the Million Veteran Program. Polygenic risk scores were generated in UK Biobank participants who met the criteria for lifetime MDD (N = 29 471). We investigated whether genetic loading for PTSD was associated with reporting trauma in these individuals.ResultsGenetic loading for PTSD was significantly associated with reporting trauma in individuals with MDD [OR 1.04 (95% CI 1.01-1.07), Empirical-p = 0.02]. PTSD was significantly more genetically correlated with recurrent MDD than with MDD in individuals not reporting trauma (rg differences = ~0.2, p < 0.008). Participants who had experienced recurrent MDD reported significantly higher rates of trauma than participants who had experienced single-episode MDD (χ2 > 166, p < 0.001).ConclusionsOur findings point towards the existence of genetic variants associated with trauma sensitivity that might be shared between PTSD and MDD, although replication with better powered GWAS is needed. Our findings corroborate previous research highlighting trauma exposure as a key risk factor for recurrent MDD.

Published
2022

12. Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Author

Maihofer, Adam X, Choi, Karmel W, Coleman, Jonathan RI, Daskalakis, Nikolaos P, Denckla, Christy A, Ketema, Elizabeth, Morey, Rajendra A, Polimanti, Renato, Ratanatharathorn, Andrew, Torres, Katy, Wingo, Aliza P, Zai, Clement C, Aiello, Allison E, Almli, Lynn M, Amstadter, Ananda B, Andersen, Soren B, Andreassen, Ole A, Arbisi, Paul A, Ashley-Koch, Allison E, Austin, S Bryn, Avdibegović, Esmina, Borglum, Anders D, Babić, Dragan, Bækvad-Hansen, Marie, Baker, Dewleen G, Beckham, Jean C, Bierut, Laura J, Bisson, Jonathan I, Boks, Marco P, Bolger, Elizabeth A, Bradley, Bekh, Brashear, Meghan, Breen, Gerome, Bryant, Richard A, Bustamante, Angela C, Bybjerg-Grauholm, Jonas, Calabrese, Joseph R, Caldas-de-Almeida, José M, Chen, Chia-Yen, Dale, Anders M, Dalvie, Shareefa, Deckert, Jürgen, Delahanty, Douglas L, Dennis, Michelle F, Disner, Seth G, Domschke, Katharina, Duncan, Laramie E, Džubur Kulenović, Alma, Erbes, Christopher R, Evans, Alexandra, Farrer, Lindsay A, Feeny, Norah C, Flory, Janine D, Forbes, David, Franz, Carol E, Galea, Sandro, Garrett, Melanie E, Gautam, Aarti, Gelaye, Bizu, Gelernter, Joel, Geuze, Elbert, Gillespie, Charles F, Goçi, Aferdita, Gordon, Scott D, Guffanti, Guia, Hammamieh, Rasha, Hauser, Michael A, Heath, Andrew C, Hemmings, Sian MJ, Hougaard, David Michael, Jakovljević, Miro, Jett, Marti, Johnson, Eric Otto, Jones, Ian, Jovanovic, Tanja, Qin, Xue-Jun, Karstoft, Karen-Inge, Kaufman, Milissa L, Kessler, Ronald C, Khan, Alaptagin, Kimbrel, Nathan A, King, Anthony P, Koen, Nastassja, Kranzler, Henry R, Kremen, William S, Lawford, Bruce R, Lebois, Lauren AM, Lewis, Catrin, Liberzon, Israel, Linnstaedt, Sarah D, Logue, Mark W, Lori, Adriana, Lugonja, Božo, Luykx, Jurjen J, Lyons, Michael J, Maples-Keller, Jessica L, Marmar, Charles, Martin, Nicholas G, Maurer, Douglas, and Mavissakalian, Matig R

Subjects
Biological Sciences, Genetics, Anxiety Disorders, Mental Health, Brain Disorders, Post-Traumatic Stress Disorder (PTSD), Prevention, Human Genome, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide, Stress Disorders, Post-Traumatic, GWAS, Heritability, PTSD, PheWAS, Trauma, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BackgroundPosttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs).MethodsA GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms.ResultsGWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program.ConclusionsThrough using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

Published
2022

13. Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci

Author

Han, Xikun, Gharahkhani, Puya, Hamel, Andrew R., Ong, Jue Sheng, Rentería, Miguel E., Mehta, Puja, Dong, Xianjun, Pasutto, Francesca, Hammond, Christopher, Young, Terri L., Hysi, Pirro, Lotery, Andrew J., Jorgenson, Eric, Choquet, Hélène, Hauser, Michael, Cooke Bailey, Jessica N., Nakazawa, Toru, Akiyama, Masato, Shiga, Yukihiro, Fuller, Zachary L., Wang, Xin, Hewitt, Alex W., Craig, Jamie E., Pasquale, Louis R., Mackey, David A., Wiggs, Janey L., Khawaja, Anthony P., Segrè, Ayellet V., and MacGregor, Stuart

Published
2023
Full Text
View/download PDF

16. A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma

Author

Verma, Shefali S., Gudiseva, Harini V., Chavali, Venkata R.M., Salowe, Rebecca J., Bradford, Yuki, Guare, Lindsay, Lucas, Anastasia, Collins, David W., Vrathasha, Vrathasha, Nair, Rohini M., Rathi, Sonika, Zhao, Bingxin, He, Jie, Lee, Roy, Zenebe-Gete, Selam, Bowman, Anita S., McHugh, Caitlin P., Zody, Michael C., Pistilli, Maxwell, Khachatryan, Naira, Daniel, Ebenezer, Murphy, Windell, Henderer, Jeffrey, Kinzy, Tyler G., Iyengar, Sudha K., Peachey, Neal S., Taylor, Kent D., Guo, Xiuqing, Chen, Yii-Der Ida, Zangwill, Linda, Girkin, Christopher, Ayyagari, Radha, Liebmann, Jeffrey, Chuka-Okosa, Chimd M., Williams, Susan E., Akafo, Stephen, Budenz, Donald L., Olawoye, Olusola O., Ramsay, Michele, Ashaye, Adeyinka, Akpa, Onoja M., Aung, Tin, Wiggs, Janey L., Ross, Ahmara G., Cui, Qi N., Addis, Victoria, Lehman, Amanda, Miller-Ellis, Eydie, Sankar, Prithvi S., Williams, Scott M., Ying, Gui-shuang, Cooke Bailey, Jessica, Rotter, Jerome I., Weinreb, Robert, Khor, Chiea Chuen, Hauser, Michael A., Ritchie, Marylyn D., and O’Brien, Joan M.

Published
2024
Full Text
View/download PDF

17. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.

Author

Gharahkhani, Puya, Jorgenson, Eric, Hysi, Pirro, Khawaja, Anthony P, Pendergrass, Sarah, Han, Xikun, Ong, Jue Sheng, Hewitt, Alex W, Segrè, Ayellet V, Rouhana, John M, Hamel, Andrew R, Igo, Robert P, Choquet, Helene, Qassim, Ayub, Josyula, Navya S, Cooke Bailey, Jessica N, Bonnemaijer, Pieter WM, Iglesias, Adriana, Siggs, Owen M, Young, Terri L, Vitart, Veronique, Thiadens, Alberta AHJ, Karjalainen, Juha, Uebe, Steffen, Melles, Ronald B, Nair, K Saidas, Luben, Robert, Simcoe, Mark, Amersinghe, Nishani, Cree, Angela J, Hohn, Rene, Poplawski, Alicia, Chen, Li Jia, Rong, Shi-Song, Aung, Tin, Vithana, Eranga Nishanthie, NEIGHBORHOOD consortium, ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group, 23 and Me Research Team, Tamiya, Gen, Shiga, Yukihiro, Yamamoto, Masayuki, Nakazawa, Toru, Currant, Hannah, Birney, Ewan, Wang, Xin, Auton, Adam, Lupton, Michelle K, Martin, Nicholas G, Ashaye, Adeyinka, Olawoye, Olusola, Williams, Susan E, Akafo, Stephen, Ramsay, Michele, Hashimoto, Kazuki, Kamatani, Yoichiro, Akiyama, Masato, Momozawa, Yukihide, Foster, Paul J, Khaw, Peng T, Morgan, James E, Strouthidis, Nicholas G, Kraft, Peter, Kang, Jae H, Pang, Chi Pui, Pasutto, Francesca, Mitchell, Paul, Lotery, Andrew J, Palotie, Aarno, van Duijn, Cornelia, Haines, Jonathan L, Hammond, Chris, Pasquale, Louis R, Klaver, Caroline CW, Hauser, Michael, Khor, Chiea Chuen, Mackey, David A, Kubo, Michiaki, Cheng, Ching-Yu, Craig, Jamie E, MacGregor, Stuart, and Wiggs, Janey L

Subjects
NEIGHBORHOOD consortium, ANZRAG consortium, Biobank Japan project, FinnGen study, UK Biobank Eye and Vision Consortium, GIGA study group, and Me Research Team, Humans, Glaucoma, Open-Angle, Genetic Predisposition to Disease, Genotype, Polymorphism, Single Nucleotide, Asian Continental Ancestry Group, European Continental Ancestry Group, Genome-Wide Association Study, Genetic Loci, Glaucoma, Open-Angle, Polymorphism, Single Nucleotide
Abstract

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Published
2021

18. Examining Individual and Synergistic Contributions of PTSD and Genetics to Blood Pressure: A Trans-Ethnic Meta-Analysis

Author

Sumner, Jennifer A, Maihofer, Adam X, Michopoulos, Vasiliki, Rothbaum, Alex O, Almli, Lynn M, Andreassen, Ole A, Ashley-Koch, Allison E, Baker, Dewleen G, Beckham, Jean C, Bradley, Bekh, Breen, Gerome, Coleman, Jonathan RI, Dale, Anders M, Dennis, Michelle F, Feeny, Norah C, Franz, Carol E, Garrett, Melanie E, Gillespie, Charles F, Guffanti, Guia, Hauser, Michael A, Hemmings, Sian MJ, Jovanovic, Tanja, Kimbrel, Nathan A, Kremen, William S, Lawford, Bruce R, Logue, Mark W, Lori, Adriana, Lyons, Michael J, Maples-Keller, Jessica, Mavissakalian, Matig R, McGlinchey, Regina E, Mehta, Divya, Mellor, Rebecca, Milberg, William, Miller, Mark W, Morris, Charles Phillip, Panizzon, Matthew S, Ressler, Kerry J, Risbrough, Victoria B, Rothbaum, Barbara O, Roy-Byrne, Peter, Seedat, Soraya, Smith, Alicia K, Stevens, Jennifer S, van den Heuvel, Leigh Luella, Voisey, Joanne, Young, Ross McD, Zoellner, Lori A, Nievergelt, Caroline M, and Wolf, Erika J

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Mental Illness, Cardiovascular, Anxiety Disorders, Post-Traumatic Stress Disorder (PTSD), Hypertension, Brain Disorders, Mental Health, Prevention, Good Health and Well Being, posttraumatic stress disorder, genetics, blood pressure, trans-ethnic, meta-analysis, Cognitive Sciences, Biological psychology
Abstract

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European (n = 70,870) and African (n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: β = 2.83, standard error (SE) = 0.06, p < 1E-20; DBP: β = 1.32, SE = 0.04, p < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study - United Kingdom Biobank - PTSD symptoms were negatively associated with SBP levels (β = -1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (β = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (β = 2.81, SE = 1.13, p = 0.01); no significant association was observed for DBP (β = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.

Published
2021

19. Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR.

Author

Smith, Alicia K, Ratanatharathorn, Andrew, Maihofer, Adam X, Naviaux, Robert K, Aiello, Allison E, Amstadter, Ananda B, Ashley-Koch, Allison E, Baker, Dewleen G, Beckham, Jean C, Boks, Marco P, Bromet, Evelyn, Dennis, Michelle, Galea, Sandro, Garrett, Melanie E, Geuze, Elbert, Guffanti, Guia, Hauser, Michael A, Katrinli, Seyma, Kilaru, Varun, Kessler, Ronald C, Kimbrel, Nathan A, Koenen, Karestan C, Kuan, Pei-Fen, Li, Kefeng, Logue, Mark W, Lori, Adriana, Luft, Benjamin J, Miller, Mark W, Naviaux, Jane C, Nugent, Nicole R, Qin, Xuejun, Ressler, Kerry J, Risbrough, Victoria B, Rutten, Bart PF, Stein, Murray B, Ursano, Robert J, Vermetten, Eric, Vinkers, Christiaan H, Wang, Lin, Youssef, Nagy A, INTRuST Clinical Consortium, VA Mid-Atlantic MIRECC Workgroup, PGC PTSD Epigenetics Workgroup, Uddin, Monica, and Nievergelt, Caroline M

Subjects
INTRuST Clinical Consortium, VA Mid-Atlantic MIRECC Workgroup, PGC PTSD Epigenetics Workgroup, Humans, Wounds and Injuries, Kynurenine, Repressor Proteins, Case-Control Studies, Cohort Studies, Stress Disorders, Post-Traumatic, DNA Methylation, Epigenesis, Genetic, Military Personnel, Female, Male, Basic Helix-Loop-Helix Transcription Factors, Epigenome, Stress Disorders, Post-Traumatic, Epigenesis, Genetic
Abstract

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

Published
2020

20. A Dynamically Controlled Recurrent Neural Network for Modeling Dynamical Systems

Author

Fu, Yiwei, Saab Jr, Samer, Ray, Asok, and Hauser, Michael

Subjects
Computer Science - Neural and Evolutionary Computing, Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

This work proposes a novel neural network architecture, called the Dynamically Controlled Recurrent Neural Network (DCRNN), specifically designed to model dynamical systems that are governed by ordinary differential equations (ODEs). The current state vectors of these types of dynamical systems only depend on their state-space models, along with the respective inputs and initial conditions. Long Short-Term Memory (LSTM) networks, which have proven to be very effective for memory-based tasks, may fail to model physical processes as they tend to memorize, rather than learn how to capture the information on the underlying dynamics. The proposed DCRNN includes learnable skip-connections across previously hidden states, and introduces a regularization term in the loss function by relying on Lyapunov stability theory. The regularizer enables the placement of eigenvalues of the transfer function induced by the DCRNN to desired values, thereby acting as an internal controller for the hidden state trajectory. The results show that, for forecasting a chaotic dynamical system, the DCRNN outperforms the LSTM in $100$ out of $100$ randomized experiments by reducing the mean squared error of the LSTM's forecasting by $80.0\% \pm 3.0\%$.

Published
2019

21. Training products of expert capsules with mixing by dynamic routing

Author

Hauser, Michael

Subjects
Computer Science - Machine Learning, Computer Science - Neural and Evolutionary Computing, Statistics - Machine Learning
Abstract

This study develops an unsupervised learning algorithm for products of expert capsules with dynamic routing. Analogous to binary-valued neurons in Restricted Boltzmann Machines, the magnitude of a squashed capsule firing takes values between zero and one, representing the probability of the capsule being on. This analogy motivates the design of an energy function for capsule networks. In order to have an efficient sampling procedure where hidden layer nodes are not connected, the energy function is made consistent with dynamic routing in the sense of the probability of a capsule firing, and inference on the capsule network is computed with the dynamic routing between capsules procedure. In order to optimize the log-likelihood of the visible layer capsules, the gradient is found in terms of this energy function. The developed unsupervised learning algorithm is used to train a capsule network on standard vision datasets, and is able to generate realistic looking images from its learned distribution.

Published
2019

22. Training capsules as a routing-weighted product of expert neurons

Author

Hauser, Michael

Subjects
Computer Science - Neural and Evolutionary Computing, Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

Capsules are the multidimensional analogue to scalar neurons in neural networks, and because they are multidimensional, much more complex routing schemes can be used to pass information forward through the network than what can be used in traditional neural networks. This work treats capsules as collections of neurons in a fully connected neural network, where sub-networks connecting capsules are weighted according to the routing coefficients determined by routing by agreement. An energy function is designed to reflect this model, and it follows that capsule networks with dynamic routing can be formulated as a product of expert neurons. By alternating between dynamic routing, which acts to both find subnetworks within the overall network as well as to mix the model distribution, and updating the parameters by the gradient of the contrastive divergence, a bottom-up, unsupervised learning algorithm is constructed for capsule networks with dynamic routing. The model and its training algorithm are qualitatively tested in the generative sense, and is able to produce realistic looking images from standard vision datasets.

Published
2019

23. On Residual Networks Learning a Perturbation from Identity

Author

Hauser, Michael

Subjects
Computer Science - Neural and Evolutionary Computing
Abstract

The purpose of this work is to test and study the hypothesis that residual networks are learning a perturbation from identity. Residual networks are enormously important deep learning models, with many theories attempting to explain how they function; learning a perturbation from identity is one such theory. In order to answer this question, the magnitudes of the perturbations are measured in both an absolute sense as well as in a scaled sense, with each form having its relative benefits and drawbacks. Additionally, a stopping rule is developed that can be used to decide the depth of the residual network based on the average perturbation magnitude being less than a given epsilon. With this analysis a better understanding of how residual networks process and transform data from input to output is formed. Parallel experiments are conducted on MNIST as well as CIFAR10 for various sized residual networks with between 6 and 300 residual blocks. It is found that, in this setting, the average scaled perturbation magnitude is roughly inversely proportional to increasing the number of residual blocks, and from this it follows that for sufficiently large residual networks, they are learning a perturbation from identity.

Published
2019

25. The genetic architecture of the human cerebral cortex

Author

Grasby, Katrina L, Jahanshad, Neda, Painter, Jodie N, Colodro-Conde, Lucía, Bralten, Janita, Hibar, Derrek P, Lind, Penelope A, Pizzagalli, Fabrizio, Ching, Christopher RK, McMahon, Mary Agnes B, Shatokhina, Natalia, Zsembik, Leo CP, Thomopoulos, Sophia I, Zhu, Alyssa H, Strike, Lachlan T, Agartz, Ingrid, Alhusaini, Saud, Almeida, Marcio AA, Alnæs, Dag, Amlien, Inge K, Andersson, Micael, Ard, Tyler, Armstrong, Nicola J, Ashley-Koch, Allison, Atkins, Joshua R, Bernard, Manon, Brouwer, Rachel M, Buimer, Elizabeth EL, Bülow, Robin, Bürger, Christian, Cannon, Dara M, Chakravarty, Mallar, Chen, Qiang, Cheung, Joshua W, Couvy-Duchesne, Baptiste, Dale, Anders M, Dalvie, Shareefa, de Araujo, Tânia K, de Zubicaray, Greig I, de Zwarte, Sonja MC, Braber, Anouk den, Doan, Nhat Trung, Dohm, Katharina, Ehrlich, Stefan, Engelbrecht, Hannah-Ruth, Erk, Susanne, Fan, Chun Chieh, Fedko, Iryna O, Foley, Sonya F, Ford, Judith M, Fukunaga, Masaki, Garrett, Melanie E, Ge, Tian, Giddaluru, Sudheer, Goldman, Aaron L, Green, Melissa J, Groenewold, Nynke A, Grotegerd, Dominik, Gurholt, Tiril P, Gutman, Boris A, Hansell, Narelle K, Harris, Mathew A, Harrison, Marc B, Haswell, Courtney C, Hauser, Michael, Herms, Stefan, Heslenfeld, Dirk J, Ho, New Fei, Hoehn, David, Hoffmann, Per, Holleran, Laurena, Hoogman, Martine, Hottenga, Jouke-Jan, Ikeda, Masashi, Janowitz, Deborah, Jansen, Iris E, Jia, Tianye, Jockwitz, Christiane, Kanai, Ryota, Karama, Sherif, Kasperaviciute, Dalia, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Klein, Marieke, Knapp, Michael, Knodt, Annchen R, Krämer, Bernd, Lam, Max, Lancaster, Thomas M, Lee, Phil H, Lett, Tristram A, Lewis, Lindsay B, Lopes-Cendes, Iscia, Luciano, Michelle, Macciardi, Fabio, Marquand, Andre F, Mathias, Samuel R, Melzer, Tracy R, and Milaneschi, Yuri

Subjects
Biological Sciences, Genetics, Neurosciences, Mental Health, Brain Disorders, Stem Cell Research, 2.1 Biological and endogenous factors, Aetiology, Neurological, Attention Deficit Disorder with Hyperactivity, Brain Mapping, Cerebral Cortex, Cognition, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Organ Size, Parkinson Disease, Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN Consortium, IMAGEN Consortium, SYS Consortium, Parkinson’s Progression Markers Initiative, Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group, General Science & Technology
Abstract

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Published
2020

26. The GenomeAsia 100K Project enables genetic discoveries across Asia

Author

Wall, Jeffrey D, Stawiski, Eric W, Ratan, Aakrosh, Kim, Hie Lim, Kim, Changhoon, Gupta, Ravi, Suryamohan, Kushal, Gusareva, Elena S, Purbojati, Rikky Wenang, Bhangale, Tushar, Stepanov, Vadim, Kharkov, Vladimir, Schroeder, Markus S, Ramprasad, Vedam, Tom, Jennifer, Durinck, Steffen, Bei, Qixin, Li, Jiani, Guillory, Joseph, Phalke, Sameer, Basu, Analabha, Stinson, Jeremy, Nair, Sandhya, Malaichamy, Sivasankar, Biswas, Nidhan K, Chambers, John C, Cheng, Keith C, George, Joyner T, Khor, Seik Soon, Kim, Jong-Il, Cho, Belong, Menon, Ramesh, Sattibabu, Thiramsetti, Bassi, Akshi, Deshmukh, Manjari, Verma, Anjali, Gopalan, Vivek, Shin, Jong-Yeon, Pratapneni, Mahesh, Santhosh, Sam, Tokunaga, Katsushi, Md-Zain, Badrul M, Chan, Kok Gan, Parani, Madasamy, Natarajan, Purushothaman, Hauser, Michael, Allingham, R Rand, Santiago-Turla, Cecilia, Ghosh, Arkasubhra, Gadde, Santosh Gopi Krishna, Fuchsberger, Christian, Forer, Lukas, Schoenherr, Sebastian, Sudoyo, Herawati, Lansing, J Stephen, Friedlaender, Jonathan, Koki, George, Cox, Murray P, Hammer, Michael, Karafet, Tatiana, Ang, Khai C, Mehdi, Syed Q, Radha, Venkatesan, Mohan, Viswanathan, Majumder, Partha P, Seshagiri, Somasekar, Seo, Jeong-Sun, Schuster, Stephan C, and Peterson, Andrew S

Subjects
Human Genome, Genetics, Biotechnology, Alleles, Asian People, Datasets as Topic, Genome, Human, Genome-Wide Association Study, Genotype, Humans, GenomeAsia100K Consortium, General Science & Technology
Abstract

The underrepresentation of non-Europeans in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world's population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the GenomeAsia 100K Project. This includes a whole-genome sequencing reference dataset from 1,739 individuals of 219 population groups and 64 countries across Asia. We catalogue genetic variation, population structure, disease associations and founder effects. We also explore the use of this dataset in imputation, to facilitate genetic studies in populations across Asia and worldwide.

Published
2019

27. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Author

Consortium, The Genetics of Glaucoma in People of African Descent, Hauser, Michael A, Allingham, R Rand, Aung, Tin, Van Der Heide, Carly J, Taylor, Kent D, Rotter, Jerome I, Wang, Shih-Hsiu J, Bonnemaijer, Pieter WM, Williams, Susan E, Abdullahi, Sadiq M, Abu-Amero, Khaled K, Anderson, Michael G, Akafo, Stephen, Alhassan, Mahmoud B, Asimadu, Ifeoma, Ayyagari, Radha, Bakayoko, Saydou, Nyamsi, Prisca Biangoup, Bowden, Donald W, Bromley, William C, Budenz, Donald L, Carmichael, Trevor R, Challa, Pratap, Chen, Yii-Der Ida, Chuka-Okosa, Chimdi M, Bailey, Jessica N Cooke, Costa, Vital Paulino, Cruz, Dianne A, DuBiner, Harvey, Ervin, John F, Feldman, Robert M, Flamme-Wiese, Miles, Gaasterland, Douglas E, Garnai, Sarah J, Girkin, Christopher A, Guirou, Nouhoum, Guo, Xiuqing, Haines, Jonathan L, Hammond, Christopher J, Herndon, Leon, Hoffmann, Thomas J, Hulette, Christine M, Hydara, Abba, Igo, Robert P, Jorgenson, Eric, Kabwe, Joyce, Kilangalanga, Ngoy Janvier, Kizor-Akaraiwe, Nkiru, Kuchtey, Rachel W, Lamari, Hasnaa, Li, Zheng, Liebmann, Jeffrey M, Liu, Yutao, Loos, Ruth JF, Melo, Monica B, Moroi, Sayoko E, Msosa, Joseph M, Mullins, Robert F, Nadkarni, Girish, Napo, Abdoulaye, Ng, Maggie CY, Nunes, Hugo Freire, Obeng-Nyarkoh, Ebenezer, Okeke, Anthony, Okeke, Suhanya, Olaniyi, Olusegun, Olawoye, Olusola, Oliveira, Mariana Borges, Pasquale, Louise R, Perez-Grossmann, Rodolfo A, Pericak-Vance, Margaret A, Qin, Xue, Ramsay, Michele, Resnikoff, Serge, Richards, Julia E, Schimiti, Rui Barroso, Sim, Kar Seng, Sponsel, William E, Svidnicki, Paulo Vinicius, Thiadens, Alberta AHJ, Uche, Nkechinyere J, van Duijn, Cornelia M, de Vasconcellos, José Paulo Cabral, Wiggs, Janey L, Zangwill, Linda M, Risch, Neil, Milea, Dan, Ashaye, Adeyinka, Klaver, Caroline CW, Weinreb, Robert N, Koch, Allison E Ashley, Fingert, John H, and Khor, Chiea Chuen

Subjects
Neurosciences, Human Genome, Aging, Genetics, Eye Disease and Disorders of Vision, Clinical Research, Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Adaptor Proteins, Signal Transducing, Aged, Amyloid beta-Peptides, Black People, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glaucoma, Open-Angle, Humans, Immunohistochemistry, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Genetics of Glaucoma in People of African Descent (GGLAD) Consortium, Medical and Health Sciences, General & Internal Medicine
Abstract

ImportancePrimary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.ObjectivesTo perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, settings, and participantsA 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.ExposuresGenetic variants associated with primary open-angle glaucoma.Main outcomes and measuresPresence of primary open-angle glaucoma. Genome-wide significance was defined as P C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P

Published
2019

28. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Author

Genetics of Glaucoma in People of African Descent (GGLAD) Consortium, Hauser, Michael A, Allingham, R Rand, Aung, Tin, Van Der Heide, Carly J, Taylor, Kent D, Rotter, Jerome I, Wang, Shih-Hsiu J, Bonnemaijer, Pieter WM, Williams, Susan E, Abdullahi, Sadiq M, Abu-Amero, Khaled K, Anderson, Michael G, Akafo, Stephen, Alhassan, Mahmoud B, Asimadu, Ifeoma, Ayyagari, Radha, Bakayoko, Saydou, Nyamsi, Prisca Biangoup, Bowden, Donald W, Bromley, William C, Budenz, Donald L, Carmichael, Trevor R, Challa, Pratap, Chen, Yii-Der Ida, Chuka-Okosa, Chimdi M, Cooke Bailey, Jessica N, Costa, Vital Paulino, Cruz, Dianne A, DuBiner, Harvey, Ervin, John F, Feldman, Robert M, Flamme-Wiese, Miles, Gaasterland, Douglas E, Garnai, Sarah J, Girkin, Christopher A, Guirou, Nouhoum, Guo, Xiuqing, Haines, Jonathan L, Hammond, Christopher J, Herndon, Leon, Hoffmann, Thomas J, Hulette, Christine M, Hydara, Abba, Igo, Robert P, Jorgenson, Eric, Kabwe, Joyce, Kilangalanga, Ngoy Janvier, Kizor-Akaraiwe, Nkiru, Kuchtey, Rachel W, Lamari, Hasnaa, Li, Zheng, Liebmann, Jeffrey M, Liu, Yutao, Loos, Ruth JF, Melo, Monica B, Moroi, Sayoko E, Msosa, Joseph M, Mullins, Robert F, Nadkarni, Girish, Napo, Abdoulaye, Ng, Maggie CY, Nunes, Hugo Freire, Obeng-Nyarkoh, Ebenezer, Okeke, Anthony, Okeke, Suhanya, Olaniyi, Olusegun, Olawoye, Olusola, Oliveira, Mariana Borges, Pasquale, Louise R, Perez-Grossmann, Rodolfo A, Pericak-Vance, Margaret A, Qin, Xue, Ramsay, Michele, Resnikoff, Serge, Richards, Julia E, Schimiti, Rui Barroso, Sim, Kar Seng, Sponsel, William E, Svidnicki, Paulo Vinicius, Thiadens, Alberta AHJ, Uche, Nkechinyere J, van Duijn, Cornelia M, de Vasconcellos, José Paulo Cabral, Wiggs, Janey L, Zangwill, Linda M, Risch, Neil, Milea, Dan, Ashaye, Adeyinka, Klaver, Caroline CW, Weinreb, Robert N, Ashley Koch, Allison E, Fingert, John H, and Khor, Chiea Chuen

Subjects
Genetics of Glaucoma in People of African Descent (GGLAD) Consortium, Humans, Glaucoma, Open-Angle, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Immunohistochemistry, Risk Factors, Case-Control Studies, Genotype, Polymorphism, Single Nucleotide, Aged, Middle Aged, African Continental Ancestry Group, Female, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Amyloid beta-Peptides, Eye Disease and Disorders of Vision, Clinical Research, Human Genome, Aging, Neurodegenerative, Genetics, Neurosciences, 2.1 Biological and endogenous factors, General & Internal Medicine, Medical and Health Sciences
Abstract

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P

Published
2019

29. The Relationship of Attention-Deficit/Hyperactivity Disorder With Posttraumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study

Author

Maihofer, Adam X., Choi, Karmel W., Coleman, Jonathan R.I., Daskalakis, Nikolaos P., Denckla, Christy A., Ketema, Elizabeth, Morey, Rajendra A., Polimanti, Renato, Ratanatharathorn, Andrew, Torres, Katy, Wingo, Aliza P., Zai, Clement C., Aiello, Allison E., Almli, Lynn M., Amstadter, Ananda B., Andersen, Soren B., Andreassen, Ole A., Arbisi, Paul A., Ashley-Koch, Allison E., Austin, S. Bryn, Avdibegovic, Esmina, Borglum, Anders D., Babic, Dragan, Bækvad-Hansen, Marie, Baker, Dewleen G., Beckham, Jean C., Bierut, Laura J., Bisson, Jonathan I., Boks, Marco P., Bolger, Elizabeth A., Bradley, Bekh, Brashear, Meghan, Breen, Gerome, Bryant, Richard A., Bustamante, Angela C., Bybjerg-Grauholm, Jonas, Calabrese, Joseph R., Caldas-de-Almeida, Jose Miguel, Chen, Chia-Yen, Dale, Anders M., Dalvie, Shareefa, Deckert, Jürgen, Delahanty, Douglas L., Dennis, Michelle F., Disner, Seth G., Domschke, Katharina, Duncan, Laramie E., Kulenovic, Alma Dzubur, Erbes, Christopher R., Evans, Alexandra, Farrer, Lindsay A., Feeny, Norah C., Flory, Janine D., Forbes, David, Franz, Carol E., Galea, Sandro, Garrett, Melanie E., Gautam, Aarti, Gelaye, Bizu, Gelernter, Joel, Geuze, Elbert, Gillespie, Charles F., Uka, Aferdita Goci, Gordon, Scott D., Guffanti, Guia, Hammamieh, Rasha, Hauser, Michael A., Heath, Andrew C., Hemmings, Sian M.J., Hougaard, David Michael, Jakovljevic, Miro, Jett, Marti, Johnson, Eric Otto, Jones, Ian, Jovanovic, Tanja, Qin, Xue-Jun, Karstoft, Karen-Inge, Kaufman, Milissa L., Kessler, Ronald C., Khan, Alaptagin, Kimbrel, Nathan A., King, Anthony P., Koen, Nastassja, Kranzler, Henry R., Kremen, William S., Lawford, Bruce R., Lebois, Lauren A.M., Lewis, Catrin, Liberzon, Israel, Linnstaedt, Sarah D., Logue, Mark W., Lori, Adriana, Lugonja, Bozo, Luykx, Jurjen J., Lyons, Michael J., Maples-Keller, Jessica L., Marmar, Charles, Martin, Nicholas G., Maurer, Douglas, Mavissakalian, Matig R., McFarlane, Alexander, McGlinchey, Regina E., McLaughlin, Katie A., McLean, Samuel A., Mehta, Divya, Mellor, Rebecca, Michopoulos, Vasiliki, Milberg, William, Miller, Mark W., Morris, Charles Phillip, Mors, Ole, Mortensen, Preben Bo, Nelson, Elliot C., Nordentoft, Merete, Norman, Sonya B., O’Donnell, Meaghan, Orcutt, Holly K., Panizzon, Matthew S., Peters, Edward S., Peterson, Alan L., Peverill, Matthew, Pietrzak, Robert H., Polusny, Melissa A., Rice, John P., Risbrough, Victoria B., Roberts, Andrea L., Rothbaum, Alex O., Rothbaum, Barbara O., Roy-Byrne, Peter, Ruggiero, Kenneth J., Rung, Ariane, Rutten, Bart P.F., Saccone, Nancy L., Sanchez, Sixto E., Schijven, Dick, Seedat, Soraya, Seligowski, Antonia V., Seng, Julia S., Sheerin, Christina M., Silove, Derrick, Smith, Alicia K., Smoller, Jordan W., Sponheim, Scott R., Stein, Dan J., Stevens, Jennifer S., Teicher, Martin H., Thompson, Wesley K., Trapido, Edward, Uddin, Monica, Ursano, Robert J., Luella van den Heuvel, Leigh, Van Hooff, Miranda, Vermetten, Eric, Vinkers, Christiaan, Voisey, Joanne, Wang, Yunpeng, Wang, Zhewu, Werge, Thomas, Williams, Michelle A., Williamson, Douglas E., Winternitz, Sherry, Wolf, Christiane, Wolf, Erika J., Yehuda, Rachel, Young, Keith A., Young, Ross McD., Zhao, Hongyu, Zoellner, Lori A., Haas, Magali, Lasseter, Heather, Provost, Allison C., Salem, Rany M., Sebat, Jonathan, Shaffer, Richard, Wu, Tianying, Ripke, Stephan, Daly, Mark J., Ressler, Kerry J., Koenen, Karestan C., Stein, Murray B., Nievergelt, Caroline M., Wendt, Frank R., Garcia-Argibay, Miguel, Cabrera-Mendoza, Brenda, Valdimarsdóttir, Unnur A., Nivard, Michel G., Larsson, Henrik, Mattheisen, Manuel, and Meier, Sandra M.

Published
2023
Full Text
View/download PDF

30. Direct Risk Assessment From Myocardial Perfusion Imaging Using Explainable Deep Learning

Author

Singh, Ananya, Miller, Robert J.H., Otaki, Yuka, Kavanagh, Paul, Hauser, Michael T., Tzolos, Evangelos, Kwiecinski, Jacek, Van Kriekinge, Serge, Wei, Chih-Chun, Sharir, Tali, Einstein, Andrew J., Fish, Mathews B., Ruddy, Terrence D., Kaufmann, Philipp A., Sinusas, Albert J., Miller, Edward J., Bateman, Timothy M., Dorbala, Sharmila, Di Carli, Marcelo, Liang, Joanna X., Huang, Cathleen, Han, Donghee, Dey, Damini, Berman, Daniel S., and Slomka, Piotr J.

Published
2023
Full Text
View/download PDF

33. Polygenic risk scores for CARDINAL study

Author

Adebamowo, Clement A., Adeyemo, Adebowale, Ashaye, Adeyinka, Akpa, Onoja M., Chikowore, Tinashe, Choudhury, Ananyo, Fakim, Yasmina J., Fatumo, Segun, Hanchard, Neil, Hauser, Michael, Mitchell, Braxton, Mulder, Nicola, Ofori-Acquah, Solomon F., Owolabi, Mayowa, Ramsay, Michèle, Tayo, Bamidele, VasanthKumar, Archana Bhavani, Zhang, Yuji, and Adebamowo, Sally N.

Published
2022
Full Text
View/download PDF

34. State Space Representations of Deep Neural Networks

Author

Hauser, Michael, Gunn, Sean, Saab Jr, Samer, and Ray, Asok

Subjects
Computer Science - Neural and Evolutionary Computing, Computer Science - Artificial Intelligence
Abstract

This paper deals with neural networks as dynamical systems governed by differential or difference equations. It shows that the introduction of skip connections into network architectures, such as residual networks and dense networks, turns a system of static equations into a system of dynamical equations with varying levels of smoothness on the layer-wise transformations. Closed form solutions for the state space representations of general dense networks, as well as $k^{th}$ order smooth networks, are found in general settings. Furthermore, it is shown that imposing $k^{th}$ order smoothness on a network architecture with $d$-many nodes per layer increases the state space dimension by a multiple of $k$, and so the effective embedding dimension of the data manifold is $k \cdot d$-many dimensions. It follows that network architectures of these types reduce the number of parameters needed to maintain the same embedding dimension by a factor of $k^2$ when compared to an equivalent first-order, residual network, significantly motivating the development of network architectures of these types. Numerical simulations were run to validate parts of the developed theory.

Published
2018
Full Text
View/download PDF

35. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

Author

Nievergelt, Caroline M, Maihofer, Adam X, Klengel, Torsten, Atkinson, Elizabeth G, Chen, Chia-Yen, Choi, Karmel W, Coleman, Jonathan RI, Dalvie, Shareefa, Duncan, Laramie E, Gelernter, Joel, Levey, Daniel F, Logue, Mark W, Polimanti, Renato, Provost, Allison C, Ratanatharathorn, Andrew, Stein, Murray B, Torres, Katy, Aiello, Allison E, Almli, Lynn M, Amstadter, Ananda B, Andersen, Søren B, Andreassen, Ole A, Arbisi, Paul A, Ashley-Koch, Allison E, Austin, S Bryn, Avdibegovic, Esmina, Babić, Dragan, Bækvad-Hansen, Marie, Baker, Dewleen G, Beckham, Jean C, Bierut, Laura J, Bisson, Jonathan I, Boks, Marco P, Bolger, Elizabeth A, Børglum, Anders D, Bradley, Bekh, Brashear, Megan, Breen, Gerome, Bryant, Richard A, Bustamante, Angela C, Bybjerg-Grauholm, Jonas, Calabrese, Joseph R, Caldas-de-Almeida, José M, Dale, Anders M, Daly, Mark J, Daskalakis, Nikolaos P, Deckert, Jürgen, Delahanty, Douglas L, Dennis, Michelle F, Disner, Seth G, Domschke, Katharina, Dzubur-Kulenovic, Alma, Erbes, Christopher R, Evans, Alexandra, Farrer, Lindsay A, Feeny, Norah C, Flory, Janine D, Forbes, David, Franz, Carol E, Galea, Sandro, Garrett, Melanie E, Gelaye, Bizu, Geuze, Elbert, Gillespie, Charles, Uka, Aferdita Goci, Gordon, Scott D, Guffanti, Guia, Hammamieh, Rasha, Harnal, Supriya, Hauser, Michael A, Heath, Andrew C, Hemmings, Sian MJ, Hougaard, David Michael, Jakovljevic, Miro, Jett, Marti, Johnson, Eric Otto, Jones, Ian, Jovanovic, Tanja, Qin, Xue-Jun, Junglen, Angela G, Karstoft, Karen-Inge, Kaufman, Milissa L, Kessler, Ronald C, Khan, Alaptagin, Kimbrel, Nathan A, King, Anthony P, Koen, Nastassja, Kranzler, Henry R, Kremen, William S, Lawford, Bruce R, Lebois, Lauren AM, Lewis, Catrin E, Linnstaedt, Sarah D, Lori, Adriana, Lugonja, Bozo, Luykx, Jurjen J, Lyons, Michael J, Maples-Keller, Jessica, Marmar, Charles, and Martin, Alicia R

Subjects
Humans, Genetic Predisposition to Disease, Ubiquitin-Protein Ligases, Stress Disorders, Post-Traumatic, Sex Factors, African Continental Ancestry Group, European Continental Ancestry Group, Veterans, Female, Male, Genome-Wide Association Study, Genetic Loci, Datasets as Topic, Human Genome, Mental Health, Biotechnology, Clinical Research, Post-Traumatic Stress Disorder (PTSD), Anxiety Disorders, Prevention, Genetics
Abstract

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Published
2019

36. Association of a Primary Open-Angle Glaucoma Genetic Risk Score With Earlier Age at Diagnosis

Author

Fan, Bao Jian, Bailey, Jessica Cooke, Igo, Rob P, Kang, Jae H, Boumenna, Tahani, Brilliant, Murray H, Budenz, Donald L, Fingert, John H, Gaasterland, Terry, Gaasterland, Douglas, Hauser, Michael A, Kraft, Peter, Lee, Richard K, Lichter, Paul R, Liu, Yutao, Moroi, Syoko E, Myers, Jonathan S, Pericak-Vance, Margaret A, Realini, Anthony, Rhee, Douglas J, Richards, Julia E, Ritch, Robert, Schuman, Joel S, Scott, William K, Singh, Kuldev, Sit, Arthur J, Vollrath, Douglas, Weinreb, Robert N, Wollstein, Gadi, Zack, Donald J, Haines, Jonathan L, Pasquale, Louis R, and Wiggs, Janey L

Subjects
Neurosciences, Clinical Research, Human Genome, Eye Disease and Disorders of Vision, Neurodegenerative, Genetics, Aging, Prevention, 2.1 Biological and endogenous factors, Aetiology, Opthalmology and Optometry, Ophthalmology & Optometry
Abstract

ImportanceGenetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations.ObjectiveTo investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis.Design, setting, and participantsA cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018.Main outcomes and measuresAssociation of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression.ResultsThe GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10-66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = -0.36; 95% CI, -0.56 to -0.16; P = 4.0 × 10-4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10-4).Conclusions and relevanceA higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.

Published
2019

38. A genome-wide association study of suicide attempts in the million veterans program identifies evidence of pan-ancestry and ancestry-specific risk loci

Author

Kimbrel, Nathan A., Ashley-Koch, Allison E., Qin, Xue J., Lindquist, Jennifer H., Garrett, Melanie E., Dennis, Michelle F., Hair, Lauren P., Huffman, Jennifer E., Jacobson, Daniel A., Madduri, Ravi K., Trafton, Jodie A., Coon, Hilary, Docherty, Anna R., Kang, Jooeun, Mullins, Niamh, Ruderfer, Douglas M., Harvey, Philip D., McMahon, Benjamin H., Oslin, David W., Hauser, Elizabeth R., Hauser, Michael A., and Beckham, Jean C.

Published
2022
Full Text
View/download PDF

40. International Codes in the Prediction of Load-Bearing Capacity of Slender Columns

Author

Strauss, Alfred, Galvão, Neryvaldo, Matos, José C., Hauser, Michael, Tãubling, Benjamin, Soliman, Mohamed, Tamini, Mohammad, Ruan, Xin, Zhu, Lingfeng, Ishibashi, Hiroki, di Prisco, Marco, Series Editor, Chen, Sheng-Hong, Series Editor, Vayas, Ioannis, Series Editor, Kumar Shukla, Sanjay, Series Editor, Sharma, Anuj, Series Editor, Kumar, Nagesh, Series Editor, Wang, Chien Ming, Series Editor, Matos, José C., editor, Lourenço, Paulo B., editor, Oliveira, Daniel V., editor, Branco, Jorge, editor, Proske, Dirk, editor, Silva, Rui A., editor, and Sousa, Hélder S., editor

Published
2021
Full Text
View/download PDF

41. Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Author

Bonnemaijer, Pieter WM, Iglesias, Adriana I, Nadkarni, Girish N, Sanyiwa, Anna J, Hassan, Hassan G, Cook, Colin, GIGA Study Group, Simcoe, Mark, Taylor, Kent D, Schurmann, Claudia, Belbin, Gillian M, Kenny, Eimear E, Bottinger, Erwin P, van de Laar, Suzanne, Wiliams, Susan EI, Akafo, Stephen K, Ashaye, Adeyinka O, Zangwill, Linda M, Girkin, Christopher A, Ng, Maggie CY, Rotter, Jerome I, Weinreb, Robert N, Li, Zheng, Allingham, R Rand, Eyes of Africa Genetics Consortium, Nag, Abhishek, Hysi, Pirro G, Meester-Smoor, Magda A, Wiggs, Janey L, NEIGHBORHOOD Consortium, Hauser, Michael A, Hammond, Christopher J, Lemij, Hans G, Loos, Ruth JF, van Duijn, Cornelia M, Thiadens, Alberta AHJ, and Klaver, Caroline CW

Subjects
GIGA Study Group, Eyes of Africa Genetics Consortium, NEIGHBORHOOD Consortium, Humans, Glaucoma, Open-Angle, Vesicular Transport Proteins, Aged, Aged, 80 and over, Middle Aged, African Continental Ancestry Group, Female, Male, Thioredoxin Reductase 2, Genome-Wide Association Study, Genetic Loci, Neurodegenerative, Human Genome, Aging, Eye Disease and Disorders of Vision, Genetics, Neurosciences, 2.1 Biological and endogenous factors, Genetics & Heredity, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine
Abstract

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.

Published
2018

42. Genomic Approaches to Posttraumatic Stress Disorder: The Psychiatric Genomic Consortium Initiative

Author

Nievergelt, Caroline M, Ashley-Koch, Allison E, Dalvie, Shareefa, Hauser, Michael A, Morey, Rajendra A, Smith, Alicia K, and Uddin, Monica

Subjects
Biological Psychology, Biological Sciences, Genetics, Psychology, Mental Health, Human Genome, Anxiety Disorders, Biotechnology, Clinical Research, Prevention, Post-Traumatic Stress Disorder (PTSD), Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Epigenomics, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Stress Disorders, Post-Traumatic, Epigenetics, Gene expression, Imaging, Psychiatric Genomics Consortium, Systems biology, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences
Abstract

Posttraumatic stress disorder (PTSD) after exposure to a traumatic event is a highly prevalent psychiatric disorder. Heritability estimates from twin studies as well as from recent molecular data (single nucleotide polymorphism-based heritability) indicate moderate to high heritability, yet robust genetic variants for PTSD have not yet been identified and the genetic architecture of this polygenic disorder remains largely unknown. To date, fewer than 10 large-scale genome-wide association studies of PTSD have been published, with findings that highlight the unique challenges for PTSD genomics, including a complex diagnostic entity with contingency of PTSD diagnosis on trauma exposure and the large genetic diversity of the study populations. The Psychiatric Genomics Consortium PTSD group has brought together more than 200 scientists with the goal to increase sample size for genome-wide association studies and other genomic analyses to sufficient numbers where robust discoveries of molecular signatures can be achieved. The sample currently includes more than 32,000 PTSD cases and 100,000 trauma-exposed control subjects, and collection is ongoing. The first results found a significant shared genetic risk of PTSD with other psychiatric disorders and sex-biased heritability estimates with higher heritability in female individuals compared with male individuals. This review describes the scope and current focus of the Psychiatric Genomics Consortium PTSD group and its expansion from the initial genome-wide association study group to nine working groups, including epigenetics, gene expression, imaging, and integrative systems biology. We further briefly outline recent findings and future directions of "omics"-based studies of PTSD, with the ultimate goal of elucidating the molecular architecture of this complex disorder to improve prevention and intervention strategies.

Published
2018

43. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Author

Cooke Bailey, Jessica N, Gharahkhani, Puya, Kang, Jae H, Butkiewicz, Mariusz, Sullivan, David A, Weinreb, Robert N, Aschard, Hugues, Allingham, R Rand, Ashley-Koch, Allison, Lee, Richard K, Moroi, Sayoko E, Brilliant, Murray H, Wollstein, Gadi, Schuman, Joel S, Fingert, John H, Budenz, Donald L, Realini, Tony, Gaasterland, Terry, Scott, William K, Singh, Kuldev, Sit, Arthur J, Igo, Robert P, Song, Yeunjoo E, Hark, Lisa, Ritch, Robert, Rhee, Douglas J, Vollrath, Douglas, Zack, Donald J, Medeiros, Felipe, Vajaranant, Thasarat S, Chasman, Daniel I, Christen, William G, Pericak-Vance, Margaret A, Liu, Yutao, Kraft, Peter, Richards, Julia E, Rosner, Bernard A, Hauser, Michael A, Craig, Jamie E, Burdon, Kathryn P, Hewitt, Alex W, Mackey, David A, Haines, Jonathan L, MacGregor, Stuart, Wiggs, Janey L, and Pasquale, Louis R

Subjects
Genetics, Neurodegenerative, Aging, 2.1 Biological and endogenous factors, Aetiology, Datasets as Topic, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Glaucoma, Open-Angle, Humans, Intraocular Pressure, Low Tension Glaucoma, Male, Metabolic Networks and Pathways, Middle Aged, Polymorphism, Single Nucleotide, Testosterone, primary open-angle glaucoma, testosterone, genetics, pathway analysis, Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry
Abstract

Purpose:Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods:We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results:In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Published
2018

44. Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets.

Author

Bailey, Jessica N Cooke, Gharahkhani, Puya, Kang, Jae H, Butkiewicz, Mariusz, Sullivan, David A, Weinreb, Robert N, Aschard, Hugues, Allingham, R Rand, Ashley-Koch, Allison, Lee, Richard K, Moroi, Sayoko E, Brilliant, Murray H, Wollstein, Gadi, Schuman, Joel S, Fingert, John H, Budenz, Donald L, Realini, Tony, Gaasterland, Terry, Scott, William K, Singh, Kuldev, Sit, Arthur J, Igo, Robert P, Song, Yeunjoo E, Hark, Lisa, Ritch, Robert, Rhee, Douglas J, Vollrath, Douglas, Zack, Donald J, Medeiros, Felipe, Vajaranant, Thasarat S, Chasman, Daniel I, Christen, William G, Pericak-Vance, Margaret A, Liu, Yutao, Kraft, Peter, Richards, Julia E, Rosner, Bernard A, Hauser, Michael A, Craig, Jamie E, Burdon, Kathryn P, Hewitt, Alex W, Mackey, David A, Haines, Jonathan L, MacGregor, Stuart, Wiggs, Janey L, Pasquale, Louis R, and Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium

Subjects
Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium, Humans, Glaucoma, Open-Angle, Testosterone, Intraocular Pressure, Gene Frequency, Genotype, Polymorphism, Single Nucleotide, Middle Aged, Female, Male, Metabolic Networks and Pathways, Genome-Wide Association Study, Low Tension Glaucoma, Datasets as Topic, primary open-angle glaucoma, testosterone, genetics, pathway analysis, Glaucoma, Open-Angle, Polymorphism, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Ophthalmology & Optometry
Abstract

Purpose:Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods:We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results:In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Published
2018

45. Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma.

Author

King, Rebecca, Struebing, Felix L, Li, Ying, Wang, Jiaxing, Koch, Allison Ashley, Cooke Bailey, Jessica N, Gharahkhani, Puya, International Glaucoma Genetics Consortium, NEIGHBORHOOD Consortium, MacGregor, Stuart, Allingham, R Rand, Hauser, Michael A, Wiggs, Janey L, and Geisert, Eldon E

Subjects
International Glaucoma Genetics Consortium, NEIGHBORHOOD Consortium, Retinal Ganglion Cells, Cornea, Cells, Cultured, Animals, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Humans, Mice, Glaucoma, Disease Models, Animal, Genetic Predisposition to Disease, Risk Factors, Chromosome Mapping, Apoptosis, Pregnancy, Polymorphism, Single Nucleotide, Female, Male, POU Domain Factors, Embryo, Mammalian, Genome-Wide Association Study, Genetic Loci, Corneal Pachymetry, Cells, Cultured, Disease Models, Animal, Embryo, Mammalian, Inbred C57BL, Inbred DBA, Transgenic, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.

Published
2018

46. Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis

Author

Aschard, Hugues, Kang, Jae H, Iglesias, Adriana I, Hysi, Pirro, Cooke Bailey, Jessica N, Khawaja, Anthony P, Allingham, R Rand, Ashley-Koch, Allison, Lee, Richard K, Moroi, Sayoko E, Brilliant, Murray H, Wollstein, Gadi, Schuman, Joel S, Fingert, John H, Budenz, Donald L, Realini, Tony, Gaasterland, Terry, Scott, William K, Singh, Kuldev, Sit, Arthur J, Igo Jr, Robert P, Song, Yeunjoo E, Hark, Lisa, Ritch, Robert, Rhee, Douglas J, Gulati, Vikas, Haven, Shane, Vollrath, Douglas, Zack, Donald J, Medeiros, Felipe, Weinreb, Robert N, Cheng, Ching-Yu, Chasman, Daniel I, Christen, William G, Pericak-Vance, Margaret A, Liu, Yutao, Kraft, Peter, Richards, Julia E, Rosner, Bernard A, Hauser, Michael A, Klaver, Caroline CW, vanDuijn, Cornelia M, Haines, Jonathan, Wiggs, Janey L, and Pasquale, Louis R

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Ophthalmology and Optometry, Eye Disease and Disorders of Vision, Human Genome, Aging, Neurodegenerative, Neurosciences, Blood Pressure, Female, Genetic Predisposition to Disease, Glaucoma, Open-Angle, Humans, Intraocular Pressure, Linkage Disequilibrium, Male, International Glaucoma Genetics Consortium, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10-27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10-5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.

Published
2017

47. Thermodynamic-Mechanical Modeling of Metastable High Alloy Austenitic CrMnNi Steels

Author

Hauser, Michael, Wendler, Marco, Mola, Javad, Fabrichnaya, Olga, Volkova, Olena, Weiß, Andreas, Hull, Robert, Series Editor, Jagadish, Chennupati, Series Editor, Kawazoe, Yoshiyuki, Series Editor, Kruzic, Jamie, Series Editor, Osgood, Richard M., Series Editor, Parisi, Jürgen, Series Editor, Pohl, Udo W., Series Editor, Seong, Tae-Yeon, Series Editor, Uchida, Shin-ichi, Series Editor, Wang, Zhiming M., Series Editor, Biermann, Horst, editor, and Aneziris, Christos G., editor

Published
2020
Full Text
View/download PDF

49. Epigenome‐wide association of PTSD from heterogeneous cohorts with a common multi‐site analysis pipeline

Author

Ratanatharathorn, Andrew, Boks, Marco P, Maihofer, Adam X, Aiello, Allison E, Amstadter, Ananda B, Ashley‐Koch, Allison E, Baker, Dewleen G, Beckham, Jean C, Bromet, Evelyn, Dennis, Michelle, Garrett, Melanie E, Geuze, Elbert, Guffanti, Guia, Hauser, Michael A, Kilaru, Varun, Kimbrel, Nathan A, Koenen, Karestan C, Kuan, Pei‐Fen, Logue, Mark W, Luft, Benjamin J, Miller, Mark W, Mitchell, Colter, Nugent, Nicole R, Ressler, Kerry J, Rutten, Bart PF, Stein, Murray B, Vermetten, Eric, Vinkers, Christiaan H, Youssef, Nagy A, Workgroup, VA Mid‐Atlantic MIRECC, Workgroup, PGC PTSD Epigenetics, Uddin, Monica, Nievergelt, Caroline M, and Smith, Alicia K

Subjects
Human Genome, Genetics, Post-Traumatic Stress Disorder (PTSD), Mental Health, Anxiety Disorders, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Adult, Cohort Studies, DNA Methylation, Epigenomics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Male, Middle Aged, Phenotype, Stress Disorders, Post-Traumatic, EWAS, meta-analysis, stress, trauma, VA Mid-Atlantic MIRECC Workgroup, PGC PTSD Epigenetics Workgroup, Clinical Sciences, Neurosciences
Abstract

Compelling evidence suggests that epigenetic mechanisms such as DNA methylation play a role in stress regulation and in the etiologic basis of stress related disorders such as Post traumatic Stress Disorder (PTSD). Here we describe the purpose and methods of an international consortium that was developed to study the role of epigenetics in PTSD. Inspired by the approach used in the Psychiatric Genomics Consortium, we brought together investigators representing seven cohorts with a collective sample size of N = 1147 that included detailed information on trauma exposure, PTSD symptoms, and genome-wide DNA methylation data. The objective of this consortium is to increase the analytical sample size by pooling data and combining expertise so that DNA methylation patterns associated with PTSD can be identified. Several quality control and analytical pipelines were evaluated for their control of genomic inflation and technical artifacts with a joint analysis procedure established to derive comparable data over the cohorts for meta-analysis. We propose methods to deal with ancestry population stratification and type I error inflation and discuss the advantages and disadvantages of applying robust error estimates. To evaluate our pipeline, we report results from an epigenome-wide association study (EWAS) of age, which is a well-characterized phenotype with known epigenetic associations. Overall, while EWAS are highly complex and subject to similar challenges as genome-wide association studies (GWAS), we demonstrate that an epigenetic meta-analysis with a relatively modest sample size can be well-powered to identify epigenetic associations. Our pipeline can be used as a framework for consortium efforts for EWAS.

Published
2017

50. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

Author

Aung, Tin, Ozaki, Mineo, Lee, Mei, Schlötzer-Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert, Haripriya, Aravind, Williams, Susan, Astakhov, Yury, Orr, Andrew, Burdon, Kathryn, Nakano, Satoko, Mori, Kazuhiko, Abu-Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica, Cherecheanu, Alina, Kang, Jae, Nelson, Sarah, Hayashi, Ken, Manabe, Shin-Ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca-Prados, Miguel, Sugiyama, Kazuhisa, Järvelä, Irma, Schlottmann, Patricio, Lerner, S, Lamari, Hasnaa, Nilgün, Yildirim, Bikbov, Mukharram, Park, Ki, Cha, Soon, Yamashiro, Kenji, Zenteno, Juan, Jonas, Jost, Kumar, Rajesh, Perera, Shamira, Chan, Anita, Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak, de Juan Marcos, Lourdes, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach-Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda, Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya-Xing, Xu, Liang, Leruez, Stéphanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthias, Berner, Daniel, Mossböck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge-Luessen, Ulrich-Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofanis, Anastasopoulos, Eleftherios, Lambropoulos, Alexandros, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan, Beni, Afsaneh, and Yazdani, Shahin

Subjects
Aged, 80 and over, Alleles, Amino Acid Oxidoreductases, Amino Acid Substitution, Asian People, Calcium Channels, Cell Adhesion, Exfoliation Syndrome, Extracellular Matrix, Eye, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, Male, Molecular Chaperones, Mutation, Missense, Point Mutation, RNA, Messenger, Spheroids, Cellular
Abstract

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017

Catalog

Books, media, physical & digital resources
See catalog results