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1. Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms

Author

Schmidt, Andreas W., Kühnapfel, Andreas, Kirsten, Holger, Grallert, Harald, Hellerbrand, Claus, Kiefer, Falk, Mann, Karl, Mueller, Sebastian, Nöthen, Markus M., Peters, Annette, Ridinger, Monika, Frank, Josef, Rietschel, Marcella, Soranzo, Nicole, Soyka, Michael, Wodarz, Norbert, Malerba, Giovanni, Gambaro, Giovanni, Gieger, Christian, Scholz, Markus, Krug, Sebastian, Michl, Patrick, Ewers, Maren, Witt, Heiko, Laumen, Helmut, and Rosendahl, Jonas

Published
2022
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2. A large-scale genome-wide association study meta-analysis of cannabis use disorder

Author

Walters, Raymond, Polimanti, Renato, Johnson, Emma, McClintick, Jeanette, Hatoum, Alexander, He, June, Wendt, Frank, Zhou, Hang, Adams, Mark, Adkins, Amy, Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna, Bigdeli, Tim, Chen, Li-Shiun, Clarke, Toni-Kim, Chou, Yi-Ling, Degenhardt, Franziska, Docherty, Anna, Edwards, Alexis, Fontanillas, Pierre, Foo, Jerome, Fox, Louis, Frank, Josef, Giegling, Ina, Gordon, Scott, Hack, Laura, Hartmann, Annette, Hartz, Sarah, Heilmann-Heimbach, Stefanie, Herms, Stefan, Hodgkinson, Colin, Hoffman, Per, Hottenga, Jouke, Kennedy, Martin, Alanne-Kinnunen, Mervi, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion, Mbarek, Hamdi, McIntosh, Andrew, McQueen, Matthew, Meyers, Jacquelyn, Milaneschi, Yuri, Palviainen, Teemu, Pearson, John, Peterson, Roseann, Ripatti, Samuli, Ryu, Euijung, Saccone, Nancy, Salvatore, Jessica, Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley, Wedow, Robbee, Wetherill, Leah, Wills, Amanda, Boardman, Jason, Chen, Danfeng, Choi, Doo-Sup, Copeland, William, Culverhouse, Robert, Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin, Elson, Sarah, Frye, Mark, Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael, Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison, Nurnberger, John, Palotie, Aarno, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc, Soyka, Michael, Treutlein, Jens, Witt, Stephanie, Wodarz, Norbert, Zill, Peter, Adkins, Daniel, Boden, Joseph, Boomsma, Dorret, Bierut, Laura, Brown, Sandra, Bucholz, Kathleen, Cichon, Sven, Costello, E. Jane, de Wit, Harriet, Diazgranados, Nancy, Dick, Danielle, Eriksson, Johan, Farrer, Lindsay, Foroud, Tatiana, Gillespie, Nathan, Goate, Alison, Goldman, David, Grucza, Richard, Hancock, Dana, Harris, Kathleen Mullan, Heath, Andrew, Hesselbrock, Victor, Hewitt, John, Hopfer, Christian, Horwood, John, Iacono, William, Johnson, Eric, Kaprio, Jaakko, Karpyak, Victor, Kendler, Kenneth, Kranzler, Henry, Krauter, Kenneth, Lichtenstein, Paul, Lind, Penelope, McGue, Matt, MacKillop, James, Madden, Pamela, Maes, Hermine, Magnusson, Patrik, Martin, Nicholas, Medland, Sarah, Montgomery, Grant, Nelson, Elliot, Nöthen, Markus, Palmer, Abraham, Pederson, Nancy, Penninx, Brenda, Porjesz, Bernice, Rice, John, Rietschel, Marcella, Riley, Brien, Rose, Richard, Rujescu, Dan, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael, Tarter, Ralph, Vanyukov, Michael, Vrieze, Scott, Wall, Tamara, Whitfield, John, Zhao, Hongyu, Neale, Benjamin, Gelernter, Joel, Edenberg, Howard, Agrawal, Arpana, Johnson, Emma C, Demontis, Ditte, Thorgeirsson, Thorgeir E, Walters, Raymond K, Hatoum, Alexander S, Paul, Sarah E, Wendt, Frank R, Reginsson, Gunnar W, Baranger, David A A, Gudbjartsson, Daniel F, Adkins, Daniel E, Adkins, Amy E, Alexander, Jeffry, Bigdeli, Tim B, Brown, Sandra A, Bucholz, Kathleen K, Bybjerg-Grauholm, Jonas, Corley, Robin P, Dick, Danielle M, Domingue, Benjamin W, Goate, Alison M, Gordon, Scott D, Hack, Laura M, Hancock, Dana B, Hartz, Sarah M, Hickie, Ian B, Hougaard, David M, Lind, Penelope A, McClintick, Jeanette N, McQueen, Matthew B, Meyers, Jacquelyn L, Montgomery, Grant W, Mors, Ole, Mortensen, Preben B, Nordentoft, Merete, Pearson, John F, Peterson, Roseann E, Reynolds, Maureen D, Rice, John P, Runarsdottir, Valgerdur, Saccone, Nancy L, Silberg, Judy L, Tarter, Ralph E, Tyrfingsson, Thorarinn, Wall, Tamara L, Webb, Bradley T, Werge, Thomas, Wright, Margaret J, Zellers, Stephanie, Adams, Mark J, Bierut, Laura J, Boardman, Jason D, Copeland, William E, Farrer, Lindsay A, Foroud, Tatiana M, Gillespie, Nathan A, Grucza, Richard A, Heath, Andrew C, Hewitt, John K, Hopfer, Christian J, Iacono, William G, Johnson, Eric O, Kendler, Kenneth S, Kennedy, Martin A, Kranzler, Henry R, Madden, Pamela A F, Maes, Hermine H, Maher, Brion S, Martin, Nicholas G, McGue, Matthew, McIntosh, Andrew M, Medland, Sarah E, Nelson, Elliot C, Riley, Brien P, Stallings, Michael C, Vanyukov, Michael M, Davis, Lea K, Bogdan, Ryan, Edenberg, Howard J, Stefansson, Kari, and Børglum, Anders D

Published
2020
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3. Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Author

Walters, Raymond K., Polimanti, Renato, Johnson, Emma C., McClintick, Jeanette N., Adams, Mark J., Adkins, Amy E., Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna M., Bigdeli, Tim B., Chen, Li-Shiun, Clarke, Toni-Kim, Chou, Yi-Ling, Degenhardt, Franziska, Docherty, Anna R., Edwards, Alexis C., Fontanillas, Pierre, Foo, Jerome C., Fox, Louis, Frank, Josef, Giegling, Ina, Gordon, Scott, Hack, Laura M., Hartmann, Annette M., Hartz, Sarah M., Heilmann-Heimbach, Stefanie, Herms, Stefan, Hodgkinson, Colin, Hoffmann, Per, Jan Hottenga, Jouke, Kennedy, Martin A., Alanne-Kinnunen, Mervi, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Lai, Dongbing, Ligthart, Lannie, Loukola, Anu, Maher, Brion S., Mbarek, Hamdi, McIntosh, Andrew M., McQueen, Matthew B., Meyers, Jacquelyn L., Milaneschi, Yuri, Palviainen, Teemu, Pearson, John F., Peterson, Roseann E., Ripatti, Samuli, Ryu, Euijung, Saccone, Nancy L., Salvatore, Jessica E., Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley T., Wedow, Robbee, Wetherill, Leah, Wills, Amanda G., 23andMe Research Team, Boardman, Jason D., Chen, Danfeng, Choi, Doo-Sup, Copeland, William E., Culverhouse, Robert C., Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W., Elson, Sarah L., Frye, Mark A., Gäbel, Wolfgang, Hayward, Caroline, Ising, Marcus, Keyes, Margaret, Kiefer, Falk, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T., Maier, Wolfgang, Mann, Karl, Männistö, Satu, Müller-Myhsok, Bertram, Murray, Alison D., Nurnberger, John I., Palotie, Aarno, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D, Ridinger, Monika, Scherbaum, Norbert, Schuckit, Marc A., Soyka, Michael, Treutlein, Jens, Witt, Stephanie, Wodarz, Norbert, Zill, Peter, Adkins, Daniel E., Boden, Joseph M., Boomsma, Dorret I., Bierut, Laura J., Brown, Sandra A., Bucholz, Kathleen K., Cichon, Sven, Costello, E. Jane, de Wit, Harriet, Diazgranados, Nancy, Dick, Danielle M., Eriksson, Johan G., Farrer, Lindsay A., Foroud, Tatiana M., Gillespie, Nathan A., Goate, Alison M., Goldman, David, Grucza, Richard A., Hancock, Dana B., Harris, Kathleen Mullan, Heath, Andrew C., Hesselbrock, Victor, Hewitt, John K., Hopfer, Christian J., Horwood, John, Iacono, William, Johnson, Eric O., Kaprio, Jaakko A., Karpyak, Victor M., Kendler, Kenneth S., Kranzler, Henry R., Krauter, Kenneth, Lichtenstein, Paul, Lind, Penelope A., McGue, Matt, MacKillop, James, Madden, Pamela A. F., Maes, Hermine H., Magnusson, Patrik, Martin, Nicholas G., Medland, Sarah E., Montgomery, Grant W., Nelson, Elliot C., Nöthen, Markus M., Palmer, Abraham A., Pedersen, Nancy L., Penninx, Brenda W. J. H., Porjesz, Bernice, Rice, John P., Rietschel, Marcella, Riley, Brien P., Rose, Richard, Rujescu, Dan, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael C., Tarter, Ralph E., Vanyukov, Michael M., Vrieze, Scott, Wall, Tamara L., Whitfield, John B., Zhao, Hongyu, Neale, Benjamin M., Gelernter, Joel, Edenberg, Howard J., and Agrawal, Arpana

Published
2018
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4. Shared genetic etiology between alcohol dependence and major depressive disorder

Author

Foo, Jerome C., Streit, Fabian, Treutlein, Jens, Ripke, Stephan, Witt, Stephanie H., Strohmaier, Jana, Degenhardt, Franziska, Forstner, Andreas J., Hoffmann, Per, Soyka, Michael, Dahmen, Norbert, Scherbaum, Norbert, Wodarz, Norbert, Heilmann-Heimbach, Stefanie, Herms, Stefan, Cichon, Sven, Preuss, Ulrich, Gaebel, Wolfgang, Ridinger, Monika, Hoffmann, Sabine, Schulze, Thomas G., Maier, Wolfgang, Zill, Peter, Müller-Myhsok, Bertram, Ising, Marcus, Lucae, Susanne, Nöthen, Markus M., Mann, Karl, Kiefer, Falk, Rietschel, Marcella, and Frank, Josef

Published
2018
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5. Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts

Author

Schwantes-An, Tae-Hwi, Zhang, Juan, Chen, Li-Shiun, Hartz, Sarah M., Culverhouse, Robert C., Chen, Xiangning, Coon, Hilary, Frank, Josef, Kamens, Helen M., Konte, Bettina, Kovanen, Leena, Latvala, Antti, Legrand, Lisa N., Maher, Brion S., Melroy, Whitney E., Nelson, Elliot C., Reid, Mark W., Robinson, Jason D., Shen, Pei-Hong, Yang, Bao-Zhu, Andrews, Judy A., Aveyard, Paul, Beltcheva, Olga, Brown, Sandra A., Cannon, Dale S., Cichon, Sven, Corley, Robin P., Dahmen, Norbert, Degenhardt, Louisa, Foroud, Tatiana, Gaebel, Wolfgang, Giegling, Ina, Glatt, Stephen J., Grucza, Richard A., Hardin, Jill, Hartmann, Annette M., Heath, Andrew C., Herms, Stefan, Hodgkinson, Colin A., Hoffmann, Per, Hops, Hyman, Huizinga, David, Ising, Marcus, Johnson, Eric O., Johnstone, Elaine, Kaneva, Radka P., Kendler, Kenneth S., Kiefer, Falk, Kranzler, Henry R., Krauter, Ken S., Levran, Orna, Lucae, Susanne, Lynskey, Michael T., Maier, Wolfgang, Mann, Karl, Martin, Nicholas G., Mattheisen, Manuel, Montgomery, Grant W., Müller-Myhsok, Bertram, Murphy, Michael F., Neale, Michael C., Nikolov, Momchil A., Nishita, Denise, Nöthen, Markus M., Nurnberger, John, Partonen, Timo, Pergadia, Michele L., Reynolds, Maureen, Ridinger, Monika, Rose, Richard J., Rouvinen-Lagerström, Noora, Scherbaum, Norbert, Schmäl, Christine, Soyka, Michael, Stallings, Michael C., Steffens, Michael, Treutlein, Jens, Tsuang, Ming, Wall, Tamara L., Wodarz, Norbert, Yuferov, Vadim, Zill, Peter, Bergen, Andrew W., Chen, Jingchun, Cinciripini, Paul M., Edenberg, Howard J., Ehringer, Marissa A., Ferrell, Robert E., Gelernter, Joel, Goldman, David, Hewitt, John K., Hopfer, Christian J., Iacono, William G., Kaprio, Jaakko, Kreek, Mary Jeanne, Kremensky, Ivo M., Madden, Pamela A.F., McGue, Matt, Munafò, Marcus R., Philibert, Robert A., Rietschel, Marcella, Roy, Alec, Rujescu, Dan, Saarikoski, Sirkku T., Swan, Gary E., Todorov, Alexandre A., Vanyukov, Michael M., Weiss, Robert B., Bierut, Laura J., and Saccone, Nancy L.

Published
2016
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7. A genome-wide association study of alcohol dependence

Author

Bierut, Laura J., Agrawal, Arpana, Bucholz, Kathleen K., Doheny, Kimberly F., Laurie, Cathy, Pugh, Elizabeth, Fisher, Sherri, Fox, Louis, Howells, William, Bertelsen, Sarah, Hinrichs, Anthony L., Almasy, Laura, Breslau, Naomi, Culverhouse, Robert C., Dick, Danielle M., Edenberg, Howard J., Foroud, Tatiana, Grucza, Richard A., Hatsukami, Dorothy, Hesselbrock, Victor, Johnson, Eric O., Kramer, John, Krueger, Robert F., Kuperman, Samuel, Lynskey, Michael, Mann, Karl, Neuman, Rosalind J., Nöthen, Markus M., Nurnberger,, John I., Porjesz, Bernice, Ridinger, Monika, Saccone, Nancy L., Saccone, Scott F., Schuckit, Marc A., Tischfield, Jay A., Wang, Jen C., Rietschel, Marcella, Goate, Alison M., Rice, John P., and King, Mary-Claire

Published
2010
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8. Genome-wide association study of alcohol dependence

Author

Treutlein, Jens, Cichon, Sven, Ridinger, Monika, Wodarz, Norbert, Soyka, Michael, Zill, Peter, Maier, Wolfgang, Moessner, Rainald, Gaebel, Wolfgang, Dahmen, Norbert, Fehr, Christoph, Scherbaum, Norbert, Steffens, Michael, Ludwig, Kerstin U., Frank, Josef, Wichmann, H. Erich, Schreiber, Stefan, Dragano, Nico, Sommer, Wolfgang H., Leonardi-Essmann, Fernando, Lourdusamy, Anbarasu, Gebicke-Haerter, Peter, Wienker, Thomas F., Sullivan, Patrick F., Nothen, Markus M., Kiefer, Falk, Spanagel, Rainer, Mann, Karl, and Rietschel, Marcella

Subjects
Alcoholism -- Genetic aspects, Disease susceptibility -- Research, Genetic polymorphisms -- Research, Health, Psychology and mental health, World Health Organization -- Reports
Published
2009

10. Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster

Author

Frank, Josef, Cichon, Sven, Treutlein, Jens, Ridinger, Monika, Mattheisen, Manuel, Hoffmann, Per, Herms, Stefan, Wodarz, Norbert, Soyka, Michael, Zill, Peter, Maier, Wolfgang, Mössner, Rainald, Gaebel, Wolfgang, Dahmen, Norbert, Scherbaum, Norbert, Schmäl, Christine, Steffens, Michael, Lucae, Susanne, Ising, Marcus, Müller-Myhsok, Bertram, Nöthen, Markus M., Mann, Karl, Kiefer, Falk, and Rietschel, Marcella

Published
2012
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12. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians

Author

Stickel, Felix, Buch, Stephan, Lau, Katharina, zu Schwabedissen, Henriette Meyer, Berg, Thomas, Ridinger, Monika, Rietschel, Marcella, Schafmayer, Clemens, Braun, Felix, Hinrichsen, Holger, Günther, Rainer, Arlt, Alexander, Seeger, Marcus, Müller, Sebastian, Seitz, Helmut Karl, Soyka, Michael, Lerch, Markus, Lammert, Frank, Sarrazin, Christoph, Kubitz, Ralf, Häussinger, Dieter, Hellerbrand, Claus, Bröring, Dieter, Schreiber, Stefan, Kiefer, Falk, Spanagel, Rainer, Mann, Karl, Datz, Christian, Krawczak, Michael, Wodarz, Norbert, Völzke, Henry, and Hampe, Jochen

Published
2011
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13. Trans-ancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Author

Walters, Raymond K., Adams, Mark J., Adkins, Amy E., Aliev, Fazil, Bacanu, Silviu-Alin, Batzler, Anthony, Bertelsen, Sarah, Biernacka, Joanna, Bigdeli, Tim B., Chen, Li-Shiun, Clarke, Toni-Kim, Chou, Yi-Ling, Degenhardt, Franziska, Docherty, Anna R., Fontanillas, Pierre, Foo, Jerome, Fox, Louis, Frank, Josef, Giegling, Ina, Gordon, Scott, Hack, Laura M., Hartmann, Annette M., Hartz, Sarah M., Heilmann-Heimbach, Stefanie, Herms, Stefan, Hodgkinson, Colin, Hoffmann, Per, Hottenga, Jouke-Jan, Kennedy, Martin A., Alanne-Kinnunen, Mervi, Konte, Bettina, Lahti, Jari, Lahti-Pulkkinen, Marius, Ligthart, Lannie, Loukola, Anu-Maria, Maher, Brion S., Mbarek, Hamdi, McIntosh, Andrew M., McQueen, Matthew B., Milaneschi, Yuri, Palviainen, Teemu, Pearson, John F., Peterson, Roseann E., Polimanti, Renato, Ripatti, Samuli, Ryu, Euijung, Saccone, Nancy L., Salvatore, Jessica E., Sanchez-Roige, Sandra, Schwandt, Melanie, Sherva, Richard, Streit, Fabian, Strohmaier, Jana, Thomas, Nathaniel, Wang, Jen-Chyong, Webb, Bradley T., Wedow, Robbee, Wetherill, Leah, Wills, Amanda G., Boardman, Jason D., Chen, Danfeng, Choi, Doo-Sup, Copeland, William E., Culverhouse, Robert C., Dahmen, Norbert, Degenhardt, Louisa, Domingue, Benjamin W., Elson, Sarah L., Frye, Mark, Gäbel, Wolfgang, Ising, Marcus, Johnson, Emma C., Keyes, Margaret, Kiefer, Falk, Kramer, John, Kuperman, Samuel, Lucae, Susanne, Lynskey, Michael T., Maier, Wolfgang, Mann, Karl, Männistö, Satu, McClintick, Jeanette Nance, Meyers, Jacquelyn L., Müller-Myhsok, Bertram, Nurnberger, John I., Palotie, Aarno, Preuss, Ulrich, Räikkönen, Katri, Reynolds, Maureen D., Ridinger, Monika, Scherbaum, Norbert, Shuckit, Marc, Soyka, Michael, Treutlein, Jens, Witt, Stephanie, Wodarz, Norbert, Zill, Peter, Adkins, Daniel E., Boden, Joseph M., Boomsma, Dorret, Bierut, Laura J, Brown, Sandra A., Bucholz, Kathleen K., Cichon, Sven, Costello, E. Jane, de Wit, Harriet, Diazgranados, Nancy, Dick, Danielle M., Eriksson, Johan G., Farrer, Lindsay A., Foroud, Tatiana M., Gillespie, Nathan A., Goate, Alison A., Goldman, David, Grucza, Richard A., Hancock, Dana B., Harris, Kathleen Mullan, Heath, Andrew C., Hesselbrock, Victor, Hewitt, John K., Hopfer, Christian, Horwood, John, Iacono, William, Johnson, Eric O., Kaprio, Jaakko A., Karpyak, Victor, Kendler, Kenneth S., Kranzler, Henry R., Krauter, Kenneth, Lichtenstein, Paul, Lind, Penelope A., McGue, Matt, MacKillop, James, Madden, Pamela A.F., Maes, Hermine, Magnusson, Patrik, Martin, Nicholas G., Medland, Sarah E., Montgomery, Grant W., Nelson, Elliot C., Nöthen, Markus, Palmer, Abraham A., Pedersen, Nancy L., Penninx, Brenda W.J.H., Porjesz, Bernice, Rice, John P., Rietschel, Marcella, Riley, Brien P., Rose, Richard, Rujescu, Dan, Shen, Pei-Hong, Silberg, Judy, Stallings, Michael C., Tarter, Ralph E., Vanyukov, Michael M., Vrieze, Scott, Wall, Tamara L., Whitfield, John B., Zhao, Hongyu, Neale, Benjamin M., Gelernter, Joel, Edenberg, Howard J., and Agrawal, Arpana

Subjects
0303 health sciences, medicine.medical_specialty, biology, Genetic genealogy, Alcohol dependence, ADH1B, Genome-wide association study, biology.organism_classification, medicine.disease, Genetic correlation, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Schizophrenia, medicine, Cannabis, Psychiatry, 030217 neurology & neurosurgery, Depression (differential diagnoses), 030304 developmental biology
Abstract

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM - IV diagnosed AD. Genome - wide data on 14,904 individuals with AD and 37,944 controls from 28 case / control and family - based studies were meta - analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome - wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E - 13) and African ancestries (rs2066702; p = 2.2E - 9). Significant genetic correlations were observed with schizophrenia, ADHD, depression, and use of cigarettes and cannabis. There was only modest genetic correlation with alcohol consumption and inconsistent associations with problem drinking. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non - pathological drinking behaviors.

Published
2018
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14. Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms

Author

Adkins, Amy E, Hack, Laura M, Raabe, Richard C, Alaimo, Joseph T, Blackwell, GinaMari G, Moscati, Arden, Poland, Ryan S, Rood, Benjamin, Patterson, Diana G, Walsh, Dermot, Consortium, Collaborative Study of the Genetics of Alcoholism, Whitfield, John B, Bigdeli, Tim B, Zhu, Gu, Montgomery, Grant W, Henders, Anjali K, Martin, Nicholas G, Heath, Andrew C, Madden, Pamela A F, Frank, Josef, Ridinger, Monika, Wodarz, Norbert, Soyka, Michael, Williamson, Vernell S, Zill, Peter, Ising, Marcus, Nöthen, Markus M, Kiefer, Falk, Rietschel, Marcella, Consortium, German Study of the Genetics of Addiction, Gelernter, Joel, Sherva, Richard, Koesterer, Ryan, Almasy, Laura, McMichael, G Omari, Zhao, Hongyu, Kranzler, Henry R, Farrer, Lindsay A, Maher, Brion S, Prescott, Carol A, Dick, Danielle M, Bacanu, Silviu A, Mathies, Laura D, Davies, Andrew G, Vladimirov, Vladimir I, Mamdani, Mohammed, Grotewiel, Mike, Bowers, M Scott, Bettinger, Jill C, Webb, Bradley T, Miles, Michael F, Kendler, Kenneth S, Riley, Brien P, Hesselbrock, Victor, Bauer, Lance, Chan, Grace, Edwards, Alexis C, Edenberg, Howard J, Xuei, Xiaoling, Nurnberger, John, O'Connor, Sean, Foroud, Tatiana, Koller, Daniel L, Wetherill, Leah, Kuperman, Samuel, Kramer, John, Porjesz, Bernice, Aliev, Fazil, Kang, Sun J, Manz, Niklas, Rangaswamy, Madhavi, Bierut, Laura, Rice, John, Bucholz, Kathleen, Rohrbaugh, John W, Wang, Jen C, Goate, Alison, Schuckit, Marc, Chan, Robin F, Tischfield, Jay, Brooks, Andrew, Taylor, Robert E, Cichon, Sven, Treutlein, Jens, Mattheisen, Manuel, Hoffmann, Per, Herms, Stefan, Maier, Wolfgang, Mössner, Rainald, Bhandari, Poonam, Degenhardt, Franziska, Gaebel, Wolfgang, Dahmen, Norbert, Scherbaum, Norbert, Schmäl, Christine, Steffens, Michael, Lucae, Susanne, Müller-Myhsok, Bertram, Mann, Karl, and Scherbaum, Norbert (Beitragende*r)

Subjects
0301 basic medicine, Male, epidemiology [Alcoholism], ved/biology.organism_classification_rank.species, Medizin, Medicine (miscellaneous), Genome-wide association study, Toxicology, methods [Genome-Wide Association Study], Mice, 0302 clinical medicine, Gene expression, epidemiology [Ireland], drug effects [Genetic Loci], genetics [Genetic Predisposition to Disease], Genetics, Gene knockdown, education.field_of_study, diagnosis [Alcoholism], Middle Aged, Psychiatry and Mental health, Alcoholism, Mice, Inbred DBA, epidemiology [Genetic Predisposition to Disease], Models, Animal, Drosophila, Female, Adult, animal structures, Population, genetics [Genetic Loci], Biology, Article, 03 medical and health sciences, Animals, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Model organism, education, Caenorhabditis elegans, Gene, Loss function, Ethanol, ved/biology, Rats, Mice, Inbred C57BL, 030104 developmental biology, genetics [Alcoholism], Genetic Loci, Case-Control Studies, Ireland, 030217 neurology & neurosurgery, Genome-Wide Association Study, administration & dosage [Ethanol]
Abstract

Background: Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. Methods: We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue. Results: We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C.elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C.elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc). Conclusions: We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.

Published
2017
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15. aCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

Author

Easton, Alanna C, Lucchesi, Walter, Lourdusamy, Anbarasu, Lenz, Bernd, Solati, Jalal, Golub, Yulia, Lewczuk, Piotr, Fernandes, Cathy, Desrivieres, Sylvane, Dawirs, Ralph R, Moll, Gunther H, Kornhuber, Johannes, Frank, Josef, Hoffmann, Per, Soyka, Michael, Kiefer, Falk, Schumann, Gunter, Peter Giese, K, Müller, Christian P, Treutlein, Jens, Cichon, Sven, Ridinger, Monika, Mattheisen, Manuel, Herms, Stefan, Wodarz, Norbert, Zill, Peter, Maier, Wolfgang, Mössner, Rainald, Gaebel, Wolfgang, Dahmen, Norbert, Scherbaum, Norbert, Schmäl, Christine, Steffens, Michael, Lucae, Susanne, Ising, Marcus, Müller-Myhsok, Bertram, Nöthen, Markus M, Mann, Karl, and Rietschel, Marcella

Subjects
Male, Dopamine, Medizin, Poison control, Alcohol, Pharmacology, Nucleus Accumbens, Mice, chemistry.chemical_compound, 0302 clinical medicine, Hypnotics and Sedatives, Medicine, Phosphorylation, 0303 health sciences, education.field_of_study, Autophosphorylation, Ventral tegmental area, Neuropsychopharmacology, Alcoholism, Psychiatry and Mental health, medicine.anatomical_structure, Original Article, Female, Corrigendum, medicine.drug, Serotonin, Alcohol Drinking, Population, Prefrontal Cortex, Nucleus accumbens, Motor Activity, Polymorphism, Single Nucleotide, 03 medical and health sciences, Animals, Humans, Genetic Predisposition to Disease, education, 030304 developmental biology, Ethanol, Dose-Response Relationship, Drug, business.industry, Alcohol dependence, Ventral Tegmental Area, Behavior, Addictive, chemistry, Case-Control Studies, Calcium-Calmodulin-Dependent Protein Kinase Type 2, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

The α-Ca(2+)/calmodulin-dependent protein kinase II (αCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of αCaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of αCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in αCaMKII autophosphorylation-deficient αCaMKII(T286A) mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in αCaMKII(T286A) mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that αCaMKII(T286A) mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in αCaMKII(T286A) mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest αCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.

Published
2013
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16. Genome-wide association study of alcohol dependence

Author

Treutlein, Jens, Cichon, Sven, Ridinger, Monika, Wodarz, Norbert, Soyka, Michael, Maier, W., Moessner, Richhild, Dahmen, Norbert, Fehr, Cindy, Scherbaum, Norbert, Wichmann, Erich, Schreiber, S., Dragano, Nico, Hofsommer, Wolfgang, Wienker, Thomas F., Sullivan, Philip F., Nothen, M., Kiefer, Falk, Spanagel, Rainer, Mann, Karl F., and Rietschel, Marcella

Subjects
Medizin
Published
2010

17. Genetic Contribution to Alcohol Dependence: Investigation of a Heterogeneous German Sample of Individuals with Alcohol Dependence, Chronic Alcoholic Pancreatitis, and Alcohol-Related Cirrhosis.

Author

Treutlein, Jens, Frank, Josef, Streit, Fabian, Reinbold, Céline S., Juraeva, Dilafruz, Degenhardt, Franziska, Rietschel, Liz, Witt, Stephanie H., Forstner, Andreas J., Ridinger, Monika, Strohmaier, Jana, Wodarz, Norbert, Dukal, Helene, Foo, Jerome C., Hoffmann, Per, Herms, Stefan, Heilmann-Heimbach, Stefanie, Soyka, Michael, Maier, Wolfgang, and Gaebel, Wolfgang

Subjects
ALCOHOL Dependence Scale, CHRONIC pancreatitis, CIRRHOSIS of the liver, ALCOHOL dehydrogenase, GENE frequency, PHENOTYPES
Abstract

The present study investigated the genetic contribution to alcohol dependence (AD) using genome-wide association data from three German samples. These comprised patients with: (i) AD; (ii) chronic alcoholic pancreatitis (ACP); and (iii) alcohol-related liver cirrhosis (ALC). Single marker, gene-based, and pathway analyses were conducted. A significant association was detected for the ADH1B locus in a gene-based approach (puncorrected = 1.2 × 10-6; pcorrected = 0.020). This was driven by the AD subsample. No association with ADH1B was found in the combined ACP + ALC sample. On first inspection, this seems surprising, since ADH1B is a robustly replicated risk gene for AD and may therefore be expected to be associated also with subgroups of AD patients. The negative finding in the ACP + ALC sample, however, may reflect genetic stratification as well as random fluctuation of allele frequencies in the cases and controls, demonstrating the importance of large samples in which the phenotype is well assessed. [ABSTRACT FROM AUTHOR]

Published
2017
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18. Recovery from alcohol dependence: Do smoking indicators predict abstinence?

Author

Hufnagel, Anna, Frick, Ulrich, Ridinger, Monika, and Wodarz, Norbert

Subjects
ALCOHOLISM, SMOKING, SMOKING cessation, DETOXIFICATION (Substance abuse treatment), SUBSTANCE abuse treatment, TEMPERANCE, PSYCHOLOGY of alcoholism, SMOKING & psychology, DRINKING behavior, ALCOHOL drinking, DISEASE relapse
Abstract

Background and Objectives: There is inconsistent evidence about the potential influence of smoking on recovery from alcohol dependence. Our study aimed at assessing the impact of smoking-behavior on relapse during a 12 months follow-up period following a detoxification in patients with Alcohol Use Disorder (AUD).Methods: Three hundred Patients with AUD (74.9% smoking) were recruited from two inpatient detoxification units in psychiatric hospitals in Germany and their alcohol consumption was prospectively followed for 1 year. Data on different indicators of smoking behavior was gathered. Cox regression model was used to evaluate potential risk factors on time to relapse of alcohol consumption. Two hundred seventy-nine participants (n = 279) were included in the final analysis.Results: Smoking increased the risk for alcohol relapse (hazard ratio = 3.962, 95% CI 1.582-9.921). However, this increased risk is slightly reduced with higher numbers of daily consumed cigarettes (hazard ratio per cigarette = .986, 95% CI .976-.995).Conclusion: Smoking reduced the probability of maintaining alcohol abstinence significantly, whereas higher number of cigarettes smoked daily diminished the increased risk of alcohol relapse in alcohol-dependent patients.Scientific Significance: Coordinated psychiatric and substance abuse interventions for different subgroups of patients with AUD in the post-acute treatment phase are necessary. Individualized treatment planning is especially important in smoking patients with AUD who are vulnerable for a relapse to alcohol drinking and for somatic complications. Our findings might support individualized treatment plans. (Am J Addict 2017;26:366-373). [ABSTRACT FROM AUTHOR]

Published
2017
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19. XRCC5 as a Risk Gene for Alcohol Dependence: Evidence from a Genome-Wide Gene-Set-Based Analysis and Follow-up Studies in Drosophila and Humans.

Author

Juraeva, Dilafruz, Treutlein, Jens, Scholz, Henrike, Frank, Josef, Degenhardt, Franziska, Cichon, Sven, Ridinger, Monika, Mattheisen, Manuel, Witt, Stephanie H, Lang, Maren, Sommer, Wolfgang H, Hoffmann, Per, Herms, Stefan, Wodarz, Norbert, Soyka, Michael, Zill, Peter, Maier, Wolfgang, Jünger, Elisabeth, Gaebel, Wolfgang, and Dahmen, Norbert

Subjects
GENOMES, ALCOHOL Dependence Scale, DIAGNOSIS of alcoholism, SUBSTANCE abuse, ALCOHOLISM, DROSOPHILA
Abstract

Genetic factors have as large role as environmental factors in the etiology of alcohol dependence (AD). Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of AD, many true findings may be missed owing to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set-based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets, of which 5 could be replicated in an independent sample. Clustered in these gene-sets were novel and previously identified susceptibility genes. The most frequently present gene, ie in 6 out of 19 gene-sets, was X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5). Previous human and animal studies have implicated XRCC5 in alcohol sensitivity. This phenotype is inversely correlated with the development of AD, presumably as more alcohol is required to achieve the desired effects. In the present study, the functional role of XRCC5 in AD was further validated in animals and humans. Drosophila mutants with reduced function of Ku80-the homolog of mammalian XRCC5-due to RNAi silencing showed reduced sensitivity to ethanol. In humans with free access to intravenous ethanol self-administration in the laboratory, the maximum achieved blood alcohol concentration was influenced in an allele-dose-dependent manner by genetic variation in XRCC5. In conclusion, our convergent approach identified new candidates and generated independent evidence for the involvement of XRCC5 in alcohol dependence. [ABSTRACT FROM AUTHOR]

Published
2015
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21. Effects of the Circadian Rhythm Gene Period 1 (Per1)on Psychosocial Stress-Induced Alcohol Drinking.

Author

Dong, Li, Bilbao, Ainhoa, Laucht, Manfred, Henriksson, Richard, Yakovleva, Tatjana, Ridinger, Monika, Desrivieres, Sylvane, Clarke, Toni-Kim, Lourdusamy, Anbarasu, Smolka, Michael N., Cichon, Sven, Blomeyer, Dorothea, Treutlein, Jens, Perreau-Lenz, Stephanie, Witt, Stephanie, Leonardi-Essmann, Fernando, Wodarz, Norbert, Zill, Peter, Soyka, Michael, and Albrecht, Urs

Subjects
GENETICS of circadian rhythms, ALCOHOL drinking, GENETIC polymorphisms, ENVIRONMENTAL risk, CORTICOTROPIN releasing hormone, TRANSCRIPTION factors, LABORATORY mice
Abstract

Objective: Circadian and stress-response systems mediate environmental changes that affect alcohol drinking. Psychosocial stress is an environmental risk factor for alcohol abuse. Circadian rhythm gene period 1 (Per1) is targeted by stress hormones and is transcriptionally activated in corticotropin releasing factor-expressing cells. The authors hypothesized that Per1 is involved in integrating stress response and circadian rhythmicity and explored its relevance to alcohol drinking. Method: In mice, the effects of stress on ethanol intake in mPer1-mutant and wild-type mice were assessed. In humans, single nucleotide polymorphisms (SNPs) in hPer1 were tested for association with alcohol drinking behavior in 273 adolescents and an adult case-control sample of 1,006 alcohol-dependent patients and 1,178 comparison subjects. In vitro experiments were conducted to measure genotype-specific expression and transcription factor binding to hPer1. Results: The mPer1-mutant mice showed enhanced alcohol consumption in response to social defeat stress relative to their wild-type littermates. An association with the frequency of heavy drinking in adolescents with the hPer1 promoter SNP rs3027172 and with psychosocial adversity was found. There was significant interaction between the rs3027172 genotype and psychosocial adversity on this drinking measure. In a confirmatory analysis, association of hPer1 rs3027172 with alcohol dependence was shown. Cortisol-induced transcriptional activation of hPer1 was reduced in human B-lymphoblastoid cells carrying the risk genotype of rs3027172. Binding affinity of the transcription factor Snail1 to the risk allele of the hPer1 SNP rs3027172 was also reduced. Conclusions: The findings indicate that the hPer1 gene regulates alcohol drinking behavior during stressful conditions and provide evidence for underlying neurobiological mechanisms. [ABSTRACT FROM AUTHOR]

Published
2011
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22. KCNJ6 is Associated with Adult Alcohol Dependence and Involved in Gene × Early Life Stress Interactions in Adolescent Alcohol Drinking.

Author

Clarke, Toni-Kim, Laucht, Manfred, Ridinger, Monika, Wodarz, Norbert, Rietschel, Marcella, Maier, Wolfgang, Lathrop, Mark, Lourdusamy, Anbarasu, Zimmermann, Ulrich S., Desrivieres, Sylvane, and Schumann, Gunter

Subjects
ALCOHOL, ALCOHOLS (Chemical class), ALCOHOLISM, PEPTIDES, DOPAMINERGIC neurons
Abstract

Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p=0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene-environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p=0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement. [ABSTRACT FROM AUTHOR]

Published
2011
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23. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

Author

Clumeck, Nicolas, Stephan, Anna-Magdalena, Nothnagel, Michael, Stickel, Felix, Cichon, Sven, Hellerbrand, Claus, Gustot, Thierry, Lammert, Frank, Lerch, Markus M, Wodarz, Norbert, Brückner, Stefan, Way, Michael, Schreiber, Stefan, Devière, Jacques, Berg, Thomas, Hampe, Jochen, Buch, Stephan, Schafmayer, Clemens, Deltenre, Pierre, Mayerle, Julia, Morgan, Marsha Y, Moreno, Christophe, Huse, Klaus, Brosch, Mario, Zeissig, Sebastian, Kiefer, Falk, Datz, Christian, Franchimont, Denis, Soyka, Michael, Zopf, Steffen, Lieb, Wolfgang, Schmelz, Renate, Aigner, Elmar, Ellinghaus, David, Nöthen, Markus M, Franke, Andre, Nischalke, Hans Dieter, Eyer, Florian, Semmo, Nasser, Ridinger, Monika, Herrmann, Alexander, Rietschel, Marcella, Rosendahl, Jonas, McQuillin, Andrew, Trépo, Eric, Sarrazin, Christoph, Frank, Josef, and Völzke, Henry

Subjects
610 Medicine & health, 3. Good health
Abstract

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

24. Sex-Specific Role for Adenylyl Cyclase Type 7 in Alcohol Dependence

Author

Desrivières, Sylvane, Pronko, Sergey P., Lourdusamy, Anbarasu, Ducci, Francesca, Hoffman, Paula L., Wodarz, Norbert, Ridinger, Monika, Rietschel, Marcella, Zelenika, Diana, Lathrop, Mark, Schumann, Gunter, and Tabakoff, Boris

Subjects
*ADENYLATE cyclase, *ALCOHOL drinking, *CELLULAR signal transduction, *GENETIC polymorphisms, *MESSENGER RNA, *LABORATORY mice, *ALCOHOLISM, SEX differences (Biology)
Abstract

Background: Alcohol has been shown to critically modulate cyclic adenosine-3′,5′ monophosphate (cAMP) signaling. A number of downstream effectors that respond to the cAMP signals (e.g., protein kinase A, cAMP response element binding protein) have, in turn, been examined in relation to alcohol consumption. These studies did not, however, delineate the point at which the actions of alcohol on the cAMP cascade might translate into differences in drinking behavior. To further understand the role of cAMP synthesis in alcohol drinking and dependence, we investigated a specific adenylyl cyclase isoform, adenylyl cyclase (AC) Type 7, whose activity is selectively enhanced by ethanol. Methods: We measured alcohol consumption and preference in mice in which one copy of the Adcy7 gene was disrupted (Adcy7 +/− ). To demonstrate relevance of this gene for alcohol dependence in humans, we tested the association of polymorphisms in the ADCY7 gene with alcohol dependence in a sample of 1703 alcohol-dependent individuals and 1347 control subjects. Results: We show that Adcy7 +/− female mice have higher preference for alcohol than wild-type mice, whereas there is little difference in alcohol consumption or preference between Adcy7 +/− male mice and wild-type control subjects. In the human sample, we found that single nucleotide polymorphisms in ADCY7 associate with alcohol dependence in women, and these markers are also associated with ADCY7 expression (messenger RNA) levels. Conclusions: These findings implicate adenylyl cyclase Type 7 as a critical component of the molecular pathways contributing to alcohol drinking and the development of alcohol dependence. [ABSTRACT FROM AUTHOR]

Published
2011
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25. Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

Author

James R. A. Skipworth, Sebastian Krug, Florence Bühler, Sebastian Gimpfl, Joachim Mössner, Anke Tönjes, Atsushi Masamune, Adrian Saftoiu, Roland H. Pfützer, Marcella Rietschel, Heiko Witt, Felix Stickel, Jens Werner, Peter Kovacs, Nicole Soranzo, Constantin Zimmer, Martin Ziegler, Helmut Laumen, Holger Kirsten, Marco J. Bruno, Joost P.H. Drenth, Markus M. Lerch, Markus M. Nöthen, Claus Hellerbrand, Annette Peters, Philippe Lévy, Jian-Min Chen, Monika Ridinger, Giulia Martina Cavestro, Emmanuelle Masson, Milena Di Leo, Peter Simon, Peter Bugert, Péter Hegyi, Karl Mann, Miklós Sahin-Tóth, Pier Alberto Testoni, Núria Malats, Rene H. M. te Morsche, Konstantin Strauch, Stephen P. Pereira, Josef Frank, Norbert Wodarz, Halina Cichoż-Lach, Jonas Rosendahl, Alexander Schneider, Marcus Hollenbach, Olfert Landt, Markus Löffler, Sergio Pedrazzoli, Volker Keim, Matthias Löhr, Marie Motyka, Sebastian Mueller, Ralph Burkhardt, Antoni Farré, Heidi Griesmann, Falk Kiefer, Giovanni Malerba, Claudia Ruffert, Markus Scholz, Francisco X. Real, Maren Ludwig, Eszter Hegyi, Harald Grallert, Hana Algül, Vinciane Rebours, Eva Rösmann, Frank Ulrich Weiss, Sonja Mohr, Robert Grützmann, Sevastitia Iordache, Michael Soyka, Milan Macek, Peter Lichtner, Patrick Michl, Claude Férec, Giovanni Gambaro, Michael Stumvoll, Katharina Seltsam, Thomas Müller, Grazyna Jurkowska, Ewa Małecka-Panas, Sebastian Beer, Julia Mayerle, Hans-Ulrich Schulz, Lena Werner, Publica, Rosendahl, Jona, Kirsten, Holger, Hegyi, Eszter, Kovacs, Peter, Weiss, Frank Ulrich, Laumen, Helmut, Lichtner, Peter, Ruffert, Claudia, Chen, Jian min, Masson, Emmanuelle, Beer, Sebastian, Zimmer, Constantin, Seltsam, Katharina, Algül, Hana, Bühler, Florence, Bruno, Marco J, Bugert, Peter, Burkhardt, Ralph, Cavestro, GIULIA MARTINA, Cichoz lach, Halina, Farré, Antoni, Frank, Josef, Gambaro, Giovanni, Gimpfl, Sebastian, Grallert, Harald, Griesmann, Heidi, Grützmann, Robert, Hellerbrand, Clau, Hegyi, Péter, Hollenbach, Marcu, Iordache, Sevastitia, Jurkowska, Grazyna, Keim, Volker, Kiefer, Falk, Krug, Sebastian, Landt, Olfert, Leo, Milena Di, Lerch, Markus M, Lévy, Philippe, Löffler, Marku, Löhr, Matthia, Ludwig, Maren, Macek, Milan, Malats, Nuria, Malecka panas, Ewa, Malerba, Giovanni, Mann, Karl, Mayerle, Julia, Mohr, Sonja, Te Morsche, Rene H. M, Motyka, Marie, Mueller, Sebastian, Müller, Thoma, Nöthen, Markus M, Pedrazzoli, Sergio, Pereira, Stephen P, Peters, Annette, Pfützer, Roland, Real, Francisco X, Rebours, Vinciane, Ridinger, Monika, Rietschel, Marcella, Rösmann, Eva, Saftoiu, Adrian, Schneider, Alexander, Schulz, Hans ulrich, Soranzo, Nicole, Soyka, Michael, Simon, Peter, Skipworth, Jame, Stickel, Felix, Strauch, Konstantin, Stumvoll, Michael, Testoni, PIER ALBERTO, Tönjes, Anke, Werner, Lena, Werner, Jen, Wodarz, Norbert, Ziegler, Martin, Masamune, Atsushi, Mössner, Joachim, Férec, Claude, Michl, Patrick, Joost, P. H. Drenth, Witt, Heiko, Scholz, Marku, Sahin tóth, Miklós, and Gastroenterology & Hepatology

Subjects
0301 basic medicine, Linkage disequilibrium, medicine.medical_specialty, Settore MED/12 - GASTROENTEROLOGIA, Population, Genome Wide Association Study, Chronic Pancreatitis, Genetic Rearrangement, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Gastroenterology, chronic pancreatitis, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Genetic predisposition, medicine, Allele, education, Genetics, education.field_of_study, medicine.disease, ddc, genetic rearrangement, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Genome wide association study, Pancreatitis, chronic pancreatiti, Chronic pancreatitis, Genetic rearrangement
Abstract

ObjectiveAlcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.Design1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.ResultsWe replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.ConclusionAn inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.

Published
2018

26. Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Author

Munn-Chernoff MA, Johnson EC, Chou YL, Coleman JRI, Thornton LM, Walters RK, Yilmaz Z, Baker JH, Hübel C, Gordon S, Medland SE, Watson HJ, Gaspar HA, Bryois J, Hinney A, Leppä VM, Mattheisen M, Ripke S, Yao S, Giusti-Rodríguez P, Hanscombe KB, Adan RAH, Alfredsson L, Ando T, Andreassen OA, Berrettini WH, Boehm I, Boni C, Boraska Perica V, Buehren K, Burghardt R, Cassina M, Cichon S, Clementi M, Cone RD, Courtet P, Crow S, Crowley JJ, Danner UN, Davis OSP, de Zwaan M, Dedoussis G, Degortes D, DeSocio JE, Dick DM, Dikeos D, Dina C, Dmitrzak-Weglarz M, Docampo E, Duncan LE, Egberts K, Ehrlich S, Escaramís G, Esko T, Estivill X, Farmer A, Favaro A, Fernández-Aranda F, Fichter MM, Fischer K, Föcker M, Foretova L, Forstner AJ, Forzan M, Franklin CS, Gallinger S, Giegling I, Giuranna J, Gonidakis F, Gorwood P, Gratacos Mayora M, Guillaume S, Guo Y, Hakonarson H, Hatzikotoulas K, Hauser J, Hebebrand J, Helder SG, Herms S, Herpertz-Dahlmann B, Herzog W, Huckins LM, Hudson JI, Imgart H, Inoko H, Janout V, Jiménez-Murcia S, Julià A, Kalsi G, Kaminská D, Karhunen L, Karwautz A, Kas MJH, Kennedy JL, Keski-Rahkonen A, Kiezebrink K, Kim YR, Klump KL, Knudsen GPS, La Via MC, Le Hellard S, Levitan RD, Li D, Lilenfeld L, Lin BD, Lissowska J, Luykx J, Magistretti PJ, Maj M, Mannik K, Marsal S, Marshall CR, Mattingsdal M, McDevitt S, McGuffin P, Metspalu A, Meulenbelt I, Micali N, Mitchell K, Monteleone AM, Monteleone P, Nacmias B, Navratilova M, Ntalla I, O'Toole JK, Ophoff RA, Padyukov L, Palotie A, Pantel J, Papezova H, Pinto D, Rabionet R, Raevuori A, Ramoz N, Reichborn-Kjennerud T, Ricca V, Ripatti S, Ritschel F, Roberts M, Rotondo A, Rujescu D, Rybakowski F, Santonastaso P, Scherag A, Scherer SW, Schmidt U, Schork NJ, Schosser A, Seitz J, Slachtova L, Slagboom PE, Slof-Op't Landt MCT, Slopien A, Sorbi S, Świątkowska B, Szatkiewicz JP, Tachmazidou I, Tenconi E, Tortorella A, Tozzi F, Treasure J, Tsitsika A, Tyszkiewicz-Nwafor M, Tziouvas K, van Elburg AA, van Furth EF, Wagner G, Walton E, Widen E, Zeggini E, Zerwas S, Zipfel S, Bergen AW, Boden JM, Brandt H, Crawford S, Halmi KA, Horwood LJ, Johnson C, Kaplan AS, Kaye WH, Mitchell J, Olsen CM, Pearson JF, Pedersen NL, Strober M, Werge T, Whiteman DC, Woodside DB, Grove J, Henders AK, Larsen JT, Parker R, Petersen LV, Jordan J, Kennedy MA, Birgegård A, Lichtenstein P, Norring C, Landén M, Mortensen PB, Polimanti R, McClintick JN, Adkins AE, Aliev F, Bacanu SA, Batzler A, Bertelsen S, Biernacka JM, Bigdeli TB, Chen LS, Clarke TK, Degenhardt F, Docherty AR, Edwards AC, Foo JC, Fox L, Frank J, Hack LM, Hartmann AM, Hartz SM, Heilmann-Heimbach S, Hodgkinson C, Hoffmann P, Hottenga JJ, Konte B, Lahti J, Lahti-Pulkkinen M, Lai D, Ligthart L, Loukola A, Maher BS, Mbarek H, McIntosh AM, McQueen MB, Meyers JL, Milaneschi Y, Palviainen T, Peterson RE, Ryu E, Saccone NL, Salvatore JE, Sanchez-Roige S, Schwandt M, Sherva R, Streit F, Strohmaier J, Thomas N, Wang JC, Webb BT, Wedow R, Wetherill L, Wills AG, Zhou H, Boardman JD, Chen D, Choi DS, Copeland WE, Culverhouse RC, Dahmen N, Degenhardt L, Domingue BW, Frye MA, Gäebel W, Hayward C, Ising M, Keyes M, Kiefer F, Koller G, Kramer J, Kuperman S, Lucae S, Lynskey MT, Maier W, Mann K, Männistö S, Müller-Myhsok B, Murray AD, Nurnberger JI, Preuss U, Räikkönen K, Reynolds MD, Ridinger M, Scherbaum N, Schuckit MA, Soyka M, Treutlein J, Witt SH, Wodarz N, Zill P, Adkins DE, Boomsma DI, Bierut LJ, Brown SA, Bucholz KK, Costello EJ, de Wit H, Diazgranados N, Eriksson JG, Farrer LA, Foroud TM, Gillespie NA, Goate AM, Goldman D, Grucza RA, Hancock DB, Harris KM, Hesselbrock V, Hewitt JK, Hopfer CJ, Iacono WG, Johnson EO, Karpyak VM, Kendler KS, Kranzler HR, Krauter K, Lind PA, McGue M, MacKillop J, Madden PAF, Maes HH, Magnusson PKE, Nelson EC, Nöthen MM, Palmer AA, Penninx BWJH, Porjesz B, Rice JP, Rietschel M, Riley BP, Rose RJ, Shen PH, Silberg J, Stallings MC, Tarter RE, Vanyukov MM, Vrieze S, Wall TL, Whitfield JB, Zhao H, Neale BM, Wade TD, Heath AC, Montgomery GW, Martin NG, Sullivan PF, Kaprio J, Breen G, Gelernter J, Edenberg HJ, Bulik CM, and Agrawal A

Subjects
Alcoholism genetics, Depressive Disorder, Major genetics, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Schizophrenia genetics, Tobacco Use Disorder genetics, Feeding and Eating Disorders genetics, Substance-Related Disorders genetics
Abstract

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r g ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r gs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors., (© 2020 Society for the Study of Addiction.)

Published
2021
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27. Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Author

Strnad P, Buch S, Hamesch K, Fischer J, Rosendahl J, Schmelz R, Brueckner S, Brosch M, Heimes CV, Woditsch V, Scholten D, Nischalke HD, Janciauskiene S, Mandorfer M, Trauner M, Way MJ, McQuillin A, Reichert MC, Krawczyk M, Casper M, Lammert F, Braun F, von Schönfels W, Hinz S, Burmeister G, Hellerbrand C, Teufel A, Feldman A, Schattenberg JM, Bantel H, Pathil A, Demir M, Kluwe J, Boettler T, Ridinger M, Wodarz N, Soyka M, Rietschel M, Kiefer F, Weber T, Marhenke S, Vogel A, Hinrichsen H, Canbay A, Schlattjan M, Sosnowsky K, Sarrazin C, von Felden J, Geier A, Deltenre P, Sipos B, Schafmayer C, Nothnagel M, Aigner E, Datz C, Stickel F, Morgan MY, Hampe J, Berg T, and Trautwein C

Subjects
Age Distribution, Austria, Biopsy, Needle, Case-Control Studies, Confidence Intervals, Female, Genetic Carrier Screening, Genetic Variation, Germany, Humans, Immunohistochemistry, Incidence, Liver Cirrhosis, Alcoholic epidemiology, Liver Cirrhosis, Alcoholic pathology, Male, Non-alcoholic Fatty Liver Disease epidemiology, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease pathology, Odds Ratio, Polymorphism, Single Nucleotide, Prognosis, Risk Assessment, Sex Distribution, Genetic Predisposition to Disease epidemiology, Heterozygote, Liver Cirrhosis, Alcoholic genetics, alpha 1-Antitrypsin genetics
Abstract

Objective: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse., Design: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed., Results: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19))., Conclusion: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2019
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28. Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis.

Author

Rosendahl J, Kirsten H, Hegyi E, Kovacs P, Weiss FU, Laumen H, Lichtner P, Ruffert C, Chen JM, Masson E, Beer S, Zimmer C, Seltsam K, Algül H, Bühler F, Bruno MJ, Bugert P, Burkhardt R, Cavestro GM, Cichoz-Lach H, Farré A, Frank J, Gambaro G, Gimpfl S, Grallert H, Griesmann H, Grützmann R, Hellerbrand C, Hegyi P, Hollenbach M, Iordache S, Jurkowska G, Keim V, Kiefer F, Krug S, Landt O, Leo MD, Lerch MM, Lévy P, Löffler M, Löhr M, Ludwig M, Macek M, Malats N, Malecka-Panas E, Malerba G, Mann K, Mayerle J, Mohr S, Te Morsche RHM, Motyka M, Mueller S, Müller T, Nöthen MM, Pedrazzoli S, Pereira SP, Peters A, Pfützer R, Real FX, Rebours V, Ridinger M, Rietschel M, Rösmann E, Saftoiu A, Schneider A, Schulz HU, Soranzo N, Soyka M, Simon P, Skipworth J, Stickel F, Strauch K, Stumvoll M, Testoni PA, Tönjes A, Werner L, Werner J, Wodarz N, Ziegler M, Masamune A, Mössner J, Férec C, Michl P, P H Drenth J, Witt H, Scholz M, and Sahin-Tóth M

Subjects
Adult, Aged, Europe epidemiology, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Chymotrypsin genetics, Pancreatitis, Alcoholic epidemiology, Pancreatitis, Alcoholic genetics
Abstract

Objective: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus., Design: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used., Results: We replicated previously reported risk loci CLDN2-MORC4 , CTRC , PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956 . The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk., Conclusion: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Published
2018
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29. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis.

Author

Buch S, Stickel F, Trépo E, Way M, Herrmann A, Nischalke HD, Brosch M, Rosendahl J, Berg T, Ridinger M, Rietschel M, McQuillin A, Frank J, Kiefer F, Schreiber S, Lieb W, Soyka M, Semmo N, Aigner E, Datz C, Schmelz R, Brückner S, Zeissig S, Stephan AM, Wodarz N, Devière J, Clumeck N, Sarrazin C, Lammert F, Gustot T, Deltenre P, Völzke H, Lerch MM, Mayerle J, Eyer F, Schafmayer C, Cichon S, Nöthen MM, Nothnagel M, Ellinghaus D, Huse K, Franke A, Zopf S, Hellerbrand C, Moreno C, Franchimont D, Morgan MY, and Hampe J

Subjects
Adult, Aged, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Risk Factors, Acyltransferases genetics, Genome-Wide Association Study, Lipase genetics, Liver Cirrhosis, Alcoholic genetics, Membrane Proteins genetics, Polymorphism, Single Nucleotide genetics
Abstract

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

Published
2015
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30. αCaMKII autophosphorylation controls the establishment of alcohol drinking behavior.

Author

Easton AC, Lucchesi W, Lourdusamy A, Lenz B, Solati J, Golub Y, Lewczuk P, Fernandes C, Desrivieres S, Dawirs RR, Moll GH, Kornhuber J, Frank J, Hoffmann P, Soyka M, Kiefer F, Schumann G, Peter Giese K, Müller CP, Treutlein J, Cichon S, Ridinger M, Mattheisen P, Herms S, Wodarz N, Zill P, Maier W, Mössner R, Gaebel W, Dahmen N, Scherbaum N, Schmäl C, Steffens M, Lucae S, Ising M, Müller-Myhsok B, Nöthen MM, Mann K, and Rietschel M

Subjects
Animals, Behavior, Addictive metabolism, Case-Control Studies, Dopamine metabolism, Dose-Response Relationship, Drug, Ethanol pharmacology, Female, Humans, Hypnotics and Sedatives pharmacology, Male, Mice, Motor Activity drug effects, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Phosphorylation, Polymorphism, Single Nucleotide genetics, Prefrontal Cortex drug effects, Prefrontal Cortex metabolism, Serotonin metabolism, Ventral Tegmental Area drug effects, Ventral Tegmental Area physiology, Alcohol Drinking metabolism, Alcoholism genetics, Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Genetic Predisposition to Disease genetics
Abstract

The α-Ca(2+)/calmodulin-dependent protein kinase II (αCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of αCaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of αCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in αCaMKII autophosphorylation-deficient αCaMKII(T286A) mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in αCaMKII(T286A) mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that αCaMKII(T286A) mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in αCaMKII(T286A) mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest αCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.

Published
2013
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31. Effects of the circadian rhythm gene period 1 (per1) on psychosocial stress-induced alcohol drinking.

Author

Dong L, Bilbao A, Laucht M, Henriksson R, Yakovleva T, Ridinger M, Desrivieres S, Clarke TK, Lourdusamy A, Smolka MN, Cichon S, Blomeyer D, Treutlein J, Perreau-Lenz S, Witt S, Leonardi-Essmann F, Wodarz N, Zill P, Soyka M, Albrecht U, Rietschel M, Lathrop M, Bakalkin G, Spanagel R, and Schumann G

Subjects
Adolescent, Adult, Alcohol Drinking psychology, Alleles, Animals, Case-Control Studies, Female, Genotype, Humans, Male, Mice, Mice, Knockout, Polymorphism, Single Nucleotide, Stress, Psychological complications, Alcohol Drinking genetics, Period Circadian Proteins genetics, Stress, Psychological genetics
Abstract

Objective: Circadian and stress-response systems mediate environmental changes that affect alcohol drinking. Psychosocial stress is an environmental risk factor for alcohol abuse. Circadian rhythm gene period 1 (Per1) is targeted by stress hormones and is transcriptionally activated in corticotropin releasing factor-expressing cells. The authors hypothesized that Per1 is involved in integrating stress response and circadian rhythmicity and explored its relevance to alcohol drinking., Method: In mice, the effects of stress on ethanol intake in mPer1-mutant and wild-type mice were assessed. In humans, single nucleotide polymorphisms (SNPs) in hPer1 were tested for association with alcohol drinking behavior in 273 adolescents and an adult case-control sample of 1,006 alcohol-dependent patients and 1,178 comparison subjects. In vitro experiments were conducted to measure genotype-specific expression and transcription factor binding to hPer1., Results: The mPer1-mutant mice showed enhanced alcohol consumption in response to social defeat stress relative to their wild-type littermates. An association with the frequency of heavy drinking in adolescents with the hPer1 promoter SNP rs3027172 and with psychosocial adversity was found. There was significant interaction between the rs3027172 genotype and psychosocial adversity on this drinking measure. In a confirmatory analysis, association of hPer1 rs3027172 with alcohol dependence was shown. Cortisol-induced transcriptional activation of hPer1 was reduced in human B-lymphoblastoid cells carrying the risk genotype of rs3027172. Binding affinity of the transcription factor Snail1 to the risk allele of the hPer1 SNP rs3027172 was also reduced., Conclusions: The findings indicate that the hPer1 gene regulates alcohol drinking behavior during stressful conditions and provide evidence for underlying neurobiological mechanisms.

Published
2011
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