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51. Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology: identification of the cystine/glutamate transporter SLC7A11 as a top target

Author

Lohoff, Falk W., primary, Clarke, Toni-Kim, additional, Kaminsky, Zachary A., additional, Walker, Rosie M., additional, Bermingham, Mairead L., additional, Jung, Jeesun, additional, Morris, Stewart W., additional, Rosoff, Daniel, additional, Campbell, Archie, additional, Barbu, Miruna, additional, Charlet, Katrin, additional, Adams, Mark, additional, Lee, Jisoo, additional, Howard, David M., additional, O’Connell, Emma M., additional, Whalley, Heather, additional, Porteous, David J., additional, McIntosh, Andrew M., additional, and Evans, Kathryn L., additional

Published
2021
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55. Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy

Author

Buono, Russell J., primary, Bradfield, Jonathan P., additional, Wei, Zhi, additional, Sperling, Michael R., additional, Dlugos, Dennis J., additional, Privitera, Michael D., additional, French, Jacqueline A., additional, Lo, Warren, additional, Cossette, Patrick, additional, Schachter, Steven C., additional, Basehore, Heather, additional, Lohoff, Falk W., additional, Grant, Struan F. A., additional, Ferraro, Thomas N., additional, and Hakonarson, Hakon, additional

Published
2021
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58. Additional file 1 of Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L., Min, Josine L., Richmond, Rebecca C., Lu, Ake T., Sobczyk, Maria K., Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R., Mishra, Pashupati P., Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M., Ratliff, Scott M., Richardson, Tom G., Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D., Walker, Rosie M., Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R., Gieger, Christian, de Geus, Eco J. C., Harris, Sarah E., Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon L. R., Kresovich, Jacob K., Li, Shengxu, Lunetta, Kathryn L., Mangino, Massimo, Mason, Dan, McIntosh, Andrew M., Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M., Ollikainen, Miina, Pankow, James S., Pedersen, Nancy L., Peters, Annette, Polidoro, Silvia, Porteous, David J., Raitakari, Olli, Rich, Stephen S., Sandler, Dale P., Sillanpää, Elina, Smith, Alicia K., Southey, Melissa C., Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G., Van Den Berg, David J., van Dongen, Jenny, Wilson, James G., Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T., Binder, Alexandra M., Boomsma, Dorret I., Chen, Wei, Christensen, Kaare, Conneely, Karen N., Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A., Lehtimäki, Terho, Lohoff, Falk W., Milani, Lili, Milne, Roger L., Probst-Hensch, Nicole, Reiner, Alex P., Ritz, Beate, Rotter, Jerome I., Smith, Jennifer A., Taylor, Jack A., van Meurs, Joyce B. J., Vineis, Paolo, Waldenberger, Melanie, Deary, Ian J., Relton, Caroline L., Horvath, Steve, and Marioni, Riccardo E.

Abstract

Additional file 1. Individual cohort descriptions and acknowledgements.

Published
2021
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59. Additional file 5 of Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L., Min, Josine L., Richmond, Rebecca C., Lu, Ake T., Sobczyk, Maria K., Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R., Mishra, Pashupati P., Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M., Ratliff, Scott M., Richardson, Tom G., Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D., Walker, Rosie M., Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R., Gieger, Christian, de Geus, Eco J. C., Harris, Sarah E., Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon L. R., Kresovich, Jacob K., Li, Shengxu, Lunetta, Kathryn L., Mangino, Massimo, Mason, Dan, McIntosh, Andrew M., Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M., Ollikainen, Miina, Pankow, James S., Pedersen, Nancy L., Peters, Annette, Polidoro, Silvia, Porteous, David J., Raitakari, Olli, Rich, Stephen S., Sandler, Dale P., Sillanpää, Elina, Smith, Alicia K., Southey, Melissa C., Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G., Van Den Berg, David J., van Dongen, Jenny, Wilson, James G., Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T., Binder, Alexandra M., Boomsma, Dorret I., Chen, Wei, Christensen, Kaare, Conneely, Karen N., Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A., Lehtimäki, Terho, Lohoff, Falk W., Milani, Lili, Milne, Roger L., Probst-Hensch, Nicole, Reiner, Alex P., Ritz, Beate, Rotter, Jerome I., Smith, Jennifer A., Taylor, Jack A., van Meurs, Joyce B. J., Vineis, Paolo, Waldenberger, Melanie, Deary, Ian J., Relton, Caroline L., Horvath, Steve, and Marioni, Riccardo E.

Abstract

Additional file 5. Colocalization plots.

Published
2021
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60. Additional file 6 of Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L., Min, Josine L., Richmond, Rebecca C., Lu, Ake T., Sobczyk, Maria K., Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R., Mishra, Pashupati P., Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M., Ratliff, Scott M., Richardson, Tom G., Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D., Walker, Rosie M., Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R., Gieger, Christian, de Geus, Eco J. C., Harris, Sarah E., Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon L. R., Kresovich, Jacob K., Li, Shengxu, Lunetta, Kathryn L., Mangino, Massimo, Mason, Dan, McIntosh, Andrew M., Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M., Ollikainen, Miina, Pankow, James S., Pedersen, Nancy L., Peters, Annette, Polidoro, Silvia, Porteous, David J., Raitakari, Olli, Rich, Stephen S., Sandler, Dale P., Sillanpää, Elina, Smith, Alicia K., Southey, Melissa C., Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G., Van Den Berg, David J., van Dongen, Jenny, Wilson, James G., Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T., Binder, Alexandra M., Boomsma, Dorret I., Chen, Wei, Christensen, Kaare, Conneely, Karen N., Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A., Lehtimäki, Terho, Lohoff, Falk W., Milani, Lili, Milne, Roger L., Probst-Hensch, Nicole, Reiner, Alex P., Ritz, Beate, Rotter, Jerome I., Smith, Jennifer A., Taylor, Jack A., van Meurs, Joyce B. J., Vineis, Paolo, Waldenberger, Melanie, Deary, Ian J., Relton, Caroline L., Horvath, Steve, and Marioni, Riccardo E.

Abstract

Additional file 6. Review history.

Published
2021
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61. Additional file 4 of Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L., Min, Josine L., Richmond, Rebecca C., Lu, Ake T., Sobczyk, Maria K., Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R., Mishra, Pashupati P., Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M., Ratliff, Scott M., Richardson, Tom G., Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D., Walker, Rosie M., Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R., Gieger, Christian, de Geus, Eco J. C., Harris, Sarah E., Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon L. R., Kresovich, Jacob K., Li, Shengxu, Lunetta, Kathryn L., Mangino, Massimo, Mason, Dan, McIntosh, Andrew M., Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M., Ollikainen, Miina, Pankow, James S., Pedersen, Nancy L., Peters, Annette, Polidoro, Silvia, Porteous, David J., Raitakari, Olli, Rich, Stephen S., Sandler, Dale P., Sillanpää, Elina, Smith, Alicia K., Southey, Melissa C., Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G., Van Den Berg, David J., van Dongen, Jenny, Wilson, James G., Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T., Binder, Alexandra M., Boomsma, Dorret I., Chen, Wei, Christensen, Kaare, Conneely, Karen N., Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A., Lehtimäki, Terho, Lohoff, Falk W., Milani, Lili, Milne, Roger L., Probst-Hensch, Nicole, Reiner, Alex P., Ritz, Beate, Rotter, Jerome I., Smith, Jennifer A., Taylor, Jack A., van Meurs, Joyce B. J., Vineis, Paolo, Waldenberger, Melanie, Deary, Ian J., Relton, Caroline L., Horvath, Steve, and Marioni, Riccardo E.

Abstract

Additional file 4. Assessment of genomic inflation and heterogeneity.

Published
2021
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62. Additional file 3 of Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, Daniel L., Min, Josine L., Richmond, Rebecca C., Lu, Ake T., Sobczyk, Maria K., Davies, Gail, Broer, Linda, Guo, Xiuqing, Jeong, Ayoung, Jung, Jeesun, Kasela, Silva, Katrinli, Seyma, Kuo, Pei-Lun, Matias-Garcia, Pamela R., Mishra, Pashupati P., Nygaard, Marianne, Palviainen, Teemu, Patki, Amit, Raffield, Laura M., Ratliff, Scott M., Richardson, Tom G., Robinson, Oliver, Soerensen, Mette, Sun, Dianjianyi, Tsai, Pei-Chien, van der Zee, Matthijs D., Walker, Rosie M., Wang, Xiaochuan, Wang, Yunzhang, Xia, Rui, Xu, Zongli, Yao, Jie, Zhao, Wei, Correa, Adolfo, Boerwinkle, Eric, Dugué, Pierre-Antoine, Durda, Peter, Elliott, Hannah R., Gieger, Christian, de Geus, Eco J. C., Harris, Sarah E., Hemani, Gibran, Imboden, Medea, Kähönen, Mika, Kardia, Sharon L. R., Kresovich, Jacob K., Li, Shengxu, Lunetta, Kathryn L., Mangino, Massimo, Mason, Dan, McIntosh, Andrew M., Mengel-From, Jonas, Moore, Ann Zenobia, Murabito, Joanne M., Ollikainen, Miina, Pankow, James S., Pedersen, Nancy L., Peters, Annette, Polidoro, Silvia, Porteous, David J., Raitakari, Olli, Rich, Stephen S., Sandler, Dale P., Sillanpää, Elina, Smith, Alicia K., Southey, Melissa C., Strauch, Konstantin, Tiwari, Hemant, Tanaka, Toshiko, Tillin, Therese, Uitterlinden, Andre G., Van Den Berg, David J., van Dongen, Jenny, Wilson, James G., Wright, John, Yet, Idil, Arnett, Donna, Bandinelli, Stefania, Bell, Jordana T., Binder, Alexandra M., Boomsma, Dorret I., Chen, Wei, Christensen, Kaare, Conneely, Karen N., Elliott, Paul, Ferrucci, Luigi, Fornage, Myriam, Hägg, Sara, Hayward, Caroline, Irvin, Marguerite, Kaprio, Jaakko, Lawlor, Deborah A., Lehtimäki, Terho, Lohoff, Falk W., Milani, Lili, Milne, Roger L., Probst-Hensch, Nicole, Reiner, Alex P., Ritz, Beate, Rotter, Jerome I., Smith, Jennifer A., Taylor, Jack A., van Meurs, Joyce B. J., Vineis, Paolo, Waldenberger, Melanie, Deary, Ian J., Relton, Caroline L., Horvath, Steve, and Marioni, Riccardo E.

Abstract

Additional file 3. Supplementary Figures - Figures S1-S31.

Published
2021
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63. Genetic variation in PADI6-PADI4 on 1p36.13 is associated with common forms of human generalized epilepsy

Author

Buono, Russell J., Bradfield, Jonathan P., Wei, Zhi, Sperling, Michael R., Dlugos, Dennis J., Privitera, Michael D., French, Jacqueline A., Lo, Warren, Cossette, Patrick, Schachter, Steven C., Basehore, Heather, Lohoff, Falk W., Grant, Struan F.A., Ferraro, Thomas N., Hakonarson, Hakon, Buono, Russell J., Bradfield, Jonathan P., Wei, Zhi, Sperling, Michael R., Dlugos, Dennis J., Privitera, Michael D., French, Jacqueline A., Lo, Warren, Cossette, Patrick, Schachter, Steven C., Basehore, Heather, Lohoff, Falk W., Grant, Struan F.A., Ferraro, Thomas N., and Hakonarson, Hakon

Abstract

We performed a genome-wide association study (GWAS) to identify genetic variation associated with common forms of idiopathic generalized epilepsy (GE) and focal epilepsy (FE). Using a cohort of 2220 patients and 14,448 controls, we searched for single nucleotide polymorphisms (SNPs) associated with GE, FE and both forms combined. We did not find any SNPs that reached genome-wide statistical significance (p ≤ 5 × 10−8) when comparing all cases to all controls, and few SNPs of interest comparing FE cases to controls. However, we document multiple linked SNPs in the PADI6-PADI4 genes that reach genome-wide significance and are associated with disease when comparing GE cases alone to controls. PADI genes encode enzymes that deiminate arginine to citrulline in molecular pathways related to epigenetic regulation of histones and autoantibody formation. Although epilepsy genetics and treatment are focused strongly on ion channel and neurotransmitter mechanisms, these results suggest that epigenetic control of gene expression and the formation of autoantibodies may also play roles in epileptogenesis.

Published
2021

64. Fear conditioning and extinction in alcohol dependence: Evidence for abnormal amygdala reactivity

Author

Muench, Christine, Charlet, Katrin, Balderston, Nicholas L., Grillon, Christian, Heilig, Markus, Cortes, Carlos R., Momenan, Reza, Lohoff, Falk W., Muench, Christine, Charlet, Katrin, Balderston, Nicholas L., Grillon, Christian, Heilig, Markus, Cortes, Carlos R., Momenan, Reza, and Lohoff, Falk W.

Abstract

Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohens d = .89, P-(FWE) = .037) and in the left amygdala during fear renewal (Cohens d = .68, P-(FWE) = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P-(Bonferroni) = .009), depressive symptoms (r = .37, P-(Bonferroni) = .015), trait anxiety (r = .41, P-(Bonferroni) = .006), and perceived stress (r = .45, P-(Bonferroni) = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC., Funding Agencies|National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [ZIA-AA000242]; German Research FoundationGerman Research Foundation (DFG) [DFG CH1936/1-1]

Published
2021
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66. Time to relapse after 6 and 12 months' treatment of generalized anxiety disorder with venlafaxine extended release

Author

Rickels, Karl, Etemad, Bijan, Khalid-Khan, Sarosh, Lohoff, Falk W., Rynn, Moira A., and Gallop, Robert J.

Subjects
Generalized anxiety disorder -- Drug therapy, Generalized anxiety disorder -- Complications and side effects, Generalized anxiety disorder -- Research, Venlafaxine -- Dosage and administration, Venlafaxine -- Research, Diseases -- Relapse, Diseases -- Reports, Health, Psychology and mental health
Published
2010

72. Clinical predictors of non‐response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study

Author

Lin, Yian, primary, Maihofer, Adam X., additional, Stapp, Emma, additional, Ritchey, Megan, additional, Alliey‐Rodriguez, Ney, additional, Anand, Amit, additional, Balaraman, Yokesh, additional, Berrettini, Wade H., additional, Bertram, Holli, additional, Bhattacharjee, Abesh, additional, Calkin, Cynthia V., additional, Conroy, Carla, additional, Coryell, William, additional, D'Arcangelo, Nicole, additional, DeModena, Anna, additional, Biernacka, Joanna M., additional, Fisher, Carrie, additional, Frazier, Nicole, additional, Frye, Mark, additional, Gao, Keming, additional, Garnham, Julie, additional, Gershon, Elliot, additional, Glazer, Kara, additional, Goes, Fernando S., additional, Goto, Toyomi, additional, Karberg, Elizabeth, additional, Harrington, Gloria, additional, Jakobsen, Petter, additional, Kamali, Masoud, additional, Kelly, Marisa, additional, Leckband, Susan G., additional, Lohoff, Falk W., additional, Stautland, Andrea, additional, McCarthy, Michael J., additional, McInnis, Melvin G., additional, Mondimore, Francis, additional, Morken, Gunnar, additional, Nurnberger, John I., additional, Oedegaard, Ketil J., additional, Syrstad, Vigdis Elin Giever, additional, Ryan, Kelly, additional, Schinagle, Martha, additional, Schoeyen, Helle, additional, Andreassen, Ole A., additional, Shaw, Marth, additional, Shilling, Paul D., additional, Slaney, Claire, additional, Tarwater, Bruce, additional, Calabrese, Joseph R., additional, Alda, Martin, additional, Nievergelt, Caroline M., additional, Zandi, Peter P., additional, and Kelsoe, John R., additional

Published
2021
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76. Prescription opioid use and risk for major depressive disorder:a multivariable Mendelian randomization analysis

Author

Rosoff, Daniel B., Davey Smith, George, and Lohoff, Falk W

Abstract

Importance Growing evidence suggests that prescription opioid use affects depression and anxiety disorders; however, observational studies are subject to confounding, making causal inference and determining the direction of these associations difficult. Objective To investigate the potential bidirectional associations between the genetic liability for prescription opioid and other nonopioid pain medications and both major depressive disorder (MDD) and anxiety and stress-related disorders (ASRD) using genetically based methods. Design, Setting, and Participants We performed 2-sample mendelian randomization (MR) using summary statistics from genome-wide association studies (GWAS) to assess potential associations of self-reported prescription opioid and nonopioid analgesics, including nonsteroidal anti-inflammatories (NSAIDs) and acetaminophen-like derivatives use with MDD and ASRD. The GWAS data were derived from participants of predominantly European ancestry included in observational cohorts. Data were analyzed February 20, 2020, to May 4, 2020. Main Outcomes and Measures Major depressive disorder, ASRD, and self-reported pain medications (opioids, NSAIDs, anilides, and salicylic acid). Results The GWAS data were derived from participants of predominantly European ancestry included in the population-based UK Biobank and Lundbeck Foundation Initiative for Integrative Psychiatric Research studies: approximately 54% of the initial UK Biobank sample and 55.6% of the Lundbeck Foundation Initiative for Integrative Psychiatric Research sample selected for the ASRD GWAS were women. In a combined sample size of 737 473 study participants, single-variable MR showed that genetic liability for increased prescription opioid use was associated with increased risk of both MDD (odds ratio [OR] per unit increase in log odds opioid use, 1.14; 95% CI, 1.06-1.22; P

Published
2020

90. Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation

Author

Lohoff, Falk W., primary, Roy, Arunima, additional, Jung, Jeesun, additional, Longley, Martha, additional, Rosoff, Daniel B., additional, Luo, Audrey, additional, O’Connell, Emma, additional, Sorcher, Jill L., additional, Sun, Hui, additional, Schwandt, Melanie, additional, Hodgkinson, Colin A., additional, Goldman, David, additional, Momenan, Reza, additional, McIntosh, Andrew M., additional, Adams, Mark J., additional, Walker, Rosie M., additional, Evans, Kathryn L., additional, Porteous, David, additional, Smith, Alicia K., additional, Lee, Jisoo, additional, Muench, Christine, additional, Charlet, Katrin, additional, Clarke, Toni-Kim, additional, and Kaminsky, Zachary A., additional

Published
2020
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100. Epigenome-wide association study of alcohol consumption in N= 8161 individuals and relevance to alcohol use disorder pathophysiology: identification of the cystine/glutamate transporter SLC7A11 as a top target

Author

Lohoff, Falk W., Clarke, Toni-Kim, Kaminsky, Zachary A., Walker, Rosie M., Bermingham, Mairead L., Jung, Jeesun, Morris, Stewart W., Rosoff, Daniel, Campbell, Archie, Barbu, Miruna, Charlet, Katrin, Adams, Mark, Lee, Jisoo, Howard, David M., O’Connell, Emma M., Whalley, Heather, Porteous, David J., McIntosh, Andrew M., and Evans, Kathryn L.

Abstract

Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N= 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni pvalue < 6.8 × 10−8) with the five leading probes located in SLC7A11(p= 7.75 × 10−108), JDP2(p= 1.44 × 10−56), GAS5(p= 2.71 × 10−47), TRA2B(p= 3.54 × 10−42), and SLC43A1(p= 1.18 × 10−40). Genes annotated to associated CpG sites are implicated in liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer’s disease. Two-sample Mendelian randomization confirmed the causal relationship of consumption on AUD risk (inverse variance weighted (IVW) p= 5.37 × 10−09). A methylation-based predictor of alcohol consumption was able to discriminate AUD cases in two independent cohorts (p= 6.32 × 10−38and p= 5.41 × 10−14). The top EWAS probe cg06690548, located in the cystine/glutamate transporter SLC7A11, was replicated in an independent cohort of AUD and control participants (N= 615) and showed strong hypomethylation in AUD (p< 10−17). Decreased CpG methylation at this probe was consistently associated with clinical measures including increased heavy drinking days (p< 10−4), increased liver function enzymes (GGT (p= 1.03 × 10−21), ALT (p= 1.29 × 10−6), and AST (p= 1.97 × 10−8)) in individuals with AUD. Postmortem brain analyses documented increased SLC7A11expression in the frontal cortex of individuals with AUD and animal models showed marked increased expression in liver, suggesting a mechanism by which alcohol leads to hypomethylation-induced overexpression of SLC7A11. Taken together, our EWAS discovery sample and subsequent validation of the top probe in AUD suggest a strong role of abnormal glutamate signaling mediated by methylomic variation in SLC7A11. Our data are intriguing given the prominent role of glutamate signaling in brain and liver and might provide an important target for therapeutic intervention.

Published
2022
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