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

Author

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

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

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

Published
2023

2. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

Author

Mullins, Niamh, Kang, JooEun, Campos, Adrian I, Coleman, Jonathan RI, Edwards, Alexis C, Galfalvy, Hanga, Levey, Daniel F, Lori, Adriana, Shabalin, Andrey, Starnawska, Anna, Su, Mei-Hsin, Watson, Hunna J, Adams, Mark, Awasthi, Swapnil, Gandal, Michael, Hafferty, Jonathan D, Hishimoto, Akitoyo, Kim, Minsoo, Okazaki, Satoshi, Otsuka, Ikuo, Ripke, Stephan, Ware, Erin B, Bergen, Andrew W, Berrettini, Wade H, Bohus, Martin, Brandt, Harry, Chang, Xiao, Chen, Wei J, Chen, Hsi-Chung, Crawford, Steven, Crow, Scott, DiBlasi, Emily, Duriez, Philibert, Fernández-Aranda, Fernando, Fichter, Manfred M, Gallinger, Steven, Glatt, Stephen J, Gorwood, Philip, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine A, Hwu, Hai-Gwo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S, Kaye, Walter H, Keel, Pamela K, Kennedy, James L, Klump, Kelly L, Li, Dong, Liao, Shih-Cheng, Lieb, Klaus, Lilenfeld, Lisa, Liu, Chih-Min, Magistretti, Pierre J, Marshall, Christian R, Mitchell, James E, Monson, Eric T, Myers, Richard M, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W, Schmahl, Christian, Sokolowski, Marcus, Strober, Michael, Thornton, Laura M, Treasure, Janet, Tsuang, Ming T, Witt, Stephanie H, Woodside, D Blake, Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Air, Tracy M, Alda, Martin, Alfredsson, Lars, Andreassen, Ole A, Anjorin, Adebayo, Appadurai, Vivek, Soler Artigas, María, Van der Auwera, Sandra, Azevedo, M Helena, Bass, Nicholas, Bau, Claiton HD, Baune, Bernhard T, Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M, Bigdeli, Tim B, Binder, Elisabeth B, Boehnke, Michael, Boks, Marco P, Bosch, Rosa, and Braff, David L

Subjects
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Eating Disorders Working Group of the Psychiatric Genomics Consortium, German Borderline Genomics Consortium, MVP Suicide Exemplar Workgroup, VA Million Veteran Program, Humans, Risk Factors, Suicide, Attempted, Mental Disorders, Depressive Disorder, Major, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic correlation, Genome-wide association study, Pleiotropy, Polygenicity, Suicide, Suicide attempt, Human Genome, Behavioral and Social Science, Mental Health, Prevention, Genetics, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

BackgroundSuicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.MethodsWe conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.ResultsTwo loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.ConclusionsOur results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Published
2022

9. Suicide

Author

Wasserman, Danuta, additional, Sokolowski, Marcus, additional, and Carli, Vladimir, additional

Published
2020
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10. GWAS Meta-Analysis of Suicide Attempt:Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

Author

Docherty, Anna R., Mullins, Niamh, Ashley-Koch, Allison E., Qin, Xuejun, Coleman, Jonathan R.I., Shabalin, Andrey, Kang, Joo Eun, Murnyak, Balasz, Wendt, Frank, Adams, Mark, Campos, Adrian I., DiBlasi, Emily, Fullerton, Janice M., Kranzler, Henry R., Bakian, Amanda V., Monson, Eric T., Rentería, Miguel E., Walss-Bass, Consuelo, Andreassen, Ole A., Behera, Chittaranjan, Bulik, Cynthia M., Edenberg, Howard J., Kessler, Ronald C., John Mann, J., Nurnberger, John I., Pistis, Giorgio, Streit, Fabian, Ursano, Robert J., Polimanti, Renato, Dennis, Michelle, Garrett, Melanie, Hair, Lauren, Harvey, Philip, Hauser, Elizabeth R., Hauser, Michael A., Huffman, Jennifer, Jacobson, Daniel, Madduri, Ravi, McMahon, Benjamin, Oslin, David W., Trafton, Jodie, Awasthi, Swapnil, Berrettini, Wade H., Bohus, Martin, Chang, Xiao, Chen, Hsi Chung, Chen, Wei J., Christensen, Erik D.M.D., Crow, Scott, Duriez, Philibert, Edwards, Alexis C., Fernández-Aranda, Fernando, Galfalvy, Hanga, Gandal, Michael, Gorwood, Philip, Guo, Yiran, Hafferty, Jonathan D., Hakonarson, Hakon, Halmi, Katherine A., Hishimoto, Akitoyo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Kim, Minsoo, Klump, Kelly L., Levey, Daniel F., Li, Dong, Liao, Shih Cheng, Lieb, Klaus, Lilenfeld, Lisa, Marshall, Christian R., Mitchell, James E., Okazaki, Satoshi, Otsuka, Ikuo, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Ripke, Stephan, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Starnawska, Anna, Strober, Michael, Su, Mei Hsin, Thornton, Laura M., Treasure, Janet, Ware, Erin B., Watson, Hunna J., Witt, Stephanie H., Blake Woodside, D., Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Appadurai, Vivek, Artigas, María Soler, Van Der Auwera, Sandra, Helena Azevedo, M., Bass, Nicholas, Bau, Claiton H.D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Corvin, Aiden, Craddock, Nicholas, Djurovic, Srdjan, Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Gatt, Justine M., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamshere, Marian L., Hartmann, Annette M., Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Krebs, Marie Odile, Landén, Mikael, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Mehta, Divya, Melle, Ingrid, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Nievergelt, Caroline, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W.J.H., Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J.S., Trzaskowski, MacIej, Tsuang, Ming T., Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T.R., Weickert, Cynthia Shannon, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Demontis, Ditte, Erlangsen, Annette, Gelernter, Joel, Glatt, Stephen J., Hougaard, David M., Hwu, Hai Gwo, Kuo, Po Hsiu, Lewis, Cathryn M., Li, Qingqin S., Liu, Chih Min, Martin, Nicholas G., McIntosh, Andrew M., Medland, Sarah E., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Willour, Virginia, Coon, Hilary, Beckham, Jean C., Kimbrel, Nathan A., Ruderfer, Douglas M., Docherty, Anna R., Mullins, Niamh, Ashley-Koch, Allison E., Qin, Xuejun, Coleman, Jonathan R.I., Shabalin, Andrey, Kang, Joo Eun, Murnyak, Balasz, Wendt, Frank, Adams, Mark, Campos, Adrian I., DiBlasi, Emily, Fullerton, Janice M., Kranzler, Henry R., Bakian, Amanda V., Monson, Eric T., Rentería, Miguel E., Walss-Bass, Consuelo, Andreassen, Ole A., Behera, Chittaranjan, Bulik, Cynthia M., Edenberg, Howard J., Kessler, Ronald C., John Mann, J., Nurnberger, John I., Pistis, Giorgio, Streit, Fabian, Ursano, Robert J., Polimanti, Renato, Dennis, Michelle, Garrett, Melanie, Hair, Lauren, Harvey, Philip, Hauser, Elizabeth R., Hauser, Michael A., Huffman, Jennifer, Jacobson, Daniel, Madduri, Ravi, McMahon, Benjamin, Oslin, David W., Trafton, Jodie, Awasthi, Swapnil, Berrettini, Wade H., Bohus, Martin, Chang, Xiao, Chen, Hsi Chung, Chen, Wei J., Christensen, Erik D.M.D., Crow, Scott, Duriez, Philibert, Edwards, Alexis C., Fernández-Aranda, Fernando, Galfalvy, Hanga, Gandal, Michael, Gorwood, Philip, Guo, Yiran, Hafferty, Jonathan D., Hakonarson, Hakon, Halmi, Katherine A., Hishimoto, Akitoyo, Jain, Sonia, Jamain, Stéphane, Jiménez-Murcia, Susana, Johnson, Craig, Kaplan, Allan S., Kaye, Walter H., Keel, Pamela K., Kennedy, James L., Kim, Minsoo, Klump, Kelly L., Levey, Daniel F., Li, Dong, Liao, Shih Cheng, Lieb, Klaus, Lilenfeld, Lisa, Marshall, Christian R., Mitchell, James E., Okazaki, Satoshi, Otsuka, Ikuo, Pinto, Dalila, Powers, Abigail, Ramoz, Nicolas, Ripke, Stephan, Roepke, Stefan, Rozanov, Vsevolod, Scherer, Stephen W., Schmahl, Christian, Sokolowski, Marcus, Starnawska, Anna, Strober, Michael, Su, Mei Hsin, Thornton, Laura M., Treasure, Janet, Ware, Erin B., Watson, Hunna J., Witt, Stephanie H., Blake Woodside, D., Yilmaz, Zeynep, Zillich, Lea, Adolfsson, Rolf, Agartz, Ingrid, Alda, Martin, Alfredsson, Lars, Appadurai, Vivek, Artigas, María Soler, Van Der Auwera, Sandra, Helena Azevedo, M., Bass, Nicholas, Bau, Claiton H.D., Baune, Bernhard T., Bellivier, Frank, Berger, Klaus, Biernacka, Joanna M., Bigdeli, Tim B., Binder, Elisabeth B., Boehnke, Michael, Boks, Marco P., Braff, David L., Bryant, Richard, Budde, Monika, Byrne, Enda M., Cahn, Wiepke, Castelao, Enrique, Cervilla, Jorge A., Chaumette, Boris, Corvin, Aiden, Craddock, Nicholas, Djurovic, Srdjan, Foo, Jerome C., Forstner, Andreas J., Frye, Mark, Gatt, Justine M., Giegling, Ina, Grabe, Hans J., Green, Melissa J., Grevet, Eugenio H., Grigoroiu-Serbanescu, Maria, Gutierrez, Blanca, Guzman-Parra, Jose, Hamshere, Marian L., Hartmann, Annette M., Hauser, Joanna, Heilmann-Heimbach, Stefanie, Hoffmann, Per, Ising, Marcus, Jones, Ian, Jones, Lisa A., Jonsson, Lina, Kahn, René S., Kelsoe, John R., Kendler, Kenneth S., Kloiber, Stefan, Koenen, Karestan C., Kogevinas, Manolis, Krebs, Marie Odile, Landén, Mikael, Leboyer, Marion, Lee, Phil H., Levinson, Douglas F., Liao, Calwing, Lissowska, Jolanta, Mayoral, Fermin, McElroy, Susan L., McGrath, Patrick, McGuffin, Peter, McQuillin, Andrew, Mehta, Divya, Melle, Ingrid, Mitchell, Philip B., Molina, Esther, Morken, Gunnar, Nievergelt, Caroline, Nöthen, Markus M., O'Donovan, Michael C., Ophoff, Roel A., Owen, Michael J., Pato, Carlos, Pato, Michele T., Penninx, Brenda W.J.H., Potash, James B., Power, Robert A., Preisig, Martin, Quested, Digby, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Ribasés, Marta, Richarte, Vanesa, Rietschel, Marcella, Rivera, Margarita, Roberts, Andrea, Roberts, Gloria, Rouleau, Guy A., Rovaris, Diego L., Sanders, Alan R., Schofield, Peter R., Schulze, Thomas G., Scott, Laura J., Serretti, Alessandro, Shi, Jianxin, Sirignano, Lea, Sklar, Pamela, Smeland, Olav B., Smoller, Jordan W., Sonuga-Barke, Edmund J.S., Trzaskowski, MacIej, Tsuang, Ming T., Turecki, Gustavo, Vilar-Ribó, Laura, Vincent, John B., Völzke, Henry, Walters, James T.R., Weickert, Cynthia Shannon, Weickert, Thomas W., Weissman, Myrna M., Williams, Leanne M., Wray, Naomi R., Zai, Clement C., Agerbo, Esben, Børglum, Anders D., Breen, Gerome, Demontis, Ditte, Erlangsen, Annette, Gelernter, Joel, Glatt, Stephen J., Hougaard, David M., Hwu, Hai Gwo, Kuo, Po Hsiu, Lewis, Cathryn M., Li, Qingqin S., Liu, Chih Min, Martin, Nicholas G., McIntosh, Andrew M., Medland, Sarah E., Mors, Ole, Nordentoft, Merete, Olsen, Catherine M., Porteous, David, Smith, Daniel J., Stahl, Eli A., Stein, Murray B., Wasserman, Danuta, Werge, Thomas, Whiteman, David C., Willour, Virginia, Coon, Hilary, Beckham, Jean C., Kimbrel, Nathan A., and Ruderfer, Douglas M.

Abstract

Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide asso-ciation studies (GWASs) recently discovered and cross- validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic co-horts from both studies to conduct the largest GWAS meta- analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry ad-mixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and ge-netic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10–8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10–80). Significant brain tissue gene expression and drug set en-richment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major de-pressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical pheno-types. These findings provide insight into genetic fa, Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and crossvalidated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS metaanalysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attemp

Published
2023

11. Polygenic risk scores for neuropsychiatric, inflammatory, and cardio‐metabolic traits highlight possible genetic overlap with suicide attempt and treatment‐emergent suicidal ideation

Author

Fanelli, Giuseppe, Sokolowski, Marcus, Wasserman, Danuta, Kasper, Siegfried, Zohar, Joseph, Souery, Daniel, Montgomery, Stuart, Albani, Diego, Forloni, Gianluigi, Ferentinos, Panagiotis, Rujescu, Dan, Mendlewicz, Julien, De Ronchi, Diana, Serretti, Alessandro, Fabbri, Chiara, Fanelli, Giuseppe, Sokolowski, Marcu, Wasserman, Danuta, Kasper, Siegfried, Zohar, Joseph, Souery, Daniel, Montgomery, Stuart, Albani, Diego, Forloni, Gianluigi, Ferentinos, Panagioti, Rujescu, Dan, Mendlewicz, Julien, De Ronchi, Diana, Serretti, Alessandro, and Fabbri, Chiara

Subjects
Depressive Disorder, Major, major depressive disorder, Adolescent, Risk Factor, treatment-worsening/emergent suicidal ideation, Suicide, Attempted, Coronary Artery Disease, Suicidal Ideation, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Phenotype, Risk Factors, gene set, polygenic risk score, Humans, Genetic Predisposition to Disease, suicide, Genetics (clinical), Genome-Wide Association Study, Human
Abstract

Suicide is the second cause of death among youths. Genetics may contribute to suicidal phenotypes and their co-occurrence in other neuropsychiatric and medical conditions. Our study aimed to investigate the association of polygenic risk scores (PRSs) for 24 neuropsychiatric, inflammatory, and cardio-metabolic traits/diseases with suicide attempt (SA) or treatment-worsening/emergent suicidal ideation (TWESI). PRSs were computed based on summary statistics of genome-wide association studies. Regression analyses were performed between PRSs and SA or TWESI in four clinical cohorts. Results were then meta-analyzed across samples, including a total of 688 patients with SA (N-eff = 2,258) and 214 with TWESI (N-eff = 785). Stratified genetic covariance analyses were performed to investigate functionally cross-phenotype PRS associations. After Bonferroni correction, PRS for major depressive disorder (MDD) was associated with SA (OR = 1.24; 95% CI = 1.11-1.38; p = 1.73 x 10(-4)). Nominal associations were shown between PRSs for coronary artery disease (CAD) (p = 4.6 x 10(-3)), loneliness (p = .009), or chronic pain (p = .016) and SA, PRSs for MDD or CAD and TWESI (p = .043 and p = .032, respectively). Genetic covariance between MDD and SA was shown in 86 gene sets related to drugs having antisuicidal effects. A higher genetic liability for MDD may underlie a higher SA risk. Further, but milder, possible modulatory factors are genetic risk for loneliness and CAD.

Published
2022

13. Skadehändelser från broar i Sverige under år 2008–2020 samt metod för framtagande av underlag

Author

Andersson, Anna-Lena, Riesenfeld, Marcus, Fredin-Knutzén, Johan, Hadlaczky, Gergö, Sokolowski, Marcus, Andersson, Anna-Lena, Riesenfeld, Marcus, Fredin-Knutzén, Johan, Hadlaczky, Gergö, and Sokolowski, Marcus

Abstract

Det finns en särskild metodik framtagen för att klassificera vilka dödsfall inom vägtrafik och på den statliga järnvägen som är suicid respektive olycka. Det har hittills saknats en metodik för att redovisa tillförlitliga och sammanställda data över hur många personer som varje år tar sitt liv genom hopp eller faller från specificerade broar. Det beror bland annat på komplexiteten när det gäller tillgång till underlag för bedömning av dödssätt och dödsorsak. Registrering av dessa händelser inom olika myndigheter sker inte utifrån samma sökord eller kriterier vilket gör jämförelse mellan olika myndigheters underlag svårt. Genom att välja sökord och kombinera dem med ICD-koder (International Classification of Diseases and related health problems) i Rättsmedicinalverkets databas RitabQL har data tagits fram för tidsperioden 2008–2020. Perioden har valts därför att det under denna tidsperiod finns aktuella handlingar sparade digitalt i Rättsmedicinalverkets databas. Dessa ärenden har sedan granskats av en statistiker och en specialistläkare i rättsmedicin samt i vissa fall kompletterats meddata från utredare inom polisen., Rapport i samarbete mellan Trafikverket, Rättsmedicinalverket och Nationellt Centrum för Suicidforskning och Prevention (NASP) vid Karolinska Institutet och Region Stockholm

Published
2022

17. The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt

Author

Rozanov Vsevolod, Sokolowski Marcus, Geijer Thomas, Wasserman Danuta, and Wasserman Jerzy

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

Abstract Background Serotonergic neurotransmission has been implicated in suicidal behavior. Association between suicidal completers and a regulatory C(-1019)G polymorphism (rs6295) in the serotonin 1A receptor (HTR1A) gene was previously reported, whereas a following study showed no association in a sample of suicide attempters. Methods The involvement of the implicated G-allele of the 5-HTR1A C(-1019)G polymorphism (rs6295) was analyzed with the transmission disequilibrium test (TDT) in a sample of 272 suicide attempter families. Results No overtransmission of the G-allele was found in the entire sample of suicide attempters (p = 0.1460; n = 272 trios). However, a strong trend for overtransmission of the G-allele was observed in a sub-sample selected for a high level of previous traumatic and/or stressful life events prior to the suicide attempt (p = 0.0630, two-tail; n = 94 trios). Conclusion The current results show that variation at the rs6295 polymorphism of the HTR1A gene is not associated with suicide attempts generally. However, the results indicate a possible role of the G-allele in suicidal behavior in connection with high exposure to traumatic and/or stressful life events, which is in need of future investigation.

Published
2006
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22. The Exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins

Author

Hessle, Viktoria, Björk, Petra, Sokolowski, Marcus, de Valdivia, Gonzalez, Silverstein, Rebecca, Artemenko, Konstantin, Tyagi, Anu, Maddalo, Gianluca, Ilag, Leopold, Helbig, Roger, Zubarev, Roman A., Visa, Neus, Hessle, Viktoria, Björk, Petra, Sokolowski, Marcus, de Valdivia, Gonzalez, Silverstein, Rebecca, Artemenko, Konstantin, Tyagi, Anu, Maddalo, Gianluca, Ilag, Leopold, Helbig, Roger, Zubarev, Roman A., and Visa, Neus

Abstract

Eukaryotic cells have evolved quality control mechanisms to degrade aberrant mRNA molecules and prevent the synthesis of defective proteins that could be deleterious for the cell. The exosome, a protein complex with ribonuclease activity, is a key player in quality control. An early quality checkpoint takes place cotranscriptionally but little is known about the molecular mechanisms by which the exosome is recruited to the transcribed genes. Here we study the core exosome subunit Rrp4 in two insect model systems, Chironomus and Drosophila. We show that a significant fraction of Rrp4 is associated with the nascent pre-mRNPs and that a specific mRNA-binding protein, Hrp59/hnRNP M, interacts in vivo with multiple exosome subunits. Depletion of Hrp59 by RNA interference reduces the levels of Rrp4 at transcription sites, which suggests that Hrp59 is needed for the exosome to stably interact with nascent pre-mRNPs. Our results lead to a revised mechanistic model for cotranscriptional quality control in which the exosome is constantly recruited to newly synthesized RNAs through direct interactions with specific hnRNP proteins.

Published
2009
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24. The Exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins

Author

Hessle, Viktoria, primary, Björk, Petra, additional, Sokolowski, Marcus, additional, González de Valdivia, Ernesto, additional, Silverstein, Rebecca, additional, Artemenko, Konstantin, additional, Tyagi, Anu, additional, Maddalo, Gianluca, additional, Ilag, Leopold, additional, Helbig, Roger, additional, Zubarev, Roman A., additional, and Visa, Neus, additional

Published
2009
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27. Control of human papillomavirus type 1 late mRNA stability and translation by an AU-rich RNA element

Author

Sokolowski, Marcus and Sokolowski, Marcus

Abstract

Human Papillomaviruses (HPVs) infect the epithelial tissues in humans and infection with certain high-risk types is associated with cancer. The expressionof the HPV late capsid genes is dependent on cell differentiation. This may be one reason for the lack of HPV replication in vitro. Here we have studied an AU-rich sequence in the 3´ untranslated region (UTR) on the HPV type 1 (HPV-1) late mRNAs that acts in cis to posttranscriptionally inhibit HPV late gene expression in undifferentiated cells. Mapping revealed that the minimal AU-rich element (ARE) was 57 nts long, 93% AU-rich and that point mutations in two AUUUA- and three UUUUU-motifs inactivated the ARE. Analysis of the mRNA stability in HeLa cells showed that mRNAs containing the HPV-1 ARE (h1ARE) had reduced half life. The h1ARE also acted by suppressing translation independently of the effect on mRNA stability. Inhibition of translation appeared to occur by suppressing a function mediated by the 3´-poly(A) tails. Analysis of RNA-protein interactions in vitro revealed that both cytoplasmic and nuclear proteins interacted specifically with the h1ARE. Three cellular proteins were identified as the heterogeneous nuclear ribonucleoproteins (hnRNPs) C1 and C2 and the HuR protein. Recombinant HuR protein bound specifically to the AUUUA- and UUUUU-sites within the h1ARE and the apparent Kd value of HuR binding to the h1ARE or the inactive mutants thereof differed more than 50 fold. Binding of HuR and hnRNPC1/C2 to the AUUUA- and UUUUU-motifs suggested their importance for the function of the h1ARE. The h1ARE was the major negative element on HPV-1 late mRNAs whereas HPV-16 late mRNAs contained multiple negative elements. The number of negative elements correlated with the levels of virions produced by these HPV types in vivo.

Published
1999

35. The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt.

Author

Wasserman, Danuta, Geijer, Thomas, Sokolowski, Marcus, Rozanov, Vsevolod, and Wasserman, Jerzy

Subjects
SEROTONINERGIC mechanisms, SUICIDAL behavior, SEROTONIN, NEURAL transmission, GENETIC polymorphisms
Abstract

Background: Serotonergic neurotransmission has been implicated in suicidal behavior. Association between suicidal completers and a regulatory C(-1019)G polymorphism (rs6295) in the serotonin 1A receptor (HTR1A) gene was previously reported, whereas a following study showed no association in a sample of suicide attempters. Methods: The involvement of the implicated G-allele of the 5-HTR1A C(-1019)G polymorphism (rs6295) was analyzed with the transmission disequilibrium test (TDT) in a sample of 272 suicide attempter families. Results: No overtransmission of the G-allele was found in the entire sample of suicide attempters (p = 0.1460; n = 272 trios). However, a strong trend for overtransmission of the G-allele was observed in a sub-sample selected for a high level of previous traumatic and/or stressful life events prior to the suicide attempt (p = 0.0630, two-tail; n = 94 trios). Conclusion: The current results show that variation at the rs6295 polymorphism of the HTR1A gene is not associated with suicide attempts generally. However, the results indicate a possible role of the G-allele in suicidal behavior in connection with high exposure to traumatic and/or stressful life events, which is in need of future investigation. [ABSTRACT FROM AUTHOR]

Published
2006
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36. Translational Inhibition in Vitroof Human Papillomavirus Type 16 L2 mRNA Mediated through Interaction with Heterogenous Ribonucleoprotein K and Poly(rC)-binding Proteins 1 and 2*

Author

Collier, Brian, Goobar-Larsson, Laura, Sokolowski, Marcus, and Schwartz, Stefan

Abstract

Human papillomavirus (HPV) type 16 belongs to the group of “high risk” HPV types that are frequently detected in anogenital cancers. The expression of HPV-16 late genes encoding the virus capsid proteins L1 and L2 is restricted to terminally differentiated epithelial cells in the superficial layers of the squamous epithelium. We have previously identified negative elements in the 3′ end of L2 RNA that act in cisto reduce mRNA utilization without substantially affecting mRNA levels. The experiments reported here demonstrate the interaction of cellular proteins with an inhibitory sequence present in the coding region of the L2 mRNA. Using RNA gel shift assays and UV cross-linking, we have detected three cellular proteins interacting specifically with the sense strand of the L2 mRNA, two of which were identified as heterogeneous ribonucleoprotein K (hnRNP K) and the poly(rC) binding- protein (PCBP). Recombinant hnRNP K, PCBP-1, and PCBP-2 that were over expressed in bacteria and partially purified bound to the HPV-16 L2 mRNA in a sequence-specific manner. Interestingly, PCBP-1, PCBP-2, and hnRNP K specifically and efficiently inhibited translation of the HPV-16 L2 mRNA in vitro. Therefore, these proteins may play an important role in the regulation of HPV-16 late gene expression and virus production in vivo.

Published
1998
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37. [The European Psychiatric Association (EPA) guidance on suicide treatment and prevention].

Author

Wasserman D, Rihmer Z, Rujescu D, Sarchiapone M, Sokolowski M, Titelman D, Zalsman G, Zemishlany Z, and Carli V

Subjects
Adolescent, Adolescent Development, Europe, Family Therapy, Humans, Mental Disorders complications, Mental Disorders diagnosis, Mental Disorders therapy, Patient Safety, Practice Guidelines as Topic, Psychiatry, Risk Assessment, Risk Factors, Social Support, Societies, Medical, Primary Prevention methods, Suicidal Ideation, Suicide, Attempted prevention & control, Suicide, Attempted psychology
Abstract

Unlabelled: Suicide is a major public health problem in the WHO European Region accounting for over 150,000 deaths per year. Suicidal crisis: Acute intervention should start immediately in order to keep the patient alive., Diagnosis: An underlying psychiatric disorder is present in up to 90% of people who completed suicide. Comorbidity with depression, anxiety, substance abuse and personality disorders is high. In order to achieve successful prevention of suicidality, adequate diagnostic procedures and appropriate treatment for the underlying disorder are essential., Treatment: Existing evidence supports the efficacy of pharmacological treatment and cognitive behavioural therapy (CBT) in preventing suicidal behaviour. Some other psychological treatments are promising, but the supporting evidence is currently insufficient. Studies show that antidepressant treatment decreases the risk for suicidality among depressed patients. However, the risk of suicidal behaviour in depressed patients treated with antidepressants exists during the first 10-14 days of treatment, which requires careful monitoring. Short-term supplementary medication with anxiolytics and hypnotics in the case of anxiety and insomnia is recommended. TREATMENT with antidepressants of children and adolescents should only be given under supervision of a specialist. Long-term treatment with lithium has been shown to be effective in preventing both suicide and attempted suicide in patients with unipolar and bipolar depression. TREATMENT with clozapine is effective in reducing suicidal behaviour in patients with schizophrenia. Other atypical antipsychotics are promising but more evidence is required. TREATMENT team: Multidisciplinary treatment teams including psychiatrist and other professionals such as psychologist, social worker, and occupational therapist are always preferable, as integration of pharmacological, psychological and social rehabilitation is recommended especially for patients with chronic suicidality. Family: The suicidal person independently of age should always be motivated to involve family in the treatment. Social support: Psychosocial treatment and support is recommended, as the majority of suicidal patients have problems with relationships, work, school and lack functioning social networks., Safety: A secure home, public and hospital environment, without access to suicidal means is a necessary strategy in suicide prevention. Each treatment option, prescription of medication and discharge of the patient from hospital should be carefully evaluated against the involved risks. Training of personnel: Training of general practitioners (GPs) is effective in the prevention of suicide. It improves treatment of depression and anxiety, quality of the provided care and attitudes towards suicide. Continuous training including discussions about ethical and legal issues is necessary for psychiatrists and other mental health professionals.

Published
2012

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