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2. Artificial Intelligence for Dementia Research Methods Optimization

Author

Bucholc, Magda, James, Charlotte, Khleifat, Ahmad Al, Badhwar, AmanPreet, Clarke, Natasha, Dehsarvi, Amir, Madan, Christopher R., Marzi, Sarah J., Shand, Cameron, Schilder, Brian M., Tamburin, Stefano, Tantiangco, Hanz M., Lourida, Ilianna, Llewellyn, David J., and Ranson, Janice M.

Subjects
Computer Science - Machine Learning, Quantitative Biology - Quantitative Methods, Statistics - Applications, Statistics - Methodology
Abstract

Introduction: Machine learning (ML) has been extremely successful in identifying key features from high-dimensional datasets and executing complicated tasks with human expert levels of accuracy or greater. Methods: We summarize and critically evaluate current applications of ML in dementia research and highlight directions for future research. Results: We present an overview of ML algorithms most frequently used in dementia research and highlight future opportunities for the use of ML in clinical practice, experimental medicine, and clinical trials. We discuss issues of reproducibility, replicability and interpretability and how these impact the clinical applicability of dementia research. Finally, we give examples of how state-of-the-art methods, such as transfer learning, multi-task learning, and reinforcement learning, may be applied to overcome these issues and aid the translation of research to clinical practice in the future. Discussion: ML-based models hold great promise to advance our understanding of the underlying causes and pathological mechanisms of dementia., Comment: Magda Bucholc and Charlotte James joint first authors

Published
2023

3. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, Niamh, Forstner, Andreas J, O’Connell, Kevin S, Coombes, Brandon, Coleman, Jonathan RI, Qiao, Zhen, Als, Thomas D, Bigdeli, Tim B, Børte, Sigrid, Bryois, Julien, Charney, Alexander W, Drange, Ole Kristian, Gandal, Michael J, Hagenaars, Saskia P, Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M, Sloofman, Laura G, Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S, Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bækvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C, Bergen, Sarah E, Birner, Armin, Bøcker Pedersen, Carsten, Bøen, Erlend, Boks, Marco P, Bosch, Rosa, Brum, Murielle, Brumpton, Ben M, Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M, Dale, Anders M, Dalkner, Nina, David, Friederike S, Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L, Douzenis, Athanassios, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Ferrier, I Nicol, Fiorentino, Alessia, Foroud, Tatiana M, Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B, Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Giørtz Pedersen, Marianne, Gizer, Ian R, Gordon, Scott D, Gordon-Smith, Katherine, Greenwood, Tiffany A, Grove, Jakob, Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A, Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S, and Kalman, Janos L

Subjects
Biological Sciences, Genetics, Biotechnology, Serious Mental Illness, Human Genome, Bipolar Disorder, Neurosciences, Brain Disorders, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Neurological, Mental health, Good Health and Well Being, Case-Control Studies, Chromosomes, Human, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Major Histocompatibility Complex, Multifactorial Inheritance, Phenotype, Quantitative Trait Loci, Risk Factors, HUNT All-In Psychiatry, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2021

4. FAIRshake: Toolkit to Evaluate the FAIRness of Research Digital Resources

Author

Clarke, Daniel JB, Wang, Lily, Jones, Alex, Wojciechowicz, Megan L, Torre, Denis, Jagodnik, Kathleen M, Jenkins, Sherry L, McQuilton, Peter, Flamholz, Zachary, Silverstein, Moshe C, Schilder, Brian M, Robasky, Kimberly, Castillo, Claris, Idaszak, Ray, Ahalt, Stanley C, Williams, Jason, Schurer, Stephan, Cooper, Daniel J, de Miranda Azevedo, Ricardo, Klenk, Juergen A, Haendel, Melissa A, Nedzel, Jared, Avillach, Paul, Shimoyama, Mary E, Harris, Rayna M, Gamble, Meredith, Poten, Rudy, Charbonneau, Amanda L, Larkin, Jennie, Brown, C Titus, Bonazzi, Vivien R, Dumontier, Michel J, Sansone, Susanna-Assunta, and Ma'ayan, Avi

Subjects
Generic health relevance, Health Resources, Humans, Information Dissemination, Internet, Online Systems, Biochemistry and Cell Biology
Abstract

As more digital resources are produced by the research community, it is becoming increasingly important to harmonize and organize them for synergistic utilization. The findable, accessible, interoperable, and reusable (FAIR) guiding principles have prompted many stakeholders to consider strategies for tackling this challenge. The FAIRshake toolkit was developed to enable the establishment of community-driven FAIR metrics and rubrics paired with manual and automated FAIR assessments. FAIR assessments are visualized as an insignia that can be embedded within digital-resources-hosting websites. Using FAIRshake, a variety of biomedical digital resources were manually and automatically evaluated for their level of FAIRness.

Published
2019

6. Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies

Author

Lopes, Katia de Paiva, Snijders, Gijsje J. L., Humphrey, Jack, Allan, Amanda, Sneeboer, Marjolein A. M., Navarro, Elisa, Schilder, Brian M., Vialle, Ricardo A., Parks, Madison, Missall, Roy, van Zuiden, Welmoed, Gigase, Frederieke A. J., Kübler, Raphael, van Berlekom, Amber Berdenis, Hicks, Emily M., Bӧttcher, Chotima, Priller, Josef, Kahn, René S., de Witte, Lot D., and Raj, Towfique

Published
2022
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7. Fine-mapping genomic loci refines bipolar disorder risk genes

Author

Koromina, Maria, primary, Ravi, Ashvin, additional, Panagiotaropoulou, Georgia, additional, Schilder, Brian M., additional, Humphrey, Jack, additional, Braun, Alice, additional, Bidgeli, Tim, additional, Chatzinakos, Chris, additional, Coombes, Brandon, additional, Kim, Jaeyoung, additional, Liu, Xiaoxi, additional, Terao, Chikashi, additional, O'Connell, Kevin S., additional, Adams, Mark, additional, Adolfsson, Rolf, additional, Alda, Martin, additional, Alfredsson, Lars, additional, Andlauer, Till F.M., additional, Andreassen, Ole A., additional, Antoniou, Anastasia, additional, Baune, Bernhard T., additional, Bengesser, Susanne, additional, Biernacka, Joanna, additional, Boehnke, Michael, additional, Bosch, Rosa, additional, Cairns, Murray, additional, Carr, Vaughan J., additional, Casas, Miquel, additional, Catts, Stanley, additional, Cichon, Sven, additional, Corvin, Aiden, additional, Craddock, Nicholas, additional, Dafnas, Konstantinos, additional, Dalkner, Nina, additional, Dannlowski, Udo, additional, Degenhardt, Franziska, additional, Di Florio, Arianna, additional, Dikeos, Dimitris, additional, Fellendorf, Frederike Tabea, additional, Ferentinos, Panagiotis, additional, Forstner, Andreas J., additional, Forty, Liz, additional, Frye, Mark, additional, Fullerton, Janice M., additional, Gawlik, Micha, additional, Gizer, Ian R., additional, Gordon-Smith, Katherine, additional, Green, Melissa J., additional, Grigoroiu-Serbanescu, Maria, additional, Guzman-Parra, Josep, additional, Hahn, Tim, additional, Henskens, Frans, additional, Hillert, Jan, additional, Jablensky, Assen V., additional, Jones, Lisa, additional, Jones, Ian, additional, Jonsson, Lina, additional, Kelsoe, John R., additional, Kircher, Tilo, additional, Kirov, George, additional, Kittel-Schneider, Sarah, additional, Kogevinas, Manolis, additional, Landen, Mikael, additional, Leboyer, Marion, additional, Lenger, Melanie, additional, Lissowska, Jolanta, additional, Lochner, Christine, additional, Loughland, Carmel, additional, MacIntyre, Donald, additional, Martin, Nicholas G., additional, Maratou, Eirini, additional, Mathews, Carol A., additional, Mayoral, Fermin, additional, McElroy, Susan L., additional, McGregor, Nathaniel W., additional, McIntosh, Andrew, additional, McQuillin, Andrew, additional, Michie, Patricia, additional, Mitchell, Philip B., additional, Moutsatsou, Paraskevi, additional, Mowry, Bryan, additional, Mueller-Myhsok, Bertram, additional, Myers, Richard, additional, Nenadic, Igor, additional, Noethen, Markus M., additional, O'Donovan, Michael, additional, O'Donovan, Claire, additional, Ophoff, Roel A., additional, Owen, Michael J., additional, Pantelis, Chris, additional, Pato, Carlos, additional, Pato, Michele T., additional, Patrinos, George P., additional, Pawlak, Joanna M., additional, Perlis, Roy H., additional, Porichi, Evgenia, additional, Posthuma, Danielle, additional, Ramos-Quiroga, Josep Antoni, additional, Reif, Andreas, additional, Reininghaus, Eva Z., additional, Ribases, Marta, additional, Rietschel, Marcella, additional, Schall, Ulrich, additional, Schulze, Thomas G., additional, Scott, Laura, additional, Scott, Rodney J., additional, Serretti, Alessandro, additional, Shannon Weickert, Cynthia, additional, Smoller, Jordan W., additional, Soler Artigas, Maria Soler, additional, Stein, Dan J., additional, Streit, Fabian, additional, Toma, Claudio, additional, Tooney, Paul, additional, Vieta, Eduard, additional, Vincent, John B., additional, Waldman, Irwin D., additional, Weickert, Thomas, additional, Witt, Stephanie H., additional, Swiatkowska, Beata, additional, Hong, Kyung Sue Sue, additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Won, Hong-Hee, additional, Edenberg, Howard J., additional, Ripke, Stephan, additional, Raj, Towfique, additional, Coleman, Jonathan R. I., additional, and Mullins, Niamh, additional

Published
2024
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8. Dysregulation of mitochondrial and proteolysosomal genes in Parkinson’s disease myeloid cells

Author

Navarro, Elisa, Udine, Evan, Lopes, Katia de Paiva, Parks, Madison, Riboldi, Giulietta, Schilder, Brian M., Humphrey, Jack, Snijders, Gijsje J. L., Vialle, Ricardo A., Zhuang, Maojuan, Sikder, Tamjeed, Argyrou, Charalambos, Allan, Amanda, Chao, Michael J., Farrell, Kurt, Henderson, Brooklyn, Simon, Sarah, Raymond, Deborah, Elango, Sonya, Ortega, Roberto A., Shanker, Vicki, Swan, Matthew, Zhu, Carolyn W., Ramdhani, Ritesh, Walker, Ruth H., Tse, Winona, Sano, Mary, Pereira, Ana C., Ahfeldt, Tim, Goate, Alison M., Bressman, Susan, Crary, John F., de Witte, Lotje, Frucht, Steven, Saunders-Pullman, Rachel, and Raj, Towfique

Published
2021
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10. Fine-mapping genomic loci refines bipolar disorder risk genes

Author

Koromina, Maria, Ravi, Ashvin, Panagiotaropoulou, Georgia, Schilder, Brian M., Humphrey, Jack, Braun, Alice, Bidgeli, Tim, Chatzinakos, Chris, Coombes, Brandon, Kim, Jaeyoung, Liu, Xiaoxi, Terao, Chikashi, O'Connell, Kevin S., Adams, Mark, Adolfsson, Rolf, Alda, Martin, Alfredsson, Lars, Andlauer, Till, Andreassen, Ole A., Antoniou, Anastasia, Baune, Bernhard T., Bengesser, Susanne, Biernacka, Joanna, Boehnke, Michael, Bosch, Rosa, Cairns, Murray, Carr, Vaughan J., Casas Brugué, Miquel, Catts, Stanley, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Dafnas, Konstantinos, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Di Florio, Arianna, Dikeos, Dimitris, Fellendorf, Frederike Tabea, Ferentinos, Panagiotis, Forstner, Andreas Josef, Forty, Liz, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gizer, Ian R., Gordon-Smith, Katherine, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Guzman-Parra, José, Hahn, Tim, Henskens, Frans, Hillert, Jan, Jablensky, Assen V., Jones, Lisa, Jones, Ian, Jonsson, Lina, Kelsoe, John R., Kircher, Tilo, Kirov, George, Kittel-Schneider, Sarah, Kogevinas, Manolis, Landén, Mikael, Leboyer, Marion, Lenger, Melanie, Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, MacIntyre, Donald, Martin, Nicholas G., Maratou, Eirini, Mathews, Carol A., Mayoral, Fermı́n, McElroy, Susan L., McGregor, Nathaniel W., McIntosh, Andrew M., McQuillin, Andrew, Michie, Patricia, Milanova, Vihra, Mitchell, Philip B., Moutsatsou, Paraskevi, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Nenadić, Igor, Nöthen, Markus Maria, O'Donovan, Claire, O'Donovan, Michael, Ophoff, Roel André, Owen, Michael J., Pantelis, Christos, Pato, Carlos, Pato, Michele T., Patrinos, George P., Pawlak, Joanna M., Perlis, Roy H., Porichi, Evgenia, Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Schall, Ulrich, Schulze, Thomas Gerd, Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Soler Artigas, Marı́a, Stein, Dan J., Streit, Fabian, Toma, Claudio, Tooney, Paul, Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas, Witt, Stephanie H., Hong, Kyung Sue, Ikeda, Masashi, Iwata, Nakao, Świątkowska, Beata, Won, Hong-Hee, Edenberg, Howard J., Ripke, Stephan, Raj, Towfique, Coleman, Jonathan R. I., Mullins, Niamh, Koromina, Maria, Ravi, Ashvin, Panagiotaropoulou, Georgia, Schilder, Brian M., Humphrey, Jack, Braun, Alice, Bidgeli, Tim, Chatzinakos, Chris, Coombes, Brandon, Kim, Jaeyoung, Liu, Xiaoxi, Terao, Chikashi, O'Connell, Kevin S., Adams, Mark, Adolfsson, Rolf, Alda, Martin, Alfredsson, Lars, Andlauer, Till, Andreassen, Ole A., Antoniou, Anastasia, Baune, Bernhard T., Bengesser, Susanne, Biernacka, Joanna, Boehnke, Michael, Bosch, Rosa, Cairns, Murray, Carr, Vaughan J., Casas Brugué, Miquel, Catts, Stanley, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Dafnas, Konstantinos, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Di Florio, Arianna, Dikeos, Dimitris, Fellendorf, Frederike Tabea, Ferentinos, Panagiotis, Forstner, Andreas Josef, Forty, Liz, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gizer, Ian R., Gordon-Smith, Katherine, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Guzman-Parra, José, Hahn, Tim, Henskens, Frans, Hillert, Jan, Jablensky, Assen V., Jones, Lisa, Jones, Ian, Jonsson, Lina, Kelsoe, John R., Kircher, Tilo, Kirov, George, Kittel-Schneider, Sarah, Kogevinas, Manolis, Landén, Mikael, Leboyer, Marion, Lenger, Melanie, Lissowska, Jolanta, Lochner, Christine, Loughland, Carmel, MacIntyre, Donald, Martin, Nicholas G., Maratou, Eirini, Mathews, Carol A., Mayoral, Fermı́n, McElroy, Susan L., McGregor, Nathaniel W., McIntosh, Andrew M., McQuillin, Andrew, Michie, Patricia, Milanova, Vihra, Mitchell, Philip B., Moutsatsou, Paraskevi, Mowry, Bryan, Müller-Myhsok, Bertram, Myers, Richard M., Nenadić, Igor, Nöthen, Markus Maria, O'Donovan, Claire, O'Donovan, Michael, Ophoff, Roel André, Owen, Michael J., Pantelis, Christos, Pato, Carlos, Pato, Michele T., Patrinos, George P., Pawlak, Joanna M., Perlis, Roy H., Porichi, Evgenia, Posthuma, Danielle, Ramos-Quiroga, Josep Antoni, Reif, Andreas, Reininghaus, Eva Z., Ribasés, Marta, Rietschel, Marcella, Schall, Ulrich, Schulze, Thomas Gerd, Scott, Laura J., Scott, Rodney J., Serretti, Alessandro, Shannon Weickert, Cynthia, Smoller, Jordan W., Soler Artigas, Marı́a, Stein, Dan J., Streit, Fabian, Toma, Claudio, Tooney, Paul, Vieta, Eduard, Vincent, John B., Waldman, Irwin D., Weickert, Thomas, Witt, Stephanie H., Hong, Kyung Sue, Ikeda, Masashi, Iwata, Nakao, Świątkowska, Beata, Won, Hong-Hee, Edenberg, Howard J., Ripke, Stephan, Raj, Towfique, Coleman, Jonathan R. I., and Mullins, Niamh

Abstract

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Published
2024

11. Artificial intelligence for neurodegenerative experimental models.

Author

Marzi, Sarah J., Schilder, Brian M., Nott, Alexi, Frigerio, Carlo Sala, Willaime‐Morawek, Sandrine, Bucholc, Magda, Hanger, Diane P., James, Charlotte, Lewis, Patrick A., Lourida, Ilianna, Noble, Wendy, Rodriguez‐Algarra, Francisco, Sharif, Jalil‐Ahmad, Tsalenchuk, Maria, Winchester, Laura M., Yaman, Ümran, Yao, Zhi, Ranson, Janice M., and Llewellyn, David J.

Abstract

INTRODUCTION: Experimental models are essential tools in neurodegenerative disease research. However, the translation of insights and drugs discovered in model systems has proven immensely challenging, marred by high failure rates in human clinical trials. METHODS: Here we review the application of artificial intelligence (AI) and machine learning (ML) in experimental medicine for dementia research. RESULTS: Considering the specific challenges of reproducibility and translation between other species or model systems and human biology in preclinical dementia research, we highlight best practices and resources that can be leveraged to quantify and evaluate translatability. We then evaluate how AI and ML approaches could be applied to enhance both cross‐model reproducibility and translation to human biology, while sustaining biological interpretability. DISCUSSION: AI and ML approaches in experimental medicine remain in their infancy. However, they have great potential to strengthen preclinical research and translation if based upon adequate, robust, and reproducible experimental data. Highlights: There are increasing applications of AI in experimental medicine.We identified issues in reproducibility, cross‐species translation, and data curation in the field.Our review highlights data resources and AI approaches as solutions.Multi‐omics analysis with AI offers exciting future possibilities in drug discovery. [ABSTRACT FROM AUTHOR]

Published
2023
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12. Artificial intelligence for dementia genetics and omics.

Author

Bettencourt, Conceicao, Skene, Nathan, Bandres‐Ciga, Sara, Anderson, Emma, Winchester, Laura M., Foote, Isabelle F., Schwartzentruber, Jeremy, Botia, Juan A., Nalls, Mike, Singleton, Andrew, Schilder, Brian M., Humphrey, Jack, Marzi, Sarah J., Toomey, Christina E., Kleifat, Ahmad Al, Harshfield, Eric L., Garfield, Victoria, Sandor, Cynthia, Keat, Samuel, and Tamburin, Stefano

Abstract

Genetics and omics studies of Alzheimer's disease and other dementia subtypes enhance our understanding of underlying mechanisms and pathways that can be targeted. We identified key remaining challenges: First, can we enhance genetic studies to address missing heritability? Can we identify reproducible omics signatures that differentiate between dementia subtypes? Can high‐dimensional omics data identify improved biomarkers? How can genetics inform our understanding of causal status of dementia risk factors? And which biological processes are altered by dementia‐related genetic variation? Artificial intelligence (AI) and machine learning approaches give us powerful new tools in helping us to tackle these challenges, and we review possible solutions and examples of best practice. However, their limitations also need to be considered, as well as the need for coordinated multidisciplinary research and diverse deeply phenotyped cohorts. Ultimately AI approaches improve our ability to interrogate genetics and omics data for precision dementia medicine. Highlights: We have identified five key challenges in dementia genetics and omics studies.AI can enable detection of undiscovered patterns in dementia genetics and omics data.Enhanced and more diverse genetics and omics datasets are still needed.Multidisciplinary collaborative efforts using AI can boost dementia research. [ABSTRACT FROM AUTHOR]

Published
2023
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23. Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies

Author

de Paiva Lopes, Katia, primary, Snijders, Gijsje J. L., additional, Humphrey, Jack, additional, Allan, Amanda, additional, Sneeboer, Marjolein, additional, Navarro, Elisa, additional, Schilder, Brian M., additional, Vialle, Ricardo A., additional, Parks, Madison, additional, Missall, Roy, additional, van Zuiden, Welmoed, additional, Gigase, Frederieke, additional, Kübler, Raphael, additional, van Berlekom, Amber Berdenis, additional, Böttcher, Chotima, additional, Priller, Josef, additional, Kahn, René S., additional, de Witte, Lot D., additional, and Raj, Towfique, additional

Published
2020
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25. Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, Niamh, primary, Forstner, Andreas J., additional, O’Connell, Kevin S., additional, Coombes, Brandon, additional, Coleman, Jonathan R. I., additional, Qiao, Zhen, additional, Als, Thomas D., additional, Bigdeli, Tim B., additional, Børte, Sigrid, additional, Bryois, Julien, additional, Charney, Alexander W., additional, Drange, Ole Kristian, additional, Gandal, Michael J., additional, Hagenaars, Saskia P., additional, Ikeda, Masashi, additional, Kamitaki, Nolan, additional, Kim, Minsoo, additional, Krebs, Kristi, additional, Panagiotaropoulou, Georgia, additional, Schilder, Brian M., additional, Sloofman, Laura G., additional, Steinberg, Stacy, additional, Trubetskoy, Vassily, additional, Winsvold, Bendik S., additional, Won, Hong-Hee, additional, Abramova, Liliya, additional, Adorjan, Kristina, additional, Agerbo, Esben, additional, Al Eissa, Mariam, additional, Albani, Diego, additional, Alliey-Rodriguez, Ney, additional, Anjorin, Adebayo, additional, Antilla, Verneri, additional, Antoniou, Anastasia, additional, Awasthi, Swapnil, additional, Baek, Ji Hyun, additional, Bækvad-Hansen, Marie, additional, Bass, Nicholas, additional, Bauer, Michael, additional, Beins, Eva C., additional, Bergen, Sarah E., additional, Birner, Armin, additional, Bøcker Pedersen, Carsten, additional, Bøen, Erlend, additional, Boks, Marco P., additional, Bosch, Rosa, additional, Brum, Murielle, additional, Brumpton, Ben M., additional, Brunkhorst-Kanaan, Nathalie, additional, Budde, Monika, additional, Bybjerg-Grauholm, Jonas, additional, Byerley, William, additional, Cairns, Murray, additional, Casas, Miquel, additional, Cervantes, Pablo, additional, Clarke, Toni-Kim, additional, Cruceanu, Cristiana, additional, Cuellar-Barboza, Alfredo, additional, Cunningham, Julie, additional, Curtis, David, additional, Czerski, Piotr M., additional, Dale, Anders M., additional, Dalkner, Nina, additional, David, Friederike S., additional, Degenhardt, Franziska, additional, Djurovic, Srdjan, additional, Dobbyn, Amanda L., additional, Douzenis, Athanassios, additional, Elvsåshagen, Torbjørn, additional, Escott-Price, Valentina, additional, Ferrier, I. Nicol, additional, Fiorentino, Alessia, additional, Foroud, Tatiana M., additional, Forty, Liz, additional, Frank, Josef, additional, Frei, Oleksandr, additional, Freimer, Nelson B., additional, Frisén, Louise, additional, Gade, Katrin, additional, Garnham, Julie, additional, Gelernter, Joel, additional, Giørtz Pedersen, Marianne, additional, Gizer, Ian R., additional, Gordon, Scott D., additional, Gordon-Smith, Katherine, additional, Greenwood, Tiffany A., additional, Grove, Jakob, additional, Guzman-Parra, José, additional, Ha, Kyooseob, additional, Haraldsson, Magnus, additional, Hautzinger, Martin, additional, Heilbronner, Urs, additional, Hellgren, Dennis, additional, Herms, Stefan, additional, Hoffmann, Per, additional, Holmans, Peter A., additional, Huckins, Laura, additional, Jamain, Stéphane, additional, Johnson, Jessica S., additional, Kalman, Janos L., additional, Kamatani, Yoichiro, additional, Kennedy, James L., additional, Kittel-Schneider, Sarah, additional, Knowles, James A., additional, Kogevinas, Manolis, additional, Koromina, Maria, additional, Kranz, Thorsten M., additional, Kranzler, Henry R., additional, Kubo, Michiaki, additional, Kupka, Ralph, additional, Kushner, Steven A., additional, Lavebratt, Catharina, additional, Lawrence, Jacob, additional, Leber, Markus, additional, Lee, Heon-Jeong, additional, Lee, Phil H., additional, Levy, Shawn E., additional, Lewis, Catrin, additional, Liao, Calwing, additional, Lucae, Susanne, additional, Lundberg, Martin, additional, MacIntyre, Donald J., additional, Magnusson, Sigurdur H., additional, Maier, Wolfgang, additional, Maihofer, Adam, additional, Malaspina, Dolores, additional, Maratou, Eirini, additional, Martinsson, Lina, additional, Mattheisen, Manuel, additional, McCarroll, Steven A., additional, McGregor, Nathaniel W., additional, McGuffin, Peter, additional, McKay, James D., additional, Medeiros, Helena, additional, Medland, Sarah E., additional, Millischer, Vincent, additional, Montgomery, Grant W., additional, Moran, Jennifer L., additional, Morris, Derek W., additional, Mühleisen, Thomas W., additional, O’Brien, Niamh, additional, O’Donovan, Claire, additional, Loohuis, Loes M. Olde, additional, Oruc, Lilijana, additional, Papiol, Sergi, additional, Pardiñas, Antonio F., additional, Perry, Amy, additional, Pfennig, Andrea, additional, Porichi, Evgenia, additional, Potash, James B., additional, Quested, Digby, additional, Raj, Towfique, additional, Rapaport, Mark H., additional, DePaulo, J. Raymond, additional, Regeer, Eline J., additional, Rice, John P., additional, Rivas, Fabio, additional, Rivera, Margarita, additional, Roth, Julian, additional, Roussos, Panos, additional, Ruderfer, Douglas M., additional, Sánchez-Mora, Cristina, additional, Schulte, Eva C., additional, Senner, Fanny, additional, Sharp, Sally, additional, Shilling, Paul D., additional, Sigurdsson, Engilbert, additional, Sirignano, Lea, additional, Slaney, Claire, additional, Smeland, Olav B., additional, Smith, Daniel J., additional, Sobell, Janet L., additional, Søholm Hansen, Christine, additional, Artigas, Maria Soler, additional, Spijker, Anne T., additional, Stein, Dan J., additional, Strauss, John S., additional, Świątkowska, Beata, additional, Terao, Chikashi, additional, Thorgeirsson, Thorgeir E., additional, Toma, Claudio, additional, Tooney, Paul, additional, Tsermpini, Evangelia-Eirini, additional, Vawter, Marquis P., additional, Vedder, Helmut, additional, Walters, James T. R., additional, Witt, Stephanie H., additional, Xi, Simon, additional, Xu, Wei, additional, Yang, Jessica Mei Kay, additional, Young, Allan H., additional, Young, Hannah, additional, Zandi, Peter P., additional, Zhou, Hang, additional, Zillich, Lea, additional, Psychiatry, HUNT All-In, additional, Adolfsson, Rolf, additional, Agartz, Ingrid, additional, Alda, Martin, additional, Alfredsson, Lars, additional, Babadjanova, Gulja, additional, Backlund, Lena, additional, Baune, Bernhard T., additional, Bellivier, Frank, additional, Bengesser, Susanne, additional, Berrettini, Wade H., additional, Blackwood, Douglas H. R., additional, Boehnke, Michael, additional, Børglum, Anders D., additional, Breen, Gerome, additional, Carr, Vaughan J., additional, Catts, Stanley, additional, Corvin, Aiden, additional, Craddock, Nicholas, additional, Dannlowski, Udo, additional, Dikeos, Dimitris, additional, Esko, Tõnu, additional, Etain, Bruno, additional, Ferentinos, Panagiotis, additional, Frye, Mark, additional, Fullerton, Janice M., additional, Gawlik, Micha, additional, Gershon, Elliot S., additional, Goes, Fernando S., additional, Green, Melissa J., additional, Grigoroiu-Serbanescu, Maria, additional, Hauser, Joanna, additional, Henskens, Frans, additional, Hillert, Jan, additional, Hong, Kyung Sue, additional, Hougaard, David M., additional, Hultman, Christina M., additional, Hveem, Kristian, additional, Iwata, Nakao, additional, Jablensky, Assen V., additional, Jones, Ian, additional, Jones, Lisa A., additional, S. Kahn, René, additional, Kelsoe, John R., additional, Kirov, George, additional, Landén, Mikael, additional, Leboyer, Marion, additional, Lewis, Cathryn M., additional, Li, Qingqin S., additional, Lissowska, Jolanta, additional, Lochner, Christine, additional, Loughland, Carmel, additional, Martin, Nicholas G., additional, Mathews, Carol A., additional, Mayoral, Fermin, additional, McElroy, Susan L., additional, McIntosh, Andrew M., additional, McMahon, Francis J., additional, Melle, Ingrid, additional, Michie, Patricia, additional, Milani, Lili, additional, Mitchell, Philip B., additional, Morken, Gunnar, additional, Mors, Ole, additional, Mortensen, Preben Bo, additional, Mowry, Bryan, additional, Müller-Myhsok, Bertram, additional, Myers, Richard M., additional, Neale, Benjamin M., additional, Nievergelt, Caroline M., additional, Nordentoft, Merete, additional, Nöthen, Markus M., additional, O’Donovan, Michael C., additional, Oedegaard, Ketil J., additional, Olsson, Tomas, additional, Owen, Michael J., additional, Paciga, Sara A., additional, Pantelis, Chris, additional, Pato, Carlos, additional, Pato, Michele T., additional, Patrinos, George P., additional, Perlis, Roy H., additional, Posthuma, Danielle, additional, Ramos-Quiroga, Josep Antoni, additional, Reif, Andreas, additional, Reininghaus, Eva Z., additional, Ribasés, Marta, additional, Rietschel, Marcella, additional, Ripke, Stephan, additional, Rouleau, Guy A., additional, Saito, Takeo, additional, Schall, Ulrich, additional, Schalling, Martin, additional, Schofield, Peter R., additional, Schulze, Thomas G., additional, Scott, Laura J., additional, Scott, Rodney J., additional, Serretti, Alessandro, additional, Weickert, Cynthia Shannon, additional, Smoller, Jordan W., additional, Stefansson, Hreinn, additional, Stefansson, Kari, additional, Stordal, Eystein, additional, Streit, Fabian, additional, Sullivan, Patrick F., additional, Turecki, Gustavo, additional, Vaaler, Arne E., additional, Vieta, Eduard, additional, Vincent, John B., additional, Waldman, Irwin D., additional, Weickert, Thomas W., additional, Werge, Thomas, additional, Wray, Naomi R., additional, Zwart, John-Anker, additional, Biernacka, Joanna M., additional, Nurnberger, John I., additional, Cichon, Sven, additional, Edenberg, Howard J., additional, Stahl, Eli A., additional, McQuillin, Andrew, additional, Di Florio, Arianna, additional, Ophoff, Roel A., additional, and Andreassen, Ole A., additional

Published
2020
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26. Discordant transcriptional signatures of mitochondrial genes in Parkinson’s disease human myeloid cells

Author

Navarro, Elisa, primary, Udine, Evan, additional, de Paiva Lopes, Katia, additional, Parks, Madison, additional, Riboldi, Giulietta, additional, Schilder, Brian M., additional, Humphrey, Jack, additional, Snijders, Gijsje J. L., additional, Vialle, Ricardo A., additional, Zhuang, Maojuan, additional, Sikder, Tamjeed, additional, Argyrou, Charalambos, additional, Allan, Amanda, additional, Chao, Michael, additional, Farrell, Kurt, additional, Henderson, Brooklyn, additional, Simon, Sarah, additional, Raymond, Deborah, additional, Elango, Sonya, additional, Ortega, Roberto A., additional, Shanker, Vicki, additional, Swan, Matthew, additional, Zhu, Carolyn W., additional, Ramdhani, Ritesh, additional, Walker, Ruth H., additional, Tse, Winona, additional, Sano, Mary, additional, Pereira, Ana C., additional, Ahfeldt, Tim, additional, Goate, Alison M., additional, Bressman, Susan, additional, Crary, John F., additional, de Witte, Lotje, additional, Frucht, Steven, additional, Saunders-Pullman, Rachel, additional, and Raj, Towfique, additional

Published
2020
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29. echolocatoR: an automated end-to-end statistical and functional genomic fine-mapping pipeline.

Author

Schilder, Brian M, Humphrey, Jack, and Raj, Towfique

Subjects
*LOCUS (Genetics), *LINKAGE disequilibrium, *EPIGENOMICS, *PHENOTYPES
Abstract

Summary echolocatoR integrates a diverse suite of statistical and functional fine-mapping tools to identify, test enrichment in, and visualize high-confidence causal consensus variants in any phenotype. It requires minimal input from users (a summary statistics file), can be run in a single R function, and provides extensive access to relevant datasets (e.g. reference linkage disequilibrium panels, quantitative trait loci, genome-wide annotations, cell-type-specific epigenomics), thereby enabling rapid, robust and scalable end-to-end fine-mapping investigations. Availability and implementation echolocatoR is an open-source R package available through GitHub under the GNU General Public License (Version 3) license: https://github.com/RajLabMSSM/echolocatoR. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Published
2022
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30. FAIRshake: Toolkit to Evaluate the FAIRness of Research Digital Resources

Author

Clarke, Daniel J. B., Clarke, Daniel J. B., Wang, Lily, Jones, Alex, Wojciechowicz, Megan L., Torre, Denis, Jagodnik, Kathleen M., Jenkins, Sherry L., McQuilton, Peter, Flamholz, Zachary, Silverstein, Moshe C., Schilder, Brian M., Robasky, Kimberly, Castillo, Claris, Idaszak, Ray, Ahalt, Stanley C., Williams, Jason, Schurer, Stephan, Cooper, Daniel J., Azevedo, Ricardo de Miranda, Klenk, Juergen A., Haendel, Melissa A., Nedzel, Jared, Avillach, Paul, Shimoyama, Mary E., Harris, Rayna M., Gamble, Meredith, Poten, Rudy, Charbonneau, Amanda L., Larkin, Jennie, Brown, C. Titus, Bonazzi, Vivien R., Dumontier, Michel J., Sansone, Susanna-Assunta, Ma'ayan, Avi, Clarke, Daniel J. B., Clarke, Daniel J. B., Wang, Lily, Jones, Alex, Wojciechowicz, Megan L., Torre, Denis, Jagodnik, Kathleen M., Jenkins, Sherry L., McQuilton, Peter, Flamholz, Zachary, Silverstein, Moshe C., Schilder, Brian M., Robasky, Kimberly, Castillo, Claris, Idaszak, Ray, Ahalt, Stanley C., Williams, Jason, Schurer, Stephan, Cooper, Daniel J., Azevedo, Ricardo de Miranda, Klenk, Juergen A., Haendel, Melissa A., Nedzel, Jared, Avillach, Paul, Shimoyama, Mary E., Harris, Rayna M., Gamble, Meredith, Poten, Rudy, Charbonneau, Amanda L., Larkin, Jennie, Brown, C. Titus, Bonazzi, Vivien R., Dumontier, Michel J., Sansone, Susanna-Assunta, and Ma'ayan, Avi

Abstract

As more digital resources are produced by the research community, it is becoming increasingly important to harmonize and organize them for synergistic utilization. The findable, accessible, interoperable, and reusable (FAIR) guiding principles have prompted many stakeholders to consider strategies for tackling this challenge. The FAIRshake toolkit was developed to enable the establishment of community-driven FAIR metrics and rubrics paired with manual and automated FAIR assessments. FAIR assessments are visualized as an insignia that can be embedded within digital-resources-hosting websites. Using FAIRshake, a variety of biomedical digital resources were manually and automatically evaluated for their level of FAIRness.

Published
2019

31. FAIRshake: toolkit to evaluate the findability, accessibility, interoperability, and reusability of research digital resources

Author

Clarke, Daniel J. B., primary, Wang, Lily, additional, Jones, Alex, additional, Wojciechowicz, Megan L., additional, Torre, Denis, additional, Jagodnik, Kathleen M., additional, Jenkins, Sherry L., additional, McQuilton, Peter, additional, Flamholz, Zachary, additional, Silverstein, Moshe C., additional, Schilder, Brian M., additional, Robasky, Kimberly, additional, Castillo, Claris, additional, Idaszak, Ray, additional, Ahalt, Stanley C., additional, Williams, Jason, additional, Schurer, Stephan, additional, Cooper, Daniel J., additional, de Miranda Azevedo, Ricardo, additional, Klenk, Juergen A., additional, Haendel, Melissa A., additional, Nedzel, Jared, additional, Avillach, Paul, additional, Shimoyama, Mary E., additional, Harris, Rayna M., additional, Gamble, Meredith, additional, Poten, Rudy, additional, Charbonneau, Amanda L., additional, Larkin, Jennie, additional, Brown, C. Titus, additional, Bonazzi, Vivien R., additional, Dumontier, Michel J., additional, Sansone, Susanna-Assunta, additional, and Ma’ayan, Avi, additional

Published
2019
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34. Evolutionary shifts dramatically reorganized the human hippocampal complex.

Author

Schilder, Brian M., Petry, Heywood M., and Hof, Patrick R.

Abstract

The hippocampal complex (HC) is central to long‐term memory storage and retrieval as well as spatial navigation across many species. Notably, humans appear to have greatly enhanced and possibly unique HC‐mediated capacities such as constructive episodic simulation. Key studies have shown that the human HC is disproportionately large amongst hominoids, but much remains unknown at the levels of substructural evolutionary reorganization and ecological selection. Here, we calculated relative sizes of 12 HC subregions in a diverse sample of 44 primate species. We then used a Bayesian phylogenetic method, selective regime analysis, to identify 27 separate evolutionary shifts in HC organization across 65 million years of primate evolution. Additionally, a series of multivariate phylogenetic regressions using HC‐related ecological variables as predictors (Diet Breadth, Population Density, Group Size, Home Range Size, and Residual Home Range) revealed that relative fascia dentata and CA1 size were both significantly predicted by species' home range size (after correcting for body size). However, perhaps the most notable finding of this study was that the shifts in HC size and subregional organization in the human lineage were the largest seen in all of primate evolution, rendering modern humans with a HC that is a clear outlier amongst all nonhuman primates investigated here. Given the extensive literature confirming the relationship between HC organization and function, these selective shifts are likely to have played a significant role in the emergence of human‐specific capacities, such as constructive episodic simulation. [ABSTRACT FROM AUTHOR]

Published
2020
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35. eXpression2Kinases (X2K) Web: linking expression signatures to upstream cell signaling networks

Author

Clarke, Daniel J B, primary, Kuleshov, Maxim V, additional, Schilder, Brian M, additional, Torre, Denis, additional, Duffy, Mary E, additional, Keenan, Alexandra B, additional, Lachmann, Alexander, additional, Feldmann, Axel S, additional, Gundersen, Gregory W, additional, Silverstein, Moshe C, additional, Wang, Zichen, additional, and Ma’ayan, Avi, additional

Published
2018
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36. Take the monkey and run

Author

Phillips, Kimberley A., primary, Hambright, M. Karen, additional, Hewes, Kelly, additional, Schilder, Brian M., additional, Ross, Corinna N., additional, and Tardif, Suzette D., additional

Published
2015
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37. Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Author

Niamh Mullins, JooEun Kang, Adrian I. Campos, Jonathan R.I. Coleman, Alexis C. Edwards, Hanga Galfalvy, Daniel F. Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J. Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D. Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B. Ware, Andrew W. Bergen, Wade H. Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J. Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M. Fichter, Steven Gallinger, Stephen J. Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A. Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S. Kaplan, Walter H. Kaye, Pamela K. Keel, James L. Kennedy, Kelly L. Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J. Magistretti, Christian R. Marshall, James E. Mitchell, Eric T. Monson, Richard M. Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W. Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M. Thornton, Janet Treasure, Ming T. Tsuang, Stephanie H. Witt, D. Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M. Air, Martin Alda, Lars Alfredsson, Ole A. Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M. Helena Azevedo, Nicholas Bass, Claiton H.D. Bau, Bernhard T. Baune, Frank Bellivier, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Elisabeth B. Binder, Michael Boehnke, Marco P. Boks, Rosa Bosch, David L. Braff, Richard Bryant, Monika Budde, Enda M. Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A. Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J. Edenberg, Ayman H. Fanous, Jerome C. Foo, Andreas J. Forstner, Mark Frye, Janice M. Fullerton, Justine M. Gatt, Pablo V. Gejman, Ina Giegling, Hans J. Grabe, Melissa J. Green, Eugenio H. Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P. Hamilton, Marian L. Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A. Jones, Lina Jonsson, René S. Kahn, John R. Kelsoe, Kenneth S. Kendler, Stefan Kloiber, Karestan C. Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H. Lee, Douglas F. Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L. McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E. Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B. Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M. Nöthen, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Carlos Pato, Michele T. Pato, Brenda W.J.H. Penninx, Jonathan Pimm, Giorgio Pistis, James B. Potash, Robert A. Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A. Rouleau, Diego L. Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R. Sanders, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Alessandro Serretti, Jianxin Shi, Stanley I. Shyn, Lea Sirignano, Pamela Sklar, Olav B. Smeland, Jordan W. Smoller, Edmund J.S. Sonuga-Barke, Gianfranco Spalletta, John S. Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B. Vincent, Henry Völzke, James T.R. Walters, Cynthia Shannon Weickert, Thomas W. Weickert, Myrna M. Weissman, Leanne M. Williams, Naomi R. Wray, Clement C. Zai, Allison E. Ashley-Koch, Jean C. Beckham, Elizabeth R. Hauser, Michael A. Hauser, Nathan A. Kimbrel, Jennifer H. Lindquist, Benjamin McMahon, David W. Oslin, Xuejun Qin, Esben Agerbo, Anders D. Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M. Hougaard, Ronald C. Kessler, Henry R. Kranzler, Qingqin S. Li, Nicholas G. Martin, Andrew M. McIntosh, Ole Mors, Merete Nordentoft, Catherine M. Olsen, David Porteous, Robert J. Ursano, Danuta Wasserman, Thomas Werge, David C. Whiteman, Cynthia M. Bulik, Hilary Coon, Ditte Demontis, Anna R. Docherty, Po-Hsiu Kuo, Cathryn M. Lewis, J. John Mann, Miguel E. Rentería, Daniel J. Smith, Eli A. Stahl, Murray B. Stein, Fabian Streit, Virginia Willour, Douglas M. Ruderfer, Manuel Mattheisen, Abdel Abdellaoui, Mark J. Adams, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Nick Craddock, Gregory E. Crawford, Gail Davies, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Valentina Escott-Price, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Josef Frank, Héléna A. Gaspar, Michael Gill, Fernando S. Goes, Scott D. Gordon, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond Depaulo, Enrico Domenici, Katharina Domschke, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Stefan Herms, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Rick Jansen, Eric Jorgenson, James A. Knowles, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Wolfgang Maier, Jonathan Marchini, Hamdi Mbarek, Christel M. Middeldorp, Evelin Mihailov, Lili Milani, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O’Reilly, Hogni Oskarsson, Caroline Hayward, Andrew C. Heath, Glyn Lewis, Pamela A.F. Madden, Patrik K. Magnusson, Andres Metspalu, Sara A. Paciga, Nancy L. Pedersen, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Danielle Posthuma, Jorge A. Quiroz, Per Qvist, John P. Rice, Brien P. Riley, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Engilbert Sigurdsson, Grant C.B. Sinnamon, Johannes H. Smit, Hreinn Stefansson, Stacy Steinberg, Jana Strohmaier, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Alexander Viktorin, Peter M. Visscher, Yunpeng Wang, Bradley T. Webb, Roy H. Perlis, David J. Porteous, Catherine Schaefer, Kari Stefansson, Henning Tiemeier, Rudolf Uher, Patrick F. Sullivan, Kevin S. O’Connell, Brandon Coombes, Zhen Qiao, Thomas D. Als, Sigrid Børte, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Verneri Antilla, Anastasia Antoniou, Ji Hyun Baek, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Erlend Bøen, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M. Czerski, Anders M. Dale, Nina Dalkner, Friederike S. David, Amanda L. Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, I. Nicol Ferrier, Alessia Fiorentino, Tatiana M. Foroud, Liz Forty, Oleksandr Frei, Nelson B. Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Ian R. Gizer, Katherine Gordon-Smith, Tiffany A. Greenwood, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Peter A. Holmans, Laura Huckins, Jessica S. Johnson, Janos L. Kalman, Yoichiro Kamatani, Sarah Kittel-Schneider, Maria Koromina, Thorsten M. Kranz, Michiaki Kubo, Ralph Kupka, Steven A. Kushner, Catharina Lavebratt, Markus Leber, Heon-Jeong Lee, Shawn E. Levy, Catrin Lewis, Martin Lundberg, Sigurdur H. Magnusson, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Nathaniel W. McGregor, James D. McKay, Helena Medeiros, Vincent Millischer, Jennifer L. Moran, Derek W. Morris, Thomas W. Mühleisen, Niamh O’Brien, Claire O’Donovan, Loes M. Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F. Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, Towfique Raj, Mark H. Rapaport, J. Raymond DePaulo, Eline J. Regeer, Fabio Rivas, Julian Roth, Panos Roussos, Fanny Senner, Sally Sharp, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Maria Soler Artigas, Anne T. Spijker, Dan J. Stein, Chikashi Terao, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H. Young, Hannah Young, Peter P. Zandi, Hang Zhou, null HUNT All-In Psychiatry, Gulja Babadjanova, Lena Backlund, Susanne Bengesser, Douglas H.R. Blackwood, Vaughan J. Carr, Stanley Catts, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Micha Gawlik, Elliot S. Gershon, Frans Henskens, Jan Hillert, Kyung Sue Hong, Christina M. Hultman, Kristian Hveem, Nakao Iwata, Assen V. Jablensky, George Kirov, Christine Lochner, Carmel Loughland, Carol A. Mathews, Francis J. McMahon, Patricia Michie, Bryan Mowry, Benjamin M. Neale, Caroline M. Nievergelt, Ketil J. Oedegaard, Tomas Olsson, Chris Pantelis, George P. Patrinos, Eva Z. Reininghaus, Takeo Saito, Ulrich Schall, Martin Schalling, Rodney J. Scott, Eystein Stordal, Arne E. Vaaler, Eduard Vieta, Irwin D. 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J., Wasserman, D., Coon, H., Demontis, D., Docherty, A. R., Kuo, P. -H., Mann, J. J., Renteria, M. E., Stein, M. B., Willour, V., Psychiatry, Biological Psychology, APH - Methodology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Public Health, Clinicum, Nuorisopsykiatria, Faculty Common Matters (Faculty of Social Sciences), Samuli Olli Ripatti / Principal Investigator, Complex Disease Genetics, Biostatistics Helsinki, Anna Keski-Rahkonen / Principal Investigator, Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Internal medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Mullins N., Kang J., Campos A.I., Coleman J.R.I., Edwards 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Nyholt D.R., O'Reilly P.F., Oskarsson H., Hayward C., Heath A.C., Lewis G., Li Q.S., Madden P.A.F., Magnusson P.K., Martin N.G., McIntosh A.M., Metspalu A., Mors O., Nordentoft M., Paciga S.A., Pedersen N.L., Painter J.N., Pedersen C.B., Pedersen M.G., Peterson R.E., Peyrot W.J., Posthuma D., Quiroz J.A., Qvist P., Rice J.P., Riley B.P., Mirza S.S., Schoevers R., Schulte E.C., Shen L., Sigurdsson E., Sinnamon G.C.B., Smit J.H., Smith D.J., Stefansson H., Steinberg S., Streit F., Strohmaier J., Tansey K.E., Teismann H., Teumer A., Thompson W., Thomson P.A., Thorgeirsson T.E., Traylor M., Treutlein J., Trubetskoy V., Uitterlinden A.G., Umbricht D., der Auwera S.V., van Hemert A.M., Viktorin A., Visscher P.M., Wang Y., Webb B.T., Perlis R.H., Porteous D.J., Schaefer C., Stefansson K., Tiemeier H., Uher R., Werge T., Lewis C.M., Breen G., Borglum A.D., Sullivan P.F., O'Connell K.S., Coombes B., Qiao Z., Als T.D., Borte S., Charney A.W., Drange O.K., Gandal M.J., Hagenaars S.P., Ikeda M., Kamitaki N., Krebs K., Panagiotaropoulou G., Schilder B.M., Sloofman L.G., Winsvold B.S., Won H.-H., Abramova L., Adorjan K., Al Eissa M., Albani D., Alliey-Rodriguez N., Antilla V., Antoniou A., Baek J.H., Bauer M., Beins E.C., Bergen S.E., Birner A., Boen E., Brum M., Brumpton B.M., Brunkhorst-Kanaan N., Byerley W., Cairns M., Cervantes P., Cruceanu C., Cuellar-Barboza A., Cunningham J., Curtis D., Czerski P.M., Dale A.M., Dalkner N., David F.S., Dobbyn A.L., Douzenis A., Elvsashagen T., Ferrier I.N., Fiorentino A., Foroud T.M., Forty L., Frei O., Freimer N.B., Frisen L., Gade K., Garnham J., Gelernter J., Gizer I.R., Gordon-Smith K., Greenwood T.A., Ha K., Haraldsson M., Hautzinger M., Heilbronner U., Hellgren D., Holmans P.A., Huckins L., Johnson J.S., Kalman J.L., Kamatani Y., Kittel-Schneider S., Koromina M., Kranz T.M., Kranzler H.R., Kubo M., Kupka R., Kushner S.A., Lavebratt C., Leber M., Lee H.-J., Levy S.E., Lewis C., Lundberg M., Magnusson S.H., Maihofer A., Malaspina D., Maratou E., Martinsson L., McGregor N.W., McKay J.D., Medeiros H., Millischer V., Moran J.L., Morris D.W., Muhleisen T.W., O'Brien N., O'Donovan C., Olde Loohuis L.M., Oruc L., Papiol S., Pardinas A.F., Perry A., Pfennig A., Porichi E., Raj T., Rapaport M.H., Regeer E.J., Rivas F., Roth J., Roussos P., Ruderfer D.M., Senner F., Sharp S., Shilling P.D., Slaney C., Sobell J.L., Artigas M.S., Spijker A.T., Stein D.J., Terao C., Toma C., Tooney P., Tsermpini E.-E., Vawter M.P., Vedder H., Xi S., Xu W., Kay Yang J.M., Young A.H., Young H., Zandi P.P., Zhou H., HUNT All-In Psychiatry, Babadjanova G., Backlund L., Bengesser S., Blackwood D.H.R., Carr V.J., Catts S., Dikeos D., Etain B., Ferentinos P., Gawlik M., Gershon E.S., Henskens F., Hillert J., Hong K.S., Hultman C.M., Hveem K., Iwata N., Jablensky A.V., Kirov G., Lochner C., Loughland C., Mathews C.A., McMahon F.J., Michie P., Mowry B., Neale B.M., Nievergelt C.M., Oedegaard K.J., Olsson T., Pantelis C., Patrinos G.P., Reininghaus E.Z., Saito T., Schall U., Schalling M., Scott R.J., Weickert C.S., Stordal E., Vaaler A.E., Vieta E., Waldman I.D., Zwart J.-A., Nurnberger J.I., Stahl E.A., Di Florio A., Adan R.A.H., Ando T., Aschauer H., Baker J.H., Bencko V., Birgegard A., Boden J.M., Boehm I., Boni C., Perica V.B., Buehren K., Bulik C.M., Burghardt R., Carlberg L., Cassina M., Clementi M., Cone R.D., Courtet P., Crowley J.J., Danner U.N., Davis O.S.P., de Zwaan M., Dedoussis G., Degortes D., DeSocio J.E., Dick D.M., Dina C., Dmitrzak-Weglarz M., Martinez E.D., Duncan L.E., Egberts K., Mattingsdal M., McDevitt S., Meulenbelt I., Micali N., Mitchell J., Mitchell K., Monteleone P., Monteleone A.M., Munn-Chernoff M.A., Nacmias B., Navratilova M., Ntalla I., Olsen C.M., O'Toole J.K., Padyukov L., Palotie A., Pantel J., Papezova H., Parker R., Pearson J.F., Ehrlich S., Escaramis G., Espeseth T., Estivill X., Farmer A., Favaro A., Fischer K., Floyd J.A.B., Focker M., Foretova L., Forzan M., Franklin C.S., Gambaro G., Giuranna J., Giusti-Rodriquez P., Gonidakis F., Gordon S., Mayora M.G., Guillaume S., Hanscombe K.B., Hatzikotoulas K., Hebebrand J., Helder S.G., Henders A.K., Herpertz-Dahlmann B., Herzog W., Hinney A., Horwood L.J., Hubel C., Petersen L.V., Purves K.L., Raevuori A., Reichborn-Kjennerud T., Ricca V., Ripatti S., Ritschel F., Roberts M., Rybakowski F., Santonastaso P., Scherag A., Schmidt U., Schork N.J., Schosser A., Seitz J., Slachtova L., Slagboom P.E., Slof-Op 't Landt M.C.T., Slopien A., Soranzo N., Sorbi S., Southam L., Steen V.W., Huckins L.M., Hudson J.I., Imgart H., Inoko H., Janout V., Jordan J., Julia A., Kalsi G., Kaminska D., Kaprio J., Karhunen L., Karwautz A., Kas M.J.H., Kennedy M.A., Keski-Rahkonen A., Kiezebrink K., Kim Y.-R., Kirk K.M., Klareskog L., Knudsen G.P.S., Larsen J.T., Le Hellard S., Leppa V.M., Lichtenstein P., Lin B.D., Lundervold A., Luykx J., Maj M., Mannik K., Marsal S., Stuber G.D., Szatkiewicz J.P., Tachmazidou I., Tenconi E., Tortorella A., Tozzi F., Tsitsika A., Tyszkiewicz-Nwafor M., Tziouvas K., van Elburg A.A., van Furth E.F., Wade T.D., Wagner G., Walton E., Whiteman D.C., Wichmann H.E., Widen E., Yao S., Zeggini E., Zerwas S., Zipfel S., Jungkunz M., Dietl L., Schwarze C.E., Dahmen N., Schott B.H., Mobascher A., Crivelli S., Dennis M.F., Harvey P.D., Carter B.W., Huffman J.E., Jacobson D., Madduri R., Olsen M.K., Pestian J., Gaziano J.M., Muralidhar S., Ramoni R., Beckham J., Chang K.-M., O'Donnell C.J., Tsao P.S., Breeling J., Huang G., Romero J.P.C., Moser J., Whitbourne S.B., Brewer J.V., Aslan M., Connor T., Argyres D.P., Stephens B., Brophy M.T., Humphries D.E., Selva L.E., Do N., Shayan S., Cho K., Pyarajan S., Hauser E., Sun Y., Zhao H., Wilson P., McArdle R., Dellitalia L., Mattocks K., Harley J., Zablocki C.J., Whittle J., Jacono F., Gutierrez S., Gibson G., Hammer K., Kaminsky L., Villareal G., Kinlay S., Xu J., Hamner M., Mathew R., Bhushan S., Iruvanti P., Godschalk M., Ballas Z., Ivins D., Mastorides S., Moorman J., Gappy S., Klein J., Ratcliffe N., Florez H., Okusaga O., Murdoch M., Sriram P., Yeh S.S., Tandon N., Jhala D., Aguayo S., Cohen D., Sharma S., Liangpunsakul S., Oursler K.A., Whooley M., Ahuja S., Constans J., Meyer P., Greco J., Rauchman M., Servatius R., Gaddy M., Wallbom A., Morgan T., Stapley T., Sherman S., Ross G., Tsao P., Strollo P., Boyko E., Meyer L., Gupta S., Huq M., Fayad J., Hung A., Lichy J., Hurley R., Robey B., Striker R., Erlangsen A., Kessler R.C., Porteous D., Ursano R.J., Wasserman D., Coon H., Demontis D., Docherty A.R., Kuo P.-H., Mann J.J., Renteria M.E., Stein M.B., and Willour V.

Subjects
LD SCORE REGRESSION, Genome-wide association study, Suicide, Attempted, 3124 Neurology and psychiatry, 0302 clinical medicine, Risk Factors, Insomnia, Suicide attempt, GWAS, Suïcidi, Depression (differential diagnoses), Cause of death, Psychiatry, 0303 health sciences, Factors de risc en les malalties, Mental Disorders, Genetic Correlation, Genome-wide Association Study, Pleiotropy, Polygenicity, Suicide, Suicide Attempt, DEPRESSION, 3. Good health, Genetic correlation, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Depressive Disorder, Major, Mental illness, Cohort, SEX, medicine.symptom, Human, medicine.medical_specialty, Risk factors in diseases, BF, Locus (genetics), BEHAVIORS, Psykiatri, EVENTS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, ddc:610, GENOME-WIDE ASSOCIATION, IDEATION, Socioeconomic status, METAANALYSIS, Biological Psychiatry, 030304 developmental biology, business.industry, Risk Factor, Genetic architecture, THOUGHTS, RC0321, business, Malalties mentals, 030217 neurology & neurosurgery
Abstract

Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu), which is supported by the Office of Research Infrastructure of the National Institutes of Health (Grant Nos. S10OD018522 and S10OD026880). This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. This work was funded by the National Institutes of Health (Grant Nos. R01MH116269 and R01MH121455 [to DMR]), NIGMS of the National Institutes of Health (Grant No. T32GM007347 [to JK]), and the Brain & Behavior Research Foundation (NARSAD Young Investigator Award No. 29551 [to NM])., BACKGROUND: Suicide 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. METHODS: We 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. RESULTS: Two 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. CONCLUSIONS: Our 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., Office of Research Infrastructure of the National Institutes of Health S10OD018522 S10OD026880, United States Department of Health & Human Services, National Institutes of Health (NIH) - USA R01MH116269 R01MH121455, NIH National Institute of General Medical Sciences (NIGMS) T32GM007347 NARSAD 29551

Published
2022

38. Fine-mapping genomic loci refines bipolar disorder risk genes.

Author

Koromina M, Ravi A, Panagiotaropoulou G, Schilder BM, Humphrey J, Braun A, Bidgeli T, Chatzinakos C, Coombes B, Kim J, Liu X, Terao C, O 'Connell KS, Adams M, Adolfsson R, Alda M, Alfredsson L, Andlauer TFM, Andreassen OA, Antoniou A, Baune BT, Bengesser S, Biernacka J, Boehnke M, Bosch R, Cairns MJ, Carr VJ, Casas M, Catts S, Cichon S, Corvin A, Craddock N, Dafnas K, Dalkner N, Dannlowski U, Degenhardt F, Di Florio A, Dikeos D, Fellendorf FT, Ferentinos P, Forstner AJ, Forty L, Frye M, Fullerton JM, Gawlik M, Gizer IR, Gordon-Smith K, Green MJ, Grigoroiu-Serbanescu M, Guzman-Parra J, Hahn T, Henskens F, Hillert J, Jablensky AV, Jones L, Jones I, Jonsson L, Kelsoe JR, Kircher T, Kirov G, Kittel-Schneider S, Kogevinas M, Landén M, Leboyer M, Lenger M, Lissowska J, Lochner C, Loughland C, MacIntyre D, Martin NG, Maratou E, Mathews CA, Mayoral F, McElroy SL, McGregor NW, McIntosh A, McQuillin A, Michie P, Mitchell PB, Moutsatsou P, Mowry B, Müller-Myhsok B, Myers RM, Nenadić I, Nievergelt C, Nöthen MM, Nurnberger J, O 'Donovan M, O'Donovan C, Ophoff RA, Owen MJ, Pantelis C, Pato C, Pato MT, Patrinos GP, Pawlak JM, Perlis RH, Porichi E, Posthuma D, Ramos-Quiroga JA, Reif A, Reininghaus EZ, Ribasés M, Rietschel M, Schall U, Schofield PR, Schulze TG, Scott L, Scott RJ, Serretti A, Shannon Weickert C, Smoller JW, Soler Artigas M, Stein DJ, Streit F, Toma C, Tooney P, Vawter MP, Vieta E, Vincent JB, Waldman ID, Weickert T, Witt SH, Hong KS, Ikeda M, Iwata N, Świątkowska B, Won HH, Edenberg HJ, Ripke S, Raj T, Coleman JRI, and Mullins N

Abstract

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 17 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, CRTC3, AP001453 . 3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, DPH1, GSDMB, MED24 and THRA in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of BD polygenic risk scores across diverse populations, and present a high-throughput fine-mapping pipeline ( https://github.com/mkoromina/SAFFARI ).

Published
2024
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39. Artificial intelligence for dementia research methods optimization.

Author

Bucholc M, James C, Khleifat AA, Badhwar A, Clarke N, Dehsarvi A, Madan CR, Marzi SJ, Shand C, Schilder BM, Tamburin S, Tantiangco HM, Lourida I, Llewellyn DJ, and Ranson JM

Subjects
Humans, Reproducibility of Results, Machine Learning, Research Design, Artificial Intelligence, Dementia diagnosis
Abstract

Artificial intelligence (AI) and machine learning (ML) approaches are increasingly being used in dementia research. However, several methodological challenges exist that may limit the insights we can obtain from high-dimensional data and our ability to translate these findings into improved patient outcomes. To improve reproducibility and replicability, researchers should make their well-documented code and modeling pipelines openly available. Data should also be shared where appropriate. To enhance the acceptability of models and AI-enabled systems to users, researchers should prioritize interpretable methods that provide insights into how decisions are generated. Models should be developed using multiple, diverse datasets to improve robustness, generalizability, and reduce potentially harmful bias. To improve clarity and reproducibility, researchers should adhere to reporting guidelines that are co-produced with multiple stakeholders. If these methodological challenges are overcome, AI and ML hold enormous promise for changing the landscape of dementia research and care. HIGHLIGHTS: Machine learning (ML) can improve diagnosis, prevention, and management of dementia. Inadequate reporting of ML procedures affects reproduction/replication of results. ML models built on unrepresentative datasets do not generalize to new datasets. Obligatory metrics for certain model structures and use cases have not been defined. Interpretability and trust in ML predictions are barriers to clinical translation., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2023
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40. Artificial intelligence for neurodegenerative experimental models.

Author

Marzi SJ, Schilder BM, Nott A, Frigerio CS, Willaime-Morawek S, Bucholc M, Hanger DP, James C, Lewis PA, Lourida I, Noble W, Rodriguez-Algarra F, Sharif JA, Tsalenchuk M, Winchester LM, Yaman Ü, Yao Z, Ranson JM, and Llewellyn DJ

Subjects
Humans, Artificial Intelligence, Reproducibility of Results, Machine Learning, Neurodegenerative Diseases, Dementia
Abstract

Introduction: Experimental models are essential tools in neurodegenerative disease research. However, the translation of insights and drugs discovered in model systems has proven immensely challenging, marred by high failure rates in human clinical trials., Methods: Here we review the application of artificial intelligence (AI) and machine learning (ML) in experimental medicine for dementia research., Results: Considering the specific challenges of reproducibility and translation between other species or model systems and human biology in preclinical dementia research, we highlight best practices and resources that can be leveraged to quantify and evaluate translatability. We then evaluate how AI and ML approaches could be applied to enhance both cross-model reproducibility and translation to human biology, while sustaining biological interpretability., Discussion: AI and ML approaches in experimental medicine remain in their infancy. However, they have great potential to strengthen preclinical research and translation if based upon adequate, robust, and reproducible experimental data., Highlights: There are increasing applications of AI in experimental medicine. We identified issues in reproducibility, cross-species translation, and data curation in the field. Our review highlights data resources and AI approaches as solutions. Multi-omics analysis with AI offers exciting future possibilities in drug discovery., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2023
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41. Artificial intelligence for dementia genetics and omics.

Author

Bettencourt C, Skene N, Bandres-Ciga S, Anderson E, Winchester LM, Foote IF, Schwartzentruber J, Botia JA, Nalls M, Singleton A, Schilder BM, Humphrey J, Marzi SJ, Toomey CE, Kleifat AA, Harshfield EL, Garfield V, Sandor C, Keat S, Tamburin S, Frigerio CS, Lourida I, Ranson JM, and Llewellyn DJ

Subjects
Humans, Machine Learning, Phenotype, Precision Medicine, Artificial Intelligence, Alzheimer Disease genetics
Abstract

Genetics and omics studies of Alzheimer's disease and other dementia subtypes enhance our understanding of underlying mechanisms and pathways that can be targeted. We identified key remaining challenges: First, can we enhance genetic studies to address missing heritability? Can we identify reproducible omics signatures that differentiate between dementia subtypes? Can high-dimensional omics data identify improved biomarkers? How can genetics inform our understanding of causal status of dementia risk factors? And which biological processes are altered by dementia-related genetic variation? Artificial intelligence (AI) and machine learning approaches give us powerful new tools in helping us to tackle these challenges, and we review possible solutions and examples of best practice. However, their limitations also need to be considered, as well as the need for coordinated multidisciplinary research and diverse deeply phenotyped cohorts. Ultimately AI approaches improve our ability to interrogate genetics and omics data for precision dementia medicine. HIGHLIGHTS: We have identified five key challenges in dementia genetics and omics studies. AI can enable detection of undiscovered patterns in dementia genetics and omics data. Enhanced and more diverse genetics and omics datasets are still needed. Multidisciplinary collaborative efforts using AI can boost dementia research., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2023
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