Browsing by Author "Estonian Biobank Research Team"

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    A cross-disorder dosage sensitivity map of the human genome
    (Elsevier, 2022) Collins, Ryan L.; Glessner, Joseph T.; Porcu, Eleonora; Lepamets, Maarja; Brandon, Rhonda; Lauricella, Christopher; Han, Lide; Morley, Theodore; Niestroj, Lisa-Marie; Ulirsch, Jacob; Everett, Selin; Howrigan, Daniel P.; Boone, Philip M.; Fu, Jack; Karczewski, Konrad J.; Kellaris, Georgios; Lowther, Chelsea; Lucente, Diane; Mohajeri, Kiana; Nõukas, Margit; Nuttle, Xander; Samocha, Kaitlin E.; Trinh, Mi; Ullah, Farid; Võsa, Urmo; Epi25 Consortium; Estonian Biobank Research Team; Hurles, Matthew E.; Aradhya, Swaroop; Davis, Erica E.; Finucane, Hilary; Gusella, James F.; Janze, Aura; Katsanis, Nicholas; Matyakhina, Ludmila; Neale, Benjamin M.; Sanders, David; Warren, Stephanie; Hodge, Jennelle C.; Lal, Dennis; Ruderfer, Douglas M.; Meck, Jeanne; Mägi, Reedik; Esko, Tõnu; Reymond, Alexandre; Kutalik, Zoltán; Hakonarson, Hakon; Sunyaev, Shamil; Brand, Harrison; Talkowski, Michael E.; Medical and Molecular Genetics, School of Medicine
    Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.
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    Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder
    (Springer Nature, 2024) Nievergelt, Caroline M.; Maihofer, Adam X.; Atkinson, Elizabeth G.; Chen, Chia-Yen; Choi, Karmel W.; Coleman, Jonathan R. I.; Daskalakis, Nikolaos P.; Duncan, Laramie E.; Polimanti, Renato; Aaronson, Cindy; Amstadter, Ananda B.; Andersen, Soren B.; Andreassen, Ole A.; Arbisi, Paul A.; Ashley-Koch, Allison E.; Austin, S. Bryn; Avdibegoviç, Esmina; Babić, Dragan; Bacanu, Silviu-Alin; Baker, Dewleen G.; Batzler, Anthony; Beckham, Jean C.; Belangero, Sintia; Benjet, Corina; Bergner, Carisa; Bierer, Linda M.; Biernacka, Joanna M.; Bierut, Laura J.; Bisson, Jonathan I.; Boks, Marco P.; Bolger, Elizabeth A.; Brandolino, Amber; Breen, Gerome; Bressan, Rodrigo Affonseca; Bryant, Richard A.; Bustamante, Angela C.; Bybjerg-Grauholm, Jonas; Bækvad-Hansen, Marie; Børglum, Anders D.; Børte, Sigrid; Cahn, Leah; Calabrese, Joseph R.; Caldas-de-Almeida, Jose Miguel; Chatzinakos, Chris; Cheema, Sheraz; Clouston, Sean A. P.; Colodro-Conde, Lucía; Coombes, Brandon J.; Cruz-Fuentes, Carlos S.; Dale, Anders M.; Dalvie, Shareefa; Davis, Lea K.; Deckert, Jürgen; Delahanty, Douglas L.; Dennis, Michelle F.; Desarnaud, Frank; DiPietro, Christopher P.; Disner, Seth G.; Docherty, Anna R.; Domschke, Katharina; Dyb, Grete; Džubur Kulenović, Alma; Edenberg, Howard J.; Evans, Alexandra; Fabbri, Chiara; Fani, Negar; Farrer, Lindsay A.; Feder, Adriana; Feeny, Norah C.; Flory, Janine D.; Forbes, David; Franz, Carol E.; Galea, Sandro; Garrett, Melanie E.; Gelaye, Bizu; Gelernter, Joel; Geuze, Elbert; Gillespie, Charles F.; Goleva, Slavina B.; Gordon, Scott D.; Goçi, Aferdita; Grasser, Lana Ruvolo; Guindalini, Camila; Haas, Magali; Hagenaars, Saskia; Hauser, Michael A.; Heath, Andrew C.; Hemmings, Sian M. J.; Hesselbrock, Victor; Hickie, Ian B.; Hogan, Kelleigh; Hougaard, David Michael; Huang, Hailiang; Huckins, Laura M.; Hveem, Kristian; Jakovljević, Miro; Javanbakht, Arash; Jenkins, Gregory D.; Johnson, Jessica; Jones, Ian; Jovanovic, Tanja; Karstoft, Karen-Inge; Kaufman, Milissa L.; Kennedy, James L.; Kessler, Ronald C.; Khan, Alaptagin; Kimbrel, Nathan A.; King, Anthony P.; Koen, Nastassja; Kotov, Roman; Kranzler, Henry R.; Krebs, Kristi; Kremen, William S.; Kuan, Pei-Fen; Lawford, Bruce R.; Lebois, Lauren A. M.; Lehto, Kelli; Levey, Daniel F.; Lewis, Catrin; Liberzon, Israel; Linnstaedt, Sarah D.; Logue, Mark W.; Lori, Adriana; Lu, Yi; Luft, Benjamin J.; Lupto, Michelle K.; Luykx, Jurjen J.; Makotkine, Iouri; Maples-Keller, Jessica L.; Marchese, Shelby; Marmar, Charles; Martin, Nicholas G.; Martínez-Levy, Gabriela A.; McAloney, Kerrie; McFarlane, Alexander; McLaughlin, Katie A.; McLean, Samuel A.; Medland, Sarah E.; Mehta, Divya; Meyers, Jacquelyn; Michopoulos, Vasiliki; Mikita, Elizabeth A.; Milani, Lili; Milberg, William; Miller, Mark W.; Morey, Rajendra A.; Morris, Charles Phillip; Mors, Ole; Mortensen, Preben Bo; Mufford, Mary S.; Nelson, Elliot C.; Nordentoft, Merete; Norman, Sonya B.; Nugent, Nicole R.; O'Donnell, Meaghan; Orcutt, Holly K.; Pan, Pedro M.; Panizzon, Matthew S.; Pathak, Gita A.; Peters, Edward S.; Peterson, Alan L.; Peverill, Matthew; Pietrzak, Robert H.; Polusny, Melissa A.; Porjesz, Bernice; Powers, Abigail; Qin, Xue-Jun; Ratanatharathorn, Andrew; Risbrough, Victoria B.; Roberts, Andrea L.; Rothbaum, Alex O.; Rothbaum, Barbara O.; Roy-Byrne, Peter; Ruggiero, Kenneth J.; Rung, Ariane; Runz, Heiko; Rutten, Bart P. F.; Saenz de Viteri, Stacey; Salum, Giovanni Abrahão; Sampson, Laura; Sanchez, Sixto E.; Santoro, Marcos; Seah, Carina; Seedat, Soraya; Seng, Julia S.; Shabalin, Andrey; Sheerin, Christina M.; Silove, Derrick; Smith, Alicia K.; Smoller, Jordan W.; Sponheim, Scott R.; Stein, Dan J.; Stensland, Synne; Stevens, Jennifer S.; Sumner, Jennifer A.; Teicher, Martin H.; Thompson, Wesley K.; Tiwari, Arun K.; Trapido, Edward; Uddin, Monica; Ursano, Robert J.; Valdimarsdóttir, Unnur; Van Hooff, Miranda; Vermetten, Eric; Vinkers, Christiaan H.; Voisey, Joanne; Wang, Yunpeng; Wang, Zhewu; Waszczuk, Monika; Weber, Heike; Wendt, Frank R.; Werge, Thomas; Williams, Michelle A.; Williamson, Douglas E.; Winsvold, Bendik S.; Winternitz, Sherry; Wolf, Christiane; Wolf, Erika J.; Xia, Yan; Xiong, Ying; Yehuda, Rachel; Young, Keith A.; Young, Ross McD.; Zai, Clement C.; Zai, Gwyneth C.; Zervas, Mark; Zhao, Hongyu; Zoellner, Lori A.; Zwart, John-Anker; deRoon-Cassini, Terri; van Rooij, Sanne J. H.; van den Heuvel, Leigh L.; AURORA Study; Estonian Biobank Research Team; FinnGen Investigators; HUNT All-In Psychiatry; Stein, Murray B.; Ressler, Kerry J.; Koenen, Karestan C.; Biochemistry and Molecular Biology, School of Medicine
    Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.