Browsing by Author "O'Connell, Kevin S."

Now showing 1 - 7 of 7
  • Thumbnail Image
    Item
    Characterisation of age and polarity at onset in bipolar disorder
    (Cambridge University Press, 2021-12) Kalman, Janos L.; Olde Loohuis, Loes M.; Vreeker, Annabel; McQuillin, Andrew; Stahl, Eli A.; Ruderfer, Douglas; Grigoroiu-Serbanescu, Maria; Panagiotaropoulou, Georgia; Ripke, Stephan; Bigdeli, Tim B.; Stein, Frederike; Meller, Tina; Meinert, Susanne; Pelin, Helena; Streit, Fabian; Papiol, Sergi; Adams, Mark J.; Adolfsson, Rolf; Adorjan, Kristina; Agartz, Ingrid; Aminoff, Sofie R.; Anderson-Schmidt, Heike; Andreassen, Ole A.; Ardau, Raffaella; Aubry, Jean-Michel; Balaban, Ceylan; Bass, Nicholas; Baune, Bernhard T.; Bellivier, Frank; Benabarre, Antoni; Bengesser, Susanne; Berrettini, Wade H.; Boks, Marco P.; Bromet, Evelyn J.; Brosch, Katharina; Budde, Monika; Byerley, William; Cervantes, Pablo; Chillotti, Catina; Cichon, Sven; Clark, Scott R.; Comes, Ashley L.; Corvin, Aiden; Coryell, William; Craddock, Nick; Craig, David W.; Croarkin, Paul E.; Cruceanu, Cristiana; Czerski, Piotr M.; Dalkner, Nina; Dannlowski, Udo; Degenhardt, Franziska; Del Zompo, Maria; DePaulo, J. Raymond; Djurovic, Srdjan; Edenberg, Howard J.; Al Eissa, Mariam; Elvsåshagen, Torbjørn; Etain, Bruno; Fanous, Ayman H.; Fellendorf, Frederike; Fiorentino, Alessia; Forstner, Andreas J.; Frye, Mark A.; Fullerton, Janice M.; Gade, Katrin; Garnham, Julie; Gershon, Elliot; Gill, Michael; Goes, Fernando S.; Gordon-Smith, Katherine; Grof, Paul; Guzman-Parra, Jose; Hahn, Tim; Hasler, Roland; Heilbronner, Maria; Heilbronner, Urs; Jamain, Stephane; Jimenez, Esther; Jones, Ian; Jones, Lisa; Jonsson, Lina; Kahn, Rene S.; Kelsoe, John R.; Kennedy, James L.; Kircher, Tilo; Kirov, George; Kittel-Schneider, Sarah; Klöhn-Saghatolislam, Farah; Knowles, James A.; Kranz, Thorsten M.; Lagerberg, Trine Vik; Landen, Mikael; Lawson, William B.; Leboyer, Marion; Li, Qingqin S.; Maj, Mario; Malaspina, Dolores; Manchia, Mirko; Mayoral, Fermin; McElroy, Susan L.; McInnis, Melvin G.; McIntosh, Andrew M.; Medeiros, Helena; Melle, Ingrid; Milanova, Vihra; Mitchell, Philip B.; Monteleone, Palmiero; Monteleone, Alessio Maria; Nöthen, Markus M.; Novak, Tomas; Nurnberger, John I.; O'Brien, Niamh; O'Connell, Kevin S.; O'Donovan, Claire; O'Donovan, Michael C.; Opel, Nils; Ortiz, Abigail; Owen, Michael J.; Pålsson, Erik; Pato, Carlos; Pato, Michele T.; Pawlak, Joanna; Pfarr, Julia-Katharina; Pisanu, Claudia; Potash, James B.; Rapaport, Mark H.; Reich-Erkelenz, Daniela; Reif, Andreas; Reininghaus, Eva; Repple, Jonathan; Richard-Lepouriel, Hélène; Rietschel, Marcella; Ringwald, Kai; Roberts, Gloria; Rouleau, Guy; Schaupp, Sabrina; Scheftner, William A.; Schmitt, Simon; Schofield, Peter R.; Schubert, K. Oliver; Schulte, Eva C.; Schweizer, Barbara; Senner, Fanny; Severino, Giovanni; Sharp, Sally; Slaney, Claire; Smeland, Olav B.; Sobell, Janet L.; Squassina, Alessio; Stopkova, Pavla; Strauss, John; Tortorella, Alfonso; Turecki, Gustavo; Twarowska-Hauser, Joanna; Veldic, Marin; Vieta, Eduard; Vincent, John B.; Xu, Wei; Zai, Clement C.; Zandi, Peter P.; Psychiatric Genomics Consortium (PGC) Bipolar Disorder Working Group; International Consortium on Lithium Genetics (ConLiGen); Colombia-US Cross Disorder Collaboration in Psychiatric Genetics; Di Florio, Arianna; Smoller, Jordan W.; Biernacka, Joanna M.; McMahon, Francis J.; Alda, Martin; Müller-Myhsok, Bertram; Koutsouleris, Nikolaos; Falkai, Peter; Freimer, Nelson B.; Andlauer, Till F.M.; Schulze, Thomas G.; Ophoff, Roel A.; Biochemistry and Molecular Biology, School of Medicine
    Background: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions: AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
  • Thumbnail Image
    Item
    Fine-mapping genomic loci refines bipolar disorder risk genes
    (medRxiv, 2024-02-13) 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 F. M.; Andreassen, Ole A.; Antoniou, Anastasia; Baune, Bernhard T.; Bengesser, Susanne; Biernacka, Joanna; Boehnke, Michael; Bosch, Rosa; Cairns, Murray; Carr, Vaughan J.; Casas, 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 J.; 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, Fermin; McElroy, Susan L.; McGregor, Nathaniel W.; McIntosh, Andrew; McQuillin, Andrew; Michie, Patricia; Milanova, Vihra; Mitchell, Philip B.; Moutsatsou, Paraskevi; Mowry, Bryan; Müller-Myhsok, Bertram; Myers, Richard; Nenadić, Igor; Nöthen, Markus M.; O'Donovan, Claire; O'Donovan, Michael; Ophoff, Roel A.; Owen, Michael J.; Pantelis, Chris; 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 G.; Scott, Laura; Scott, Rodney J.; Serretti, Alessandro; Shannon Weickert, Cynthia; Smoller, Jordan W.; Soler Artigas, Maria; 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; Biochemistry and Molecular Biology, School of Medicine
    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).
  • Thumbnail Image
    Item
    Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci
    (medRxiv, 2024-03-13) Strom, Nora I.; Gerring, Zachary F.; Galimberti, Marco; Yu, Dongmei; Halvorsen, Matthew W.; Abdellaoui, Abdel; Rodriguez-Fontenla, Cristina; Sealock, Julia M.; Bigdeli, Tim; Coleman, Jonathan R.; Mahjani, Behrang; Thorp, Jackson G.; Bey, Katharina; Burton, Christie L.; Luykx, Jurjen J.; Zai, Gwyneth; Alemany, Silvia; Andre, Christine; Askland, Kathleen D.; Banaj, Nerisa; Barlassina, Cristina; Becker Nissen, Judith; Bienvenu, O. Joseph; Black, Donald; Bloch, Michael H.; Boberg, Julia; Børte, Sigrid; Bosch, Rosa; Breen, Michael; Brennan, Brian P.; Brentani, Helena; Buxbaum, Joseph D.; Bybjerg-Grauholm, Jonas; Byrne, Enda M.; Cabana-Dominguez, Judith; Camarena, Beatriz; Camarena, Adrian; Cappi, Carolina; Carracedo, Angel; Casas, Miguel; Cavallini, Maria Cristina; Ciullo, Valentina; Cook, Edwin H.; Crosby, Jesse; Cullen, Bernadette A.; De Schipper, Elles J.; Delorme, Richard; Djurovic, Srdjan; Elias, Jason A.; Estivill, Xavier; Falkenstein, Martha J.; Fundin, Bengt T.; Garner, Lauryn; German, Chris; Gironda, Christina; Goes, Fernando S.; Grados, Marco A.; Grove, Jakob; Guo, Wei; Haavik, Jan; Hagen, Kristen; Harrington, Kelly; Havdahl, Alexandra; Höffler, Kira D.; Hounie, Ana G.; Hucks, Donald; Hultman, Christina; Janecka, Magdalena; Jenike, Eric; Karlsson, Elinor K.; Kelley, Kara; Klawohn, Julia; Krasnow, Janice E.; Krebs, Kristi; Lange, Christoph; Lanzagorta, Nuria; Levey, Daniel; Lindblad-Toh, Kerstin; Macciardi, Fabio; Maher, Brion; Mathes, Brittany; McArthur, Evonne; McGregor, Nathaniel; McLaughlin, Nicole C.; Meier, Sandra; Miguel, Euripedes C.; Mulhern, Maureen; Nestadt, Paul S.; Nurmi, Erika L.; O'Connell, Kevin S.; Osiecki, Lisa; Ousdal, Olga Therese; Palviainen, Teemu; Pedersen, Nancy L.; Piras, Fabrizio; Piras, Federica; Potluri, Sriramya; Rabionet, Raquel; Ramirez, Alfredo; Rauch, Scott; Reichenberg, Abraham; Riddle, Mark A.; Ripke, Stephan; Rosário, Maria C.; Sampaio, Aline S.; Schiele, Miriam A.; Skogholt, Anne Heidi; Sloofman, Laura G.; Smit, Jan; Soler, Artigas María; Thomas, Laurent F.; Tifft, Eric; Vallada, Homero; van Kirk, Nathanial; Veenstra-VanderWeele, Jeremy; Vulink, Nienke N.; Walker, Christopher P.; Wang, Ying; Wendland, Jens R.; Winsvold, Bendik S.; Yao, Yin; Zhou, Hang; 23andMe Research Team; VA Million Veteran Program; Estonian Biobank; CoGa research team; iPSYCH; HUNT research team; NORDiC research team; Agrawal, Arpana; Alonso, Pino; Berberich, Götz; Bucholz, Kathleen K.; Bulik, Cynthia M.; Cath, Danielle; Denys, Damiaan; Eapen, Valsamma; Edenberg, Howard; Falkai, Peter; Fernandez, Thomas V.; Fyer, Abby J.; Gaziano, J. M.; Geller, Dan A.; Grabe, Hans J.; Greenberg, Benjamin D.; Hanna, Gregory L.; Hickie, Ian B.; Hougaard, David M.; Kathmann, Norbert; Kennedy, James; Lai, Dongbing; Landén, Mikael; Le Hellard, Stéphanie; Leboyer, Marion; Lochner, Christine; McCracken, James T.; Medland, Sarah E.; Mortensen, Preben B.; Neale, Benjamin M.; Nicolini, Humberto; Nordentoft, Merete; Pato, Michele; Pato, Carlos; Pauls, David L.; Piacentini, John; Pittenger, Christopher; Posthuma, Danielle; Ramos-Quiroga, Josep Antoni; Rasmussen, Steven A.; Richter, Margaret A.; Rosenberg, David R.; Ruhrmann, Stephan; Samuels, Jack F.; Sandin, Sven; Sandor, Paul; Spalletta, Gianfranco; Stein, Dan J.; Stewart, S. Evelyn; Storch, Eric A.; Stranger, Barbara E.; Turiel, Maurizio; Werge, Thomas; Andreassen, Ole A.; Børglum, Anders D.; Walitza, Susanne; Hveem, Kristian; Hansen, Bjarne K.; Rück, Christian P.; Martin, Nicholas G.; Milani, Lili; Mors, Ole; Reichborn-Kjennerud, Ted; Ribasés, Marta; Kvale, Gerd; Mataix-Cols, David; Domschke, Katharina; Grünblatt, Edna; Wagner, Michael; Zwart, John-Anker; Breen, Gerome; Nestadt, Gerald; Kaprio, Jaakko; Arnold, Paul D.; Grice, Dorothy E.; Knowles, James A.; Ask, Helga; Verweij, Karin J.; Davis, Lea K.; Smit, Dirk J.; Crowley, James J.; Scharf, Jeremiah M.; Stein, Murray B.; Gelernter, Joel; Mathews, Carol A.; Derks, Eske M.; Mattheisen, Manuel; Biochemistry and Molecular Biology, School of Medicine
    Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder.
  • Thumbnail Image
    Item
    Genome-wide association study identifies 48 common genetic variants associated with handedness
    (Springer Nature, 2021) Cuellar-Partida, Gabriel; Tung, Joyce Y.; Eriksson, Nicholas; Albrecht, Eva; Aliev, Fazil; Andreassen, Ole A.; Barroso, Inês; Beckmann, Jacques S.; Boks, Marco P.; Boomsma, Dorret I.; Boyd, Heather A.; Breteler, Monique M. B.; Campbell, Harry; Chasman, Daniel I.; Cherkas, Lynn F.; Davies, Gail; de Geus, Eco J. C.; Deary, Ian J.; Deloukas, Panos; Dick, Danielle M.; Duffy, David L.; Eriksson, Johan G.; Esko, Tõnu; Feenstra, Bjarke; Geller, Frank; Gieger, Christian; Giegling, Ina; Gordon, Scott D.; Han, Jiali; Hansen, Thomas F.; Hartmann, Annette M.; Hayward, Caroline; Heikkilä, Kauko; Hicks, Andrew A.; Hirschhorn, Joel N.; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Hwang, Liang-Dar; Ikram, M. Arfan; Kaprio, Jaakko; Kemp, John P.; Khaw, Kay-Tee; Klopp, Norman; Konte, Bettina; Kutalik, Zoltan; Lahti, Jari; Li, Xin; Loos, Ruth J. F.; Luciano, Michelle; Magnusson, Sigurdur H.; Mangino, Massimo; Marques-Vidal, Pedro; Martin, Nicholas G.; McArdle, Wendy L.; McCarthy, Mark I.; Medina-Gomez, Carolina; Melbye, Mads; Melville, Scott A.; Metspalu, Andres; Milani, Lili; Mooser, Vincent; Nelis, Mari; Nyholt, Dale R.; O'Connell, Kevin S.; Ophoff, Roel A.; Palmer, Cameron; Palotie, Aarno; Palviainen, Teemu; Pare, Guillaume; Paternoster, Lavinia; Peltonen, Leena; Penninx, Brenda W. J. H.; Polasek, Ozren; Pramstaller, Peter P.; Prokopenko, Inga; Raikkonen, Katri; Ripatti, Samuli; Rivadeneira, Fernando; Rudan, Igor; Rujescu, Dan; Smit, Johannes H.; Smith, George Davey; Smoller, Jordan W.; Soranzo, Nicole; Spector, Tim D.; St. Pourcain, Beate; Starr, John M.; Stefánsson, Hreinn; Steinberg, Stacy; Teder-Laving, Maris; Thorleifsson, Gudmar; Stefánsson, Kári; Timpson, Nicholas J.; Uitterlinden, André G.; van Duijn, Cornelia M.; van Rooij, Frank J. A.; Vink, Jaqueline M.; Vollenweider, Peter; Vuoksimaa, Eero; Waeber, Gérard; Wareham, Nicholas J.; Warrington, Nicole; Waterworth, Dawn; Werge, Thomas; Wichmann, H-Erich; Widen, Elisabeth; Willemsen, Gonneke; Wright, Alan F.; Wright, Margaret J.; Xu, Mousheng; Zhao, Jing Hua; Kraft, Peter; Hinds, David A.; Lindgren, Cecilia M.; Mägi, Reedik; Neale, Benjamin M.; Evans, David M.; Medland, Sarah E.; Epidemiology, School of Public Health
    Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
  • Thumbnail Image
    Item
    Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
    (Springer Nature, 2021-06) Mullins, Niamh; Forstner, Andreas J.; O'Connell, Kevin S.; Coombes, Brandon; Coleman, Jonathan R.I.; 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; Pedersen, Carsten Bøcker; 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; Pedersen, Marianne Giørtz; 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.; Kalman, Janos L.; Kamatani, Yoichiro; Kennedy, James L.; Kittel-Schneider, Sarah; Knowles, James A.; Kogevinas, Manolis; Koromina, Maria; Kranz, Thorsten M.; Kranzler, Henry R.; Kubo, Michiaki; Kupka, Ralph; Kushner, Steven A.; Lavebratt, Catharina; Lawrence, Jacob; Leber, Markus; Lee, Heon-Jeong; Lee, Phil H.; Levy, Shawn E.; Lewis, Catrin; Liao, Calwing; Lucae, Susanne; Lundberg, Martin; MacIntyre, Donald J.; Magnusson, Sigurdur H.; Maier, Wolfgang; Maihofer, Adam; Malaspina, Dolores; Maratou, Eirini; Martinsson, Lina; Mattheisen, Manuel; McCarroll, Steven A.; McGregor, Nathaniel W.; McGuffin, Peter; McKay, James D.; Medeiros, Helena; Medland, Sarah E.; Millischer, Vincent; Montgomery, Grant W.; Moran, Jennifer L.; Morris, Derek W.; Mühleisen, Thomas W.; O'Brien, Niamh; O'Donovan, Claire; Loohuis, Loes M. Olde; Oruc, Lilijana; Papiol, Sergi; Pardiñas, Antonio F.; Perry, Amy; Pfennig, Andrea; Porichi, Evgenia; Potash, James B.; Quested, Digby; Raj, Towfique; Rapaport, Mark H.; DePaulo, J. Raymond; Regeer, Eline J.; Rice, John P.; Rivas, Fabio; Rivera, Margarita; Roth, Julian; Roussos, Panos; Ruderfer, Douglas M.; Sánchez-Mora, Cristina; Schulte, Eva C.; Senner, Fanny; Sharp, Sally; Shilling, Paul D.; Sigurdsson, Engilbert; Sirignano, Lea; Slaney, Claire; Smeland, Olav B.; Smith, Daniel J.; Sobell, Janet L.; Søholm Hansen, Christine; Artigas, Maria Soler; Spijker, Anne T.; Stein, Dan J.; Strauss, John S.; Świątkowska, Beata; Terao, Chikashi; Thorgeirsson, Thorgeir E.; Toma, Claudio; Tooney, Paul; Tsermpini, Evangelia-Eirini; Vawter, Marquis P.; Vedder, Helmut; Walters, James T.R.; Witt, Stephanie H.; Xi, Simon; Xu, Wei; Yang, Jessica Mei Kay; Young, Allan H.; Young, Hannah; Zandi, Peter P.; Zhou, Hang; Zillich, Lea; Adolfsson, Rolf; Agartz, Ingrid; Alda, Martin; Alfredsson, Lars; Babadjanova, Gulja; Backlund, Lena; Baune, Bernhard T.; Bellivier, Frank; Bengesser, Susanne; Berrettini, Wade H.; Blackwood, Douglas H.R.; Boehnke, Michael; Børglum, Anders D.; Breen, Gerome; Carr, Vaughan J.; Catts, Stanley; Corvin, Aiden; Craddock, Nicholas; Dannlowski, Udo; Dikeos, Dimitris; Esko, Tõnu; Etain, Bruno; Ferentinos, Panagiotis; Frye, Mark; Fullerton, Janice M.; Gawlik, Micha; Gershon, Elliot S.; Goes, Fernando S.; Green, Melissa J.; Grigoroiu-Serbanescu, Maria; Hauser, Joanna; Henskens, Frans; Hillert, Jan; Hong, Kyung Sue; Hougaard, David M.; Hultman, Christina M.; Hveem, Kristian; Iwata, Nakao; Jablensky, Assen V.; Jones, Ian; Jones, Lisa A.; Kahn, René S.; Kelsoe, John R.; Kirov, George; Landén, Mikael; Leboyer, Marion; Lewis, Cathryn M.; Li, Qingqin S.; Lissowska, Jolanta; Lochner, Christine; Loughland, Carmel; Martin, Nicholas G.; Mathews, Carol A.; Mayoral, Fermin; McElroy, Susan L.; McIntosh, Andrew M.; McMahon, Francis J.; Melle, Ingrid; Michie, Patricia; Milani, Lili; Mitchell, Philip B.; Morken, Gunnar; Mors, Ole; Mortensen, Preben Bo; Mowry, Bryan; Müller-Myhsok, Bertram; Myers, Richard M.; Neale, Benjamin M.; Nievergelt, Caroline M.; Nordentoft, Merete; Nöthen, Markus M.; O'Donovan, Michael C.; Oedegaard, Ketil J.; Olsson, Tomas; Owen, Michael J.; Paciga, Sara A.; Pantelis, Chris; Pato, Carlos; Pato, Michele T.; Patrinos, George P.; Perlis, Roy H.; Posthuma, Danielle; Ramos-Quiroga, Josep Antoni; Reif, Andreas; Reininghaus, Eva Z.; Ribasés, Marta; Rietschel, Marcella; Ripke, Stephan; Rouleau, Guy A.; Saito, Takeo; Schall, Ulrich; Schalling, Martin; Schofield, Peter R.; Schulze, Thomas G.; Scott, Laura J.; Scott, Rodney J.; Serretti, Alessandro; Weickert, Cynthia Shannon; Smoller, Jordan W.; Stefansson, Hreinn; Stefansson, Kari; Stordal, Eystein; Streit, Fabian; Sullivan, Patrick F.; Turecki, Gustavo; Vaaler, Arne E.; Vieta, Eduard; Vincent, John B.; Waldman, Irwin D.; Weickert, Thomas W.; Werge, Thomas; Wray, Naomi R.; Zwart, John-Anker; Biernacka, Joanna M.; Nurnberger, John I.; Cichon, Sven; Edenberg, Howard J.; Stahl, Eli A.; McQuillin, Andrew; Florio, Arianna Di; Ophoff, Roel A.; Andreassen, Ole A.; Medical and Molecular Genetics, School of Medicine
    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.
  • Thumbnail Image
    Item
    Identification of risk variants and cross-disorder pleiotropy through multi-ancestry genome-wide analysis of alcohol use disorder
    (Springer Nature, 2025) Icick, Romain; Shadrin, Alexey; Holen, Børge; Karadag, Naz; Parker, Nadine; O'Connell, Kevin S.; Frei, Oleksandr; Bahrami, Shahram; Collier Høegh, Margrethe; Vik Lagerberg, Trine; Cheng, Weiqiu; Seibert, Tyler M.; Djurovic, Srdjan; Dale, Anders M.; Zhou, Hang; Edenberg, Howard J.; Gelernter, Joel; Smeland, Olav B.; Hindley, Guy; Andreassen, Ole A.; Biochemistry and Molecular Biology, School of Medicine
    Alcohol use disorder (AUD) is highly heritable and burdensome worldwide. Genome-wide association studies (GWASs) can provide new evidence regarding the aetiology of AUD. We report a multi-ancestry GWAS focusing on a narrow AUD phenotype, using novel statistical tools in a total sample of 1,041,450 individuals [102,079 cases; European, 75,583; African, 20,689 (mostly African-American); Hispanic American, 3,449; East Asian, 2,254; South Asian, 104; descent]. Cross-ancestry functional analyses were performed with European and African samples. Thirty-seven genome-wide significant loci (105 variants) were identified, of which seven were novel for AUD and six for other alcohol phenotypes. Loci were mapped to genes, which show altered expression in brain regions relevant for AUD (striatum, hypothalamus, and prefrontal cortex) and encode potential drug targets (GABAergic, dopaminergic and serotonergic neurons). African-specific analysis yielded a unique pattern of immune-related gene sets. Polygenic overlap and positive genetic correlations showed extensive shared genetic architecture between AUD and both mental and general medical phenotypes, suggesting they are not only complications of alcohol use but also share genetic liability with AUD. Leveraging a cross-ancestry approach allowed identification of novel genetic loci for AUD and underscores the value of multi-ancestry genetic studies. These findings advance our understanding of AUD risk and clinically-relevant comorbidities.
  • Thumbnail Image
    Item
    The Landscape of Shared and Divergent Genetic Influences across 14 Psychiatric Disorders
    (medRxiv, 2025-01-15) Grotzinger, Andrew D.; Werme, Josefin; Peyrot, Wouter J.; Frei, Oleksandr; de Leeuw, Christiaan; Bicks, Lucy K.; Guo, Qiuyu; Margolis, Michael P.; Coombes, Brandon J.; Batzler, Anthony; Pazdernik, Vanessa; Biernacka, Joanna M.; Andreassen, Ole A.; Anttila, Verneri; Børglum, Anders D.; Cai, Na; Demontis, Ditte; Edenberg, Howard J.; Faraone, Stephen V.; Franke, Barbara; Gandal, Michael J.; Gelernter, Joel; Hettema, John M.; Jonas, Katherine G.; Knowles, James A.; Koenen, Karestan C.; Maihofer, Adam X.; Mallard, Travis T.; Mattheisen, Manuel; Mitchell, Karen S.; Neale, Benjamin M.; Nievergelt, Caroline M.; Nurnberger, John I.; O'Connell, Kevin S.; Robinson, Elise B.; Sanchez-Roige, Sandra S.; Santangelo, Susan L.; Stefansson, Hreinn; Stefansson, Kari; Stein, Murray B.; Strom, Nora I.; Thornton, Laura M.; Tucker-Drob, Elliot M.; Verhulst, Brad; Waldman, Irwin D.; Walters, G. Bragi; Wray, Naomi R.; Anxiety Disorders Working Group; Attention-Deficit/Hyperactivity Disorder (ADHD) Working Group; Autism Spectrum Disorders Working Group; Bipolar Disorder Working Group; Eating Disorders Working Group; Major Depressive Disorder Working Group; Nicotine Dependence GenOmics (iNDiGO) Consortium; Obsessive-Compulsive Disorder Working Group; Post-Traumatic Stress Disorder Working Group; Schizophrenia Working Group; Substance Use Disorders Working Group; Tourette Syndrome Working Group; Lee, Phil H.; Kendler, Kenneth S.; Smoller, Jordan W.; Biochemistry and Molecular Biology, School of Medicine
    Psychiatric disorders display high levels of comorbidity and genetic overlap 1,2. Genomic methods have shown that even for schizophrenia and bipolar disorder, two disorders long-thought to be etiologically distinct 3, the majority of genetic signal is shared 4. Furthermore, recent cross-disorder analyses have uncovered over a hundred pleiotropic loci shared across eight disorders 5. However, the full scope of shared and disorder-specific genetic basis of psychopathology remains largely uncharted. Here, we address this gap by triangulating across a suite of cutting-edge statistical genetic and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Our analyses identify and characterize five underlying genomic factors 6 that explain the majority of the genetic variance of the individual disorders (~66% on average) and are associated with 268 pleiotropic loci. We observed particularly high levels of polygenic overlap 7 and local genetic correlation 8 and very few disorder-specific loci 9 for two factors defined by: (i) schizophrenia and bipolar disorder ("SB factor"), and by (ii) major depression, PTSD, and anxiety ("internalizing factor"). At the functional level, we applied multiple methods 10-12 which demonstrated that the shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the internalizing factor was associated with oligodendrocyte biology. By comparison, the genetic signal shared across all 14 disorders was enriched for broad biological processes (e.g., transcriptional regulation). These results indicate increasing differentiation of biological function at different levels of shared cross-disorder risk, from quite general vulnerability to more specific pathways associated with subsets of disorders. These observations may inform a more neurobiologically valid psychiatric nosology and implicate novel targets for therapeutic developments designed to treat commonly occurring comorbid presentations.