Browsing by Author "Børglum, Anders D."

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    Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits
    (Elsevier, 2021-06-15) Martin, Joanna; Khramtsova, Ekaterina A.; Goleva, Slavina B.; Blokland, Gabriëlla A.M.; Traglia, Michela; Walters, Raymond K.; Hübel, Christopher; Coleman, Jonathan R.I.; Breen, Gerome; Børglum, Anders D.; Demontis, Ditte; Grove, Jakob; Werge, Thomas; Bralten, Janita; Bulik, Cynthia M.; Lee, Phil H.; Mathews, Carol A.; Peterson, Roseann E.; Winham, Stacey J.; Wray, Naomi; Edenberg, Howard J.; Guo, Wei; Yao, Yin; Neale, Benjamin M.; Faraone, Stephen V.; Petryshen, Tracey L.; Weiss, Lauren A.; Duncan, Laramie E.; Goldstein, Jill M.; Smoller, Jordan W.; Stranger, Barbara E.; Davis, Lea K.; Biochemistry and Molecular Biology, School of Medicine
    Background: The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits. Methods: Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (rg < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations. Results: We observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although <1 for educational attainment and risk-taking behavior. We identified 4 genes with significant sex-differentiated effects across 3 traits. Several trait pairs shared sex-differentiated effects. The top genes with sex-differentiated effects were enriched for multiple gene sets, including neuron- and synapse-related sets. Most between-trait genetic correlation estimates were not significantly different between sexes, with exceptions (educational attainment and risk-taking behavior). Conclusions: Sex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic and unlikely to fully account for observed sex-differentiated attributes. Larger sample sizes are needed to identify sex-differentiated effects for most traits. For well-powered studies, we identified genes with sex-differentiated effects that were enriched for neuron-related and other biological functions. This work motivates further investigation of genetic and environmental influences on sex differences.
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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.
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    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.
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    Genome-wide association study in individuals of European and African ancestry and multi-trait analysis of opioid use disorder identifies 19 independent genome-wide significant risk loci
    (Springer, 2022-10) Deak, Joseph D.; Zhou, Hang; Galimberti, Marco; Levey, Daniel F.; Wendt, Frank R.; Sanchez-Roige, Sandra; Hatoum, Alexander S.; Johnson, Emma C.; Nunez, Yaira Z.; Demontis, Ditte; Børglum, Anders D.; Rajagopal, Veera M.; Jennings, Mariela V.; Kember, Rachel L.; Justice, Amy C.; Edenberg, Howard J.; Agrawal, Arpana; Polimanti, Renato; Kranzler, Henry R.; Gelernter, Joel; Biochemistry and Molecular Biology, School of Medicine
    Despite the large toll of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci. We performed a large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (Multi-trait analysis of GWAS) with genetically correlated substance use disorders (SUDs). Meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total N = 639,063 (Ncases = 20,686;Neffective = 77,026) across ancestries. OUD cases were defined as having a lifetime OUD diagnosis, and controls as anyone not known to meet OUD criteria. We estimated SNP-heritability (h2SNP) and genetic correlations (rg). Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A leave-one-out polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3. The EUR meta-analysis identified three genome-wide significant (GWS; p ≤ 5 × 10−8) lead SNPs—one at FURIN (rs11372849; p = 9.54 × 10−10) and two OPRM1 variants (rs1799971, p = 4.92 × 10−09; rs79704991, p = 1.11 × 10−08; r2 = 0.02). Rs1799971 (p = 4.91 × 10−08) and another OPRM1 variant (rs9478500; p = 1.95 × 10−08; r2 = 0.03) were identified in the cross-ancestry meta-analysis. Estimated h2SNP was 12.75%, with strong rg with CanUD (rg = 0.82; p = 1.14 × 10−47) and AUD (rg = 0.77; p = 6.36 × 10−78). The OUD-MTAG resulted in a GWAS Nequivalent = 128,748 and 18 independent GWS loci, some mapping to genes or gene regions that have previously been associated with psychiatric or addiction phenotypes. The OUD-MTAG PRS accounted for 3.81% of OUD variance (beta = 0.61;s.e. = 0.066; p = 2.00 × 10−16) compared to 2.41% (beta = 0.45; s.e. = 0.058; p = 2.90 × 10−13) explained by the OUD PRS. The current study identified OUD variant associations at OPRM1, single variant associations with FURIN, and 18 GWS associations in the OUD-MTAG. The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared across SUDs.
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    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.
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    Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits
    (Nature, 2020-07) Zhou, Hang; Sealock, Julia M.; Sanchez-Roige, Sandra; Clarke, Toni-Kim; Levey, Daniel F.; Cheng, Zhongshan; Li, Boyang; Polimanti, Renato; Kember, Rachel L.; Smith, Rachel Vickers; Thygesen, Johan H.; Morgan, Marsha Y.; Atkinson, Stephen R.; Thursz, Mark R.; Nyegaard, Mette; Mattheisen, Manuel; Børglum, Anders D.; Johnson, Emma C.; Justice, Amy C.; Palmer, Abraham A.; McQuillin, Andrew; Davis, Lea K.; Edenberg, Howard J.; Agrawal, Arpana; Kranzler, Henry R.; Gelernter, Joel; Medical and Molecular Genetics, School of Medicine
    Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU, combining alcohol use disorder and problematic drinking, in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n = 67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in conserved and regulatory genomic regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other traits.
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    GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors
    (American Psychiatric Association, 2023) Docherty, Anna R.; Mullins, Niamh; Ashley-Koch, Allison E.; Qin, Xuejun; Coleman, Jonathan R. I.; Shabalin, Andrey; Kang, JooEun; Murnyak, Balasz; Wendt, Frank; Adams, Mark; Campos, Adrian I.; DiBlasi, Emily; Fullerton, Janice M.; Kranzler, Henry R.; Bakian, Amanda V.; Monson, Eric T.; Rentería, Miguel E.; Walss-Bass, Consuelo; Andreassen, Ole A.; Behera, Chittaranjan; Bulik, Cynthia M.; Edenberg, Howard J.; Kessler, Ronald C.; Mann, J. John; Nurnberger, John I., Jr.; Pistis, Giorgio; Streit, Fabian; Ursano, Robert J.; Polimanti, Renato; Dennis, Michelle; Garrett, Melanie; Hair, Lauren; Harvey, Philip; Hauser, Elizabeth R.; Hauser, Michael A.; Huffman, Jennifer; Jacobson, Daniel; Madduri, Ravi; McMahon, Benjamin; Oslin, David W.; Trafton, Jodie; Awasthi, Swapnil; Berrettini, Wade H.; Bohus, Martin; Chang, Xiao; Chen, Hsi-Chung; Chen, Wei J.; Christensen, Erik D.; Crow, Scott; Duriez, Philibert; Edwards, Alexis C.; Fernández-Aranda, Fernando; Galfalvy, Hanga; Gandal, Michael; Gorwood, Philip; Guo, Yiran; Hafferty, Jonathan D.; Hakonarson, Hakon; Halmi, Katherine A.; Hishimoto, Akitoyo; Jain, Sonia; Jamain, Stéphane; Jiménez-Murcia, Susana; Johnson, Craig; Kaplan, Allan S.; Kaye, Walter H.; Keel, Pamela K.; Kennedy, James L.; Kim, Minsoo; Klump, Kelly L.; Levey, Daniel F.; Li, Dong; Liao, Shih-Cheng; Lieb, Klaus; Lilenfeld, Lisa; Marshall, Christian R.; Mitchell, James E.; Okazaki, Satoshi; Otsuka, Ikuo; Pinto, Dalila; Powers, Abigail; Ramoz, Nicolas; Ripke, Stephan; Roepke, Stefan; Rozanov, Vsevolod; Scherer, Stephen W.; Schmahl, Christian; Sokolowski, Marcus; Starnawska, Anna; Strober, Michael; Su, Mei-Hsin; Thornton, Laura M.; Treasure, Janet; Ware, Erin B.; Watson, Hunna J.; Witt, Stephanie H.; Woodside, D. Blake; Yilmaz, Zeynep; Zillich, Lea; Adolfsson, Rolf; Agartz, Ingrid; Alda, Martin; Alfredsson, Lars; Appadurai, Vivek; Artigas, María Soler; Van der Auwera, Sandra; Azevedo, M. Helena; Bass, Nicholas; Bau, Claiton H. D.; Baune, Bernhard T.; Bellivier, Frank; Berger, Klaus; Biernacka, Joanna M.; Bigdeli, Tim B.; Binder, Elisabeth B.; Boehnke, Michael; Boks, Marco P.; Braff, David L.; Bryant, Richard; Budde, Monika; Byrne, Enda M.; Cahn, Wiepke; Castelao, Enrique; Cervilla, Jorge A.; Chaumette, Boris; Corvin, Aiden; Craddock, Nicholas; Djurovic, Srdjan; Foo, Jerome C.; Forstner, Andreas J.; Frye, Mark; Gatt, Justine M.; Giegling, Ina; Grabe, Hans J.; Green, Melissa J.; Grevet, Eugenio H.; Grigoroiu-Serbanescu, Maria; Gutierrez, Blanca; Guzman-Parra, Jose; Hamshere, Marian L.; Hartmann, Annette M.; Hauser, Joanna; Heilmann-Heimbach, Stefanie; Hoffmann, Per; Ising, Marcus; Jones, Ian; Jones, Lisa A.; Jonsson, Lina; Kahn, René S.; Kelsoe, John R.; Kendler, Kenneth S.; Kloiber, Stefan; Koenen, Karestan C.; Kogevinas, Manolis; Krebs, Marie-Odile; Landén, Mikael; Leboyer, Marion; Lee, Phil H.; Levinson, Douglas F.; Liao, Calwing; Lissowska, Jolanta; Mayoral, Fermin; McElroy, Susan L.; McGrath, Patrick; McGuffin, Peter; McQuillin, Andrew; Mehta, Divya; Melle, Ingrid; Mitchell, Philip B.; Molina, Esther; Morken, Gunnar; Nievergelt, Caroline; Nöthen, Markus M.; O'Donovan, Michael C.; Ophoff, Roel A.; Owen, Michael J.; Pato, Carlos; Pato, Michele T.; Penninx, Brenda W. J. H.; Potash, James B.; Power, Robert A.; Preisig, Martin; Quested, Digby; Ramos-Quiroga, Josep Antoni; Reif, Andreas; Ribasés, Marta; Richarte, Vanesa; Rietschel, Marcella; Rivera, Margarita; Roberts, Andrea; Roberts, Gloria; Rouleau, Guy A.; Rovaris, Diego L.; Sanders, Alan R.; Schofield, Peter R.; Schulze, Thomas G.; Scott, Laura J.; Serretti, Alessandro; Shi, Jianxin; Sirignano, Lea; Sklar, Pamela; Smeland, Olav B.; Smoller, Jordan W.; Sonuga-Barke, Edmund J. S.; Trzaskowski, Maciej; Tsuang, Ming T.; Turecki, Gustavo; Vilar-Ribó, Laura; Vincent, John B.; Völzke, Henry; Walters, James T. R.; Weickert, Cynthia Shannon; Weickert, Thomas W.; Weissman, Myrna M.; Williams, Leanne M.; Wray, Naomi R.; Zai, Clement C.; Agerbo, Esben; Børglum, Anders D.; Breen, Gerome; Demontis, Ditte; Erlangsen, Annette; Gelernter, Joel; Glatt, Stephen J.; Hougaard, David M.; Hwu, Hai-Gwo; Kuo, Po-Hsiu; Lewis, Cathryn M.; Li, Qingqin S.; Liu, Chih-Min; Martin, Nicholas G.; McIntosh, Andrew M.; Medland, Sarah E.; Mors, Ole; Nordentoft, Merete; Olsen, Catherine M.; Porteous, David; Smith, Daniel J.; Stahl, Eli A.; Stein, Murray B.; Wasserman, Danuta; Werge, Thomas; Whiteman, David C.; Willour, Virginia; VA Million Veteran Program (MVP); MVP Suicide Exemplar Workgroup; Suicide Working Group of the Psychiatric Genomics Consortium; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Eating Disorder Working Group of the Psychiatric Genomics Consortium; German Borderline Genomics Consortium; Coon, Hilary; Beckham, Jean C.; Kimbrel, Nathan A.; Ruderfer, Douglas M.; Psychiatry, School of Medicine
    Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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    A large-scale genome-wide association study meta-analysis of cannabis use disorder
    (Elsevier, 2020-12) Johnson, Emma C.; Demontis, Ditte; Thorgeirsson, Thorgeir E.; Walters, Raymond K.; Polimanti, Renato; Hatoum, Alexander S.; Sanchez-Roige, Sandra; Paul, Sarah E.; Wendt, Frank R.; Clarke, Toni-Kim; Lai, Dongbing; Reginsson, Gunnar W.; Zhou, Hang; He, June; Baranger, David A.A.; Gudbjartsson, Daniel F.; Wedow, Robbee; Adkins, Daniel E.; Adkins, Amy E.; Alexander, Jeffry; Bacanu, Silviu-Alin; Bigdeli, Tim B.; Boden, Joseph; Brown, Sandra A.; Bucholz, Kathleen K.; Bybjerg-Grauholm, Jonas; Corley, Robin P.; Degenhardt, Louisa; Dick, Danielle M.; Domingue, Benjamin W.; Fox, Louis; Goate, Alison M.; Gordon, Scott D.; Hack, Laura M.; Hancock, Dana B.; Hartz, Sarah M.; Hickie, Ian B.; Hougaard, David M.; Krauter, Kenneth; Lind, Penelope A.; McClintick, Jeanette N.; McQueen, Matthew B.; Meyers, Jacquelyn L.; Montgomery, Grant W.; Mors, Ole; Mortensen, Preben B.; Nordentoft, Merete; Pearson, John F.; Peterson, Roseann E.; Reynolds, Maureen D.; Rice, John P.; Runarsdottir, Valgerdur; Saccone, Nancy L.; Sherva, Richard; Silberg, Judy L.; Tarter, Ralph E.; Tyrfingsson, Thorarinn; Wall, Tamara L.; Webb, Bradley T.; Werge, Thomas; Wetherill, Leah; Wright, Margaret J.; Zellers, Stephanie; Adams, Mark J.; Bierut, Laura J.; Boardman, Jason D.; Copeland, William E.; Farrer, Lindsay A.; Foroud, Tatiana M.; Gillespie, Nathan A.; Grucza, Richard A.; Mullan Harris, Kathleen; Heath, Andrew C.; Hesselbrock, Victor; Hewitt, John K.; Hopfer, Christian J.; Horwood, John; Iacono, William G.; Johnson, Eric O.; Kendler, Kenneth S.; Kennedy, Martin A.; Kranzler, Henry R.; Madden, Pamela A.F.; Maes, Hermine H.; Maher, Brion S.; Martin, Nicholas G.; McGue, Matthew; McIntosh, Andrew M.; Medland, Sarah E.; Nelson, Elliot C.; Porjesz, Bernice; Riley, Brien P.; Stallings, Michael C.; Vanyukov, Michael M.; Vrieze, Scott; Davis, Lea K.; Bogdan, Ryan; Gelernter, Joel; Edenberg, Howard J.; Stefansson, Kari; Børglum, Anders D.; Agrawal, Arpana; Medical and Molecular Genetics, School of Medicine
    Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10-9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10-9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10-21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.
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    Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications
    (Springer Nature, 2023) Levey, Daniel F.; Galimberti, Marco; Deak, Joseph D.; Wendt, Frank R.; Bhattacharya, Arjun; Koller, Dora; Harrington, Kelly M.; Quaden, Rachel; Johnson, Emma C.; Gupta, Priya; Biradar, Mahantesh; Lam, Max; Cooke, Megan; Rajagopal, Veera M.; Empke, Stefany L. L.; Zhou, Hang; Nunez, Yaira Z.; Kranzler, Henry R.; Edenberg, Howard J.; Agrawal, Arpana; Smoller, Jordan W.; Lencz, Todd; Hougaard, David M.; Børglum, Anders D.; Demontis, Ditte; Veterans Affairs Million Veteran Program; Gaziano, J. Michael; Gandal, Michael J.; Polimanti, Renato; Stein, Murray B.; Gelernter, Joel; Biochemistry and Molecular Biology, School of Medicine
    As recreational use of cannabis is being decriminalized in many places and medical use widely sanctioned, there are growing concerns about increases in cannabis use disorder (CanUD), which is associated with numerous medical comorbidities. Here we performed a genome-wide association study of CanUD in the Million Veteran Program (MVP), followed by meta-analysis in 1,054,365 individuals (ncases = 64,314) from four broad ancestries designated by the reference panel used for assignment (European n = 886,025, African n = 123,208, admixed American n = 38,289 and East Asian n = 6,843). Population-specific methods were applied to calculate single nucleotide polymorphism-based heritability within each ancestry. Statistically significant single nucleotide polymorphism-based heritability for CanUD was observed in all but the smallest population (East Asian). We discovered genome-wide significant loci unique to each ancestry: 22 in European, 2 each in African and East Asian, and 1 in admixed American ancestries. A genetically informed causal relationship analysis indicated a possible effect of genetic liability for CanUD on lung cancer risk, suggesting potential unanticipated future medical and psychiatric public health consequences that require further study to disentangle from other known risk factors such as cigarette smoking.
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    Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals
    (Springer Nature, 2023) Zhou, Hang; Kember, Rachel L.; Deak, Joseph D.; Xu, Heng; Toikumo, Sylvanus; Yuan, Kai; Lind, Penelope A.; Farajzadeh, Leila; Wang, Lu; Hatoum, Alexander S.; Johnson, Jessica; Lee, Hyunjoon; Mallard, Travis T.; Xu, Jiayi; Johnston, Keira J. A.; Johnson, Emma C.; Galimberti, Marco; Dao, Cecilia; Levey, Daniel F.; Overstreet, Cassie; Byrne, Enda M.; Gillespie, Nathan A.; Gordon, Scott; Hickie, Ian B.; Whitfield, John B.; Xu, Ke; Zhao, Hongyu; Huckins, Laura M.; Davis, Lea K.; Sanchez-Roige, Sandra; Madden, Pamela A. F.; Heath, Andrew C.; Medland, Sarah E.; Martin, Nicholas G.; Ge, Tian; Smoller, Jordan W.; Hougaard, David M.; Børglum, Anders D.; Demontis, Ditte; Krystal, John H.; Gaziano, J. Michael; Edenberg, Howard J.; Agrawal, Arpana; Million Veteran Program; Justice, Amy C.; Stein, Murray B.; Kranzler, Henry R.; Gelernter, Joel; Biochemistry and Molecular Biology, School of Medicine
    Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.