Strom, Nora IGerring, Zachary FGalimberti, MarcoYu, DongmeiHalvorsen, Matthew WAbdellaoui, AbdelRodriguez-Fontenla, CristinaSealock, Julia MBigdeli, TimColeman, Jonathan RMahjani, BehrangThorp, Jackson GBey, KatharinaBurton, Christie LLuykx, Jurjen JZai, GwynethAlemany, SilviaAndre, ChristineAskland, Kathleen DBanaj, NerisaBarlassina, CristinaNissen, Judith BeckerBienvenu, O JosephBlack, DonaldBloch, Michael HBoberg, JuliaBørte, SigridBosch, RosaBreen, MichaelBrennan, Brian PBrentani, HelenaBuxbaum, Joseph DBybjerg-Grauholm, JonasByrne, Enda MCabana-Dominguez, JuditCamarena, BeatrizCamarena, AdrianCappi, CarolinaCarracedo, AngelCasas, MiguelCavallini, Maria CristinaCiullo, ValentinaCook, Edwin HCrosby, JesseCullen, Bernadette ADe Schipper, Elles JDelorme, RichardDjurovic, SrdjanElias, Jason AEstivill, XavierFalkenstein, Martha JFundin, Bengt TGarner, LaurynGerman, ChrisGironda, ChristinaGoes, Fernando SGrados, Marco AGrove, JakobGuo, WeiHaavik, JanHagen, KristenHarrington, KellyHavdahl, AlexandraHöffler, Kira DHounie, Ana GHucks, DonaldHultman, ChristinaJanecka, MagdalenaJenike, EricKarlsson, Elinor KKelley, KaraKlawohn, JuliaKrasnow, Janice EKrebs, KristiLange, ChristophLanzagorta, NuriaLevey, DanielLindblad-Toh, KerstinMacciardi, FabioMaher, BrionMathes, BrittanyMcArthur, EvonneMcGregor, NathanielMcLaughlin, Nicole CMeier, SandraMiguel, Euripedes CMulhern, MaureenNestadt, Paul SNurmi, Erika LO'Connell, Kevin SOsiecki, LisaOusdal, Olga TheresePalviainen, TeemuPedersen, Nancy LPiras, FabrizioPiras, FedericaPotluri, SriramyaRabionet, RaquelRamirez, AlfredoRauch, ScottReichenberg, AbrahamRiddle, Mark ARipke, StephanRosário, Maria CSampaio, Aline SSchiele, Miriam ASkogholt, Anne HeidiSloofman, Laura G Sloofman GSmit, JanSoler, Artigas MaríaThomas, Laurent FTifft, EricVallada, Homerovan Kirk, NathanialVeenstra-VanderWeele, JeremyVulink, Nienke NWalker, Christopher PWang, YingWendland, Jens RWinsvold, Bendik SYao, YinZhou, HangAgrawal, ArpanaAlonso, PinoBerberich, GötzBucholz, Kathleen KBulik, Cynthia MCath, DanielleDenys, DamiaanEapen, ValsammaEdenberg, HowardFalkai, PeterFernandez, Thomas VFyer, Abby JGaziano, J MGeller, Dan AGrabe, Hans JGreenberg, Benjamin DHanna, Gregory LHickie, Ian BHougaard, David MKathmann, NorbertKennedy, JamesLai, DongbingLandén, MikaelLe Hellard, StéphanieLeboyer, MarionLochner, ChristineMcCracken, James TMedland, Sarah EMortensen, Preben BNeale, Benjamin MNicolini, HumbertoNordentoft, MeretePato, MichelePato, CarlosPauls, David LPiacentini, JohnPittenger, ChristopherPosthuma, DanielleRamos-Quiroga, Josep AntoniRasmussen, Steven ARichter, Margaret ARosenberg, David RRuhrmann, StephanSamuels, Jack FSandin, SvenSandor, PaulSpalletta, GianfrancoStein, Dan JStewart, S EvelynStorch, Eric AStranger, Barbara ETuriel, MaurizioWerge, ThomasAndreassen, Ole ABørglum, Anders DWalitza, SusanneHveem, KristianHansen, Bjarne KRück, Christian PMartin, Nicholas GMilani, LiliMors, OleReichborn-Kjennerud, TedRibasés, MartaKvale, GerdMataix-Cols, DavidDomschke, KatharinaGrünblatt, EdnaWagner, MichaelZwart, John-AnkerBreen, GeromeNestadt, GeraldKaprio, JaakkoArnold, Paul DGrice, Dorothy EKnowles, James AAsk, HelgaVerweij, Karin JDavis, Lea KSmit, Dirk JCrowley, James JScharf, Jeremiah MStein, Murray BGelernter, JoelMathews, Carol ADerks, Eske MMattheisen, Manuel2024-07-012024-07-012024-03-13Strom NI, Gerring ZF, Galimberti M, Yu D, Halvorsen MW, Abdellaoui A, Rodriguez-Fontenla C, Sealock JM, Bigdeli T, Coleman JR, Mahjani B, Thorp JG, Bey K, Burton CL, Luykx JJ, Zai G, Alemany S, Andre C, Askland KD, Banaj N, Barlassina C, Nissen JB, Bienvenu OJ, Black D, Bloch MH, Boberg J, Børte S, Bosch R, Breen M, Brennan BP, Brentani H, Buxbaum JD, Bybjerg-Grauholm J, Byrne EM, Cabana-Dominguez J, Camarena B, Camarena A, Cappi C, Carracedo A, Casas M, Cavallini MC, Ciullo V, Cook EH, Crosby J, Cullen BA, De Schipper EJ, Delorme R, Djurovic S, Elias JA, Estivill X, Falkenstein MJ, Fundin BT, Garner L, German C, Gironda C, Goes FS, Grados MA, Grove J, Guo W, Haavik J, Hagen K, Harrington K, Havdahl A, Höffler KD, Hounie AG, Hucks D, Hultman C, Janecka M, Jenike E, Karlsson EK, Kelley K, Klawohn J, Krasnow JE, Krebs K, Lange C, Lanzagorta N, Levey D, Lindblad-Toh K, Macciardi F, Maher B, Mathes B, McArthur E, McGregor N, McLaughlin NC, Meier S, Miguel EC, Mulhern M, Nestadt PS, Nurmi EL, O'Connell KS, Osiecki L, Ousdal OT, Palviainen T, Pedersen NL, Piras F, Piras F, Potluri S, Rabionet R, Ramirez A, Rauch S, Reichenberg A, Riddle MA, Ripke S, Rosário MC, Sampaio AS, Schiele MA, Skogholt AH, Sloofman LGSG, Smit J, Soler AM, Thomas LF, Tifft E, Vallada H, van Kirk N, Veenstra-VanderWeele J, Vulink NN, Walker CP, Wang Y, Wendland JR, Winsvold BS, Yao Y, Zhou H; 23andMe Research Team; VA Million Veteran Program, Estonian Biobank; CoGa research team; iPSYCH, HUNT research team; NORDiC research team; Agrawal A, Alonso P, Berberich G, Bucholz KK, Bulik CM, Cath D, Denys D, Eapen V, Edenberg H, Falkai P, Fernandez TV, Fyer AJ, Gaziano JM, Geller DA, Grabe HJ, Greenberg BD, Hanna GL, Hickie IB, Hougaard DM, Kathmann N, Kennedy J, Lai D, Landén M, Le Hellard S, Leboyer M, Lochner C, McCracken JT, Medland SE, Mortensen PB, Neale BM, Nicolini H, Nordentoft M, Pato M, Pato C, Pauls DL, Piacentini J, Pittenger C, Posthuma D, Ramos-Quiroga JA, Rasmussen SA, Richter MA, Rosenberg DR, Ruhrmann S, Samuels JF, Sandin S, Sandor P, Spalletta G, Stein DJ, Stewart SE, Storch EA, Stranger BE, Turiel M, Werge T, Andreassen OA, Børglum AD, Walitza S, Hveem K, Hansen BK, Rück CP, Martin NG, Milani L, Mors O, Reichborn-Kjennerud T, Ribasés M, Kvale G, Mataix-Cols D, Domschke K, Grünblatt E, Wagner M, Zwart JA, Breen G, Nestadt G, Kaprio J, Arnold PD, Grice DE, Knowles JA, Ask H, Verweij KJ, Davis LK, Smit DJ, Crowley JJ, Scharf JM, Stein MB, Gelernter J, Mathews CA, Derks EM, Mattheisen M. Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci. medRxiv [Preprint]. 2024 Mar 13:2024.03.13.24304161. doi: 10.1101/2024.03.13.24304161. PMID: 38712091; PMCID: PMC11071577.10.1101/2024.03.13.2430416138712091https://hdl.handle.net/20.500.14038/53534This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.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.enThe copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Genetic and Genomic Medicineobsessive-compulsive disorderPreprintmedRxiv : the preprint server for health sciences