Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci
Authors: 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 Judit , 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 Sloofman 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 
Published: March 2024

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, highlightingWDR6, DALRD3, CTNND1and 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.