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Genome-wide Association Study Identifies 30 Obsessive-Compulsive Disorder Associated Loci

Nora I Strom,Zachary F Gerring,Marco Galimberti,Dongmei Yu,Matthew W Halvorsen,Abdel Abdellaoui,Cristina Rodriguez-Fontenla,Julia M Sealock,Tim Bigdeli,Jonathan R Coleman,Behrang Mahjani,Jackson G Thorp,Katharina Bey,Christie L Burton,Jurjen J Luykx,Gwyneth Zai,Silvia Alemany, Christine Andre,Kathleen D Askland,Nerisa Banaj,Cristina Barlassina,Judith Becker Nissen,O Joseph Bienvenu,Donald Black,Michael H Bloch,Julia Boberg,Sigrid Børte,Rosa Bosch,Michael Breen,Brian P Brennan,Helena Brentani,Joseph D Buxbaum,Jonas Bybjerg-Grauholm,Enda M Byrne,Judit Cabana-Dominguez,Beatriz Camarena,Adrian Camarena,Carolina Cappi,Angel Carracedo,Miguel Casas,Maria Cristina Cavallini,Valentina Ciullo,Edwin H Cook,Jesse Crosby,Bernadette A Cullen,Elles J De Schipper,Richard Delorme,Srdjan Djurovic,Jason A Elias,Xavier Estivill,Martha J Falkenstein,Bengt T Fundin,Lauryn Garner,Chris German,Christina Gironda,Fernando S Goes,Marco A Grados,Jakob Grove,Wei Guo,Jan Haavik,Kristen Hagen,Kelly Harrington,Alexandra Havdahl, Kira D Höffler,Ana G Hounie,Donald Hucks,Christina Hultman,Magdalena Janecka,Eric Jenike,Elinor K Karlsson,Kara Kelley,Julia Klawohn,Janice E Krasnow,Kristi Krebs,Christoph Lange,Nuria Lanzagorta,Daniel Levey,Kerstin Lindblad-Toh,Fabio Macciardi,Brion Maher,Brittany Mathes,Evonne McArthur,Nathaniel McGregor,Nicole C McLaughlin,Sandra Meier,Euripedes C Miguel,Maureen Mulhern,Paul S Nestadt,Erika L Nurmi,Kevin S O'Connell,Lisa Osiecki,Olga Therese Ousdal,Teemu Palviainen,Nancy L Pedersen,Fabrizio Piras,Federica Piras,Sriramya Potluri,Raquel Rabionet,Alfredo Ramirez,Scott Rauch,Abraham Reichenberg,Mark A Riddle,Stephan Ripke,Maria C Rosário,Aline S Sampaio,Miriam A Schiele,Anne Heidi Skogholt, G Sloofman,Jan Smit,Artigas María Soler,Laurent F Thomas,Eric Tifft,Homero Vallada, Nathanial van Kirk,Jeremy Veenstra-VanderWeele, Nienke N Vulink,Christopher P Walker,Ying Wang,Jens R Wendland,Bendik S Winsvold,Yin Yao,Hang Zhou,2andMe Research Team, VA Million Veteran Program, Estonian Biobank, CoGa research team, iPSYCH, HUNT research team, NORDiC research team,Arpana Agrawal,Pino Alonso,Götz Berberich,Kathleen K Bucholz,Cynthia M Bulik,Danielle Cath,Damiaan Denys,Valsamma Eapen,Howard Edenberg,Peter Falkai,Thomas V Fernandez,Abby J Fyer, J M Gaziano,Dan A Geller,Hans J Grabe,Benjamin D Greenberg,Gregory L Hanna,Ian B Hickie,David M Hougaard,Norbert Kathmann,James Kennedy,Dongbing Lai,Mikael Landén,Stéphanie Le Hellard,Marion Leboyer,Christine Lochner,James T McCracken,Sarah E Medland,Preben B Mortensen,Benjamin M Neale,Humberto Nicolini,Merete Nordentoft,Michele Pato,Carlos Pato,David L Pauls,John Piacentini,Christopher Pittenger,Danielle Posthuma,Josep Antoni Ramos-Quiroga,Steven A Rasmussen,Margaret A Richter,David R Rosenberg,Stephan Ruhrmann,Jack F Samuels,Sven Sandin,Paul Sandor,Gianfranco Spalletta,Dan J Stein,S Evelyn Stewart,Eric A Storch,Barbara E Stranger,Maurizio Turiel,Thomas Werge,Ole A Andreassen,Anders D Børglum,Susanne Walitza,Kristian Hveem,Bjarne K Hansen,Christian P Rück,Nicholas G Martin, Lili Milani,Ole Mors,Ted Reichborn-Kjennerud,Marta Ribasés,Gerd Kvale,David Mataix-Cols,Katharina Domschke,Edna Grünblatt,Michael Wagner,John-Anker Zwart,Gerome Breen,Gerald Nestadt,Jaakko Kaprio,Paul D Arnold,Dorothy E Grice,James A Knowles,Helga Ask, Karin J Verweij,Lea K Davis,Dirk J Smit,James J Crowley,Jeremiah M Scharf,Murray B Stein,Joel Gelernter,Carol A Mathews,Eske M Derks,Manuel Mattheisen

medrxiv(2024)

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Abstract
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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