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Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci [preprint]

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
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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
Nissen, Judith Becker
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
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
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Document Type
Preprint
Publication Date
2024-03-13
Subject Area
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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.

Source

Strom 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.

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DOI
10.1101/2024.03.13.24304161
PubMed ID
38712091
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This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.

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The 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 International