Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder

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; Julia Bäckman; Nerisa Banaj; Cristina Barlassina; Judith Becker Nissen; O Joseph Bienvenu; Donald Black; Michael H Bloch; 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; Sandra Meier; Yin Yao; Merete Nordentoft; Thomas Werge; Bjarne K Hansen; Michael Wagner; Estonian Biobank

doi:10.1038/s41588-025-02189-z

Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder

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, Julia BäckmanNerisa Banaj, Cristina Barlassina, Judith Becker Nissen, O Joseph Bienvenu, Donald Black, Michael H Bloch, 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, Sandra Meier, Yin Yao, Merete Nordentoft, Thomas Werge, Bjarne K Hansen, Michael Wagner, Estonian Biobank

20 Citations (Scopus)

Abstract

Obsessive-compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

Original language	English
Journal	Nature Genetics
Volume	57
Issue number	6
Pages (from-to)	1389-1401
Number of pages	13
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-025-02189-z
Publication status	Published - Jun 2025

Keywords

Humans
Obsessive-Compulsive Disorder/genetics
Genome-Wide Association Study
Genetic Predisposition to Disease
Polymorphism, Single Nucleotide
Adult
Female
Male
Genetic Loci
Case-Control Studies

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Strom, N. I., Gerring, Z. F., Galimberti, M., Yu, D., Halvorsen, M. W., Abdellaoui, A., Rodriguez-Fontenla, C., Sealock, J. M., Bigdeli, T., Coleman, J. R., Mahjani, B., Thorp, J. G., Bey, K., Burton, C. L., Luykx, J. J., Zai, G., Alemany, S., Andre, C., Askland, K. D., ... Estonian Biobank (2025). Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder. Nature Genetics, 57(6), 1389-1401. https://doi.org/10.1038/s41588-025-02189-z

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, Bäckman, J, Banaj, N, Barlassina, C, Nissen, JB, Bienvenu, OJ, Black, D, Bloch, MH, 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, Meier, S, Yao, Y, Nordentoft, M , Werge, T, Hansen, BK, Wagner, M & Estonian Biobank 2025, 'Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder', Nature Genetics, vol. 57, no. 6, pp. 1389-1401. https://doi.org/10.1038/s41588-025-02189-z

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abstract = "Obsessive-compulsive disorder (OCD) affects \textasciitilde{}1\% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that \textasciitilde{}11,500 genetic variants explained 90\% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.",

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author = "Strom, \{Nora I\} and Gerring, \{Zachary F\} and Marco Galimberti and Dongmei Yu and Halvorsen, \{Matthew W\} and Abdel Abdellaoui and Cristina Rodriguez-Fontenla and Sealock, \{Julia M\} and Tim Bigdeli and Coleman, \{Jonathan R\} and Behrang Mahjani and Thorp, \{Jackson G\} and Katharina Bey and Burton, \{Christie L\} and Luykx, \{Jurjen J\} and Gwyneth Zai and Silvia Alemany and Christine Andre and Askland, \{Kathleen D\} and Julia B{\"a}ckman and Nerisa Banaj and Cristina Barlassina and Nissen, \{Judith Becker\} and Bienvenu, \{O Joseph\} and Donald Black and Bloch, \{Michael H\} and Sigrid B{\o}rte and Rosa Bosch and Michael Breen and Brennan, \{Brian P\} and Helena Brentani and Buxbaum, \{Joseph D\} and Jonas Bybjerg-Grauholm and Byrne, \{Enda M\} and Judit Cabana-Dominguez and Beatriz Camarena and Adrian Camarena and Carolina Cappi and Angel Carracedo and Miguel Casas and Cavallini, \{Maria Cristina\} and Valentina Ciullo and Cook, \{Edwin H\} and Jesse Crosby and Sandra Meier and Yin Yao and Merete Nordentoft and Thomas Werge and Hansen, \{Bjarne K\} and Michael Wagner and \{Estonian Biobank\}",

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AU - Strom, Nora I

AU - Gerring, Zachary F

AU - Galimberti, Marco

AU - Yu, Dongmei

AU - Halvorsen, Matthew W

AU - Abdellaoui, Abdel

AU - Rodriguez-Fontenla, Cristina

AU - Sealock, Julia M

AU - Bigdeli, Tim

AU - Coleman, Jonathan R

AU - Mahjani, Behrang

AU - Thorp, Jackson G

AU - Bey, Katharina

AU - Burton, Christie L

AU - Luykx, Jurjen J

AU - Zai, Gwyneth

AU - Alemany, Silvia

AU - Andre, Christine

AU - Askland, Kathleen D

AU - Bäckman, Julia

AU - Banaj, Nerisa

AU - Barlassina, Cristina

AU - Nissen, Judith Becker

AU - Bienvenu, O Joseph

AU - Black, Donald

AU - Bloch, Michael H

AU - Børte, Sigrid

AU - Bosch, Rosa

AU - Breen, Michael

AU - Brennan, Brian P

AU - Brentani, Helena

AU - Buxbaum, Joseph D

AU - Bybjerg-Grauholm, Jonas

AU - Byrne, Enda M

AU - Cabana-Dominguez, Judit

AU - Camarena, Beatriz

AU - Camarena, Adrian

AU - Cappi, Carolina

AU - Carracedo, Angel

AU - Casas, Miguel

AU - Cavallini, Maria Cristina

AU - Ciullo, Valentina

AU - Cook, Edwin H

AU - Crosby, Jesse

AU - Meier, Sandra

AU - Yao, Yin

AU - Nordentoft, Merete

AU - Werge, Thomas

AU - Hansen, Bjarne K

AU - Wagner, Michael

AU - Estonian Biobank

PY - 2025/6

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N2 - Obsessive-compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

AB - Obsessive-compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

KW - Humans

KW - Obsessive-Compulsive Disorder/genetics

KW - Genome-Wide Association Study

KW - Genetic Predisposition to Disease

KW - Polymorphism, Single Nucleotide

KW - Adult

KW - Female

KW - Male

KW - Genetic Loci

KW - Case-Control Studies

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U2 - 10.1038/s41588-025-02189-z

DO - 10.1038/s41588-025-02189-z

M3 - Journal article

C2 - 40360802

SN - 1061-4036

VL - 57

SP - 1389

EP - 1401

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder

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Keywords

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