Polygenic Heterogeneity Across Obsessive-Compulsive Disorder Subgroups Defined by a Comorbid Diagnosis

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  • Nora I. Strom, Humboldt University of Berlin, Karolinska Institutet, LMU Munich
  • ,
  • Jakob Grove
  • Sandra M. Meier
  • Marie Bækvad-Hansen, Statens Serum Institut, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
  • ,
  • Judith Becker Nissen
  • Thomas Damm Als
  • Matthew Halvorsen, University of North Carolina
  • ,
  • Merete Nordentoft, University of Copenhagen, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
  • ,
  • Preben B. Mortensen
  • David M. Hougaard, Statens Serum Institut, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
  • ,
  • Thomas Werge, University of Copenhagen, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
  • ,
  • Ole Mors
  • Anders D. Børglum
  • James J. Crowley, University of North Carolina
  • ,
  • Jonas Bybjerg-Grauholm, Statens Serum Institut, iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research
  • ,
  • Manuel Mattheisen, Karolinska Institutet, Dalhousie University

Among patients with obsessive-compulsive disorder (OCD), 65–85% manifest another psychiatric disorder concomitantly or at some other time point during their life. OCD is highly heritable, as are many of its comorbidities. A possible genetic heterogeneity of OCD in relation to its comorbid conditions, however, has not yet been exhaustively explored. We used a framework of different approaches to study the genetic relationship of OCD with three commonly observed comorbidities, namely major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). First, using publicly available summary statistics from large-scale genome-wide association studies, we compared genetic correlation patterns for OCD, MDD, ADHD, and ASD with 861 somatic and mental health phenotypes. Secondly, we examined how polygenic risk scores (PRS) of eight traits that showed heterogeneous correlation patterns with OCD, MDD, ADHD, and ASD partitioned across comorbid subgroups in OCD using independent unpublished data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). The comorbid subgroups comprised of patients with only OCD (N = 366), OCD and MDD (N = 1,052), OCD and ADHD (N = 443), OCD and ASD (N = 388), and OCD with more than 1 comorbidity (N = 429). We found that PRS of all traits but BMI were significantly associated with OCD across all subgroups (neuroticism: p = 1.19 × 10−32, bipolar disorder: p = 7.51 × 10−8, anorexia nervosa: p = 3.52 × 10−20, age at first birth: p = 9.38 × 10−5, educational attainment: p = 1.56 × 10−4, OCD: p = 1.87 × 10−6, insomnia: p = 2.61 × 10−5, BMI: p = 0.15). For age at first birth, educational attainment, and insomnia PRS estimates significantly differed across comorbid subgroups (p = 2.29 × 10−4, p = 1.63 × 10−4, and p = 0.045, respectively). Especially for anorexia nervosa, age at first birth, educational attainment, insomnia, and neuroticism the correlation patterns that emerged from genetic correlation analysis of OCD, MDD, ADHD, and ASD were mirrored in the PRS associations with the respective comorbid OCD groups. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across OCD comorbid subgroups.

Original languageEnglish
Article number711624
JournalFrontiers in Genetics
Volume12
Number of pages13
ISSN1664-8021
DOIs
Publication statusPublished - Aug 2021

Bibliographical note

Publisher Copyright:
© Copyright © 2021 Strom, Grove, Meier, Bækvad-Hansen, Becker Nissen, Damm Als, Halvorsen, Nordentoft, Mortensen, Hougaard, Werge, Mors, Børglum, Crowley, Bybjerg-Grauholm and Mattheisen.

    Research areas

  • attention-deficit/hyperactivity disorder, autism, comorbidity, genetic correlation, heterogeneity, major depression, obsessive-compulsive disorder, polygenic risk score

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