Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants

Mathew Halvorsen; Jack Samuels; Ying Wang; Benjamin D Greenberg; Abby J Fyer; James T McCracken; Daniel A Geller; James A Knowles; Anthony W Zoghbi; Tess D Pottinger; Marco A Grados; Mark A Riddle; O Joseph Bienvenu; Paul S Nestadt; Janice Krasnow; Fernando S Goes; Brion Maher; Gerald Nestadt; David B Goldstein

doi:10.1038/s41593-021-00876-8

Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants

Nat Neurosci. 2021 Aug;24(8):1071-1076. doi: 10.1038/s41593-021-00876-8. Epub 2021 Jun 28.

Authors

Mathew Halvorsen¹, Jack Samuels², Ying Wang³, Benjamin D Greenberg⁴, Abby J Fyer⁵, James T McCracken⁶, Daniel A Geller⁷, James A Knowles⁸, Anthony W Zoghbi^{5

9}, Tess D Pottinger⁹, Marco A Grados², Mark A Riddle², O Joseph Bienvenu², Paul S Nestadt², Janice Krasnow², Fernando S Goes², Brion Maher¹⁰, Gerald Nestadt^#¹¹, David B Goldstein^#¹²

Affiliations

¹ Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
² Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Psychiatry and Human Behavior, Brown Medical School, Providence, RI, USA.
⁵ New York State Psychiatric Institute, College of Physicians and Surgeons at Columbia University, New York, NY, USA.
⁶ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at Los Angeles, Los Angeles, CA, USA.
⁷ Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁸ SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, USA.
⁹ Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA.
¹⁰ Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
¹¹ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. gnestadt@jhmi.edu.
¹² Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, USA. dg2875@cumc.columbia.edu.

^# Contributed equally.

PMID: 34183866
DOI: 10.1038/s41593-021-00876-8

Abstract

Obsessive-compulsive disorder (OCD) affects 1-2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case-control analyses (n = 1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4-22.5, P = 2.3 × 10^-6). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR = 1.33, P = 0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR = 1.22, P = 0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR = 2.55, P = 7.33 × 10^-3). These data support a contribution of rare coding variants to OCD genetic risk.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Case-Control Studies
Cohort Studies
Exome Sequencing
Genetic Predisposition to Disease / genetics*
Humans
Loss of Function Mutation
Mutation, Missense
Obsessive-Compulsive Disorder / genetics*

Grants and funding

K23 MH121669/MH/NIMH NIH HHS/United States