A genomic study of trichotillomania and excoriation disorder in families

Abstract Trichotillomania and excoriation disorder are obsessive-compulsive related disorders that are often subclassified together as body-focused repetitive behavior (BFRB) disorders. While previous research suggests shared genetic factors, the genetic architecture of these BFRBs remains incompletely understood. Probands with trichotillomania and/or excoriation disorder and both of their biological parents were recruited for an ongoing genetic study of parent-offspring trios with BFRBs. Genome-wide array data were generated in 110 families (334 individuals total) to investigate the role of both common single-nucleotide polymorphisms and rare copy-number variants (CNVs). Polygenic risk scores were calculated using summary statistics from genome-wide association studies of related psychiatric conditions, including obsessive-compulsive disorder (OCD), depression, anxiety, and attention deficit/hyperactivity disorder. Using the polygenic transmission disequilibrium test, we observed a significant over-transmission of polygenic risk for OCD in probands of European ancestry from their parents (mean pTDT = 0.36, p = 0.01, n = 92), and a non-significant enrichment for the other conditions. Our results suggest that common variants associated with OCD may contribute to risk for BFRBs, consistent with their current classification as obsessive-compulsive related disorders. We also identified several rare CNVs in probands that overlapped genes intolerant to loss-of-function (LoF) mutations and those previously associated with neurodevelopmental disorders. The LoF-intolerant genes were enriched in biological processes relevant to synapse organization and neurodevelopment. This work provides new insight into the genetic underpinnings of these BFRB disorders, paving the way for larger genomic studies of these understudied conditions. Competing Interest Statement The authors declare that there are no conflicts of interest. In the past three years, E.O. has received research support or grants from the National Institutes of Health, Hartwell Foundation, Tourette Association of America, International OCD Foundation, Misophonia Research Fund, the Klingenstein Third Generation Foundation, Yale Center for Clinical Investigation, and Yale Child Study Center. She serves as chair of the Early Career Investigator Program Committee and on the Board of Directors for the International Society of Psychiatric Genetics (unpaid). She is also a member of the Research Committee for the American Academy of Child & Adolescent Psychiatry (unpaid). T.V.F. has received research support or grants from the National Institutes of Health, Misophonia Research Fund, New Venture Fund, and Yale Child Study Center. He received an honorarium for participation in the 2025 Pediatric Psychopharmacology Update Institute by the American Academy of Child & Adolescent Psychiatry. He is paid for expert testimony and consultation by DLA Piper LLC. M.H.B. reports grant or research support from SciSparc, Emalex Biosciences, Janssen Pharmaceuticals, Neurocrine Biosciences, and the National Institutes of Health. He has also received royalties from Wolters Kluwer for Lewis's Child and Adolescent Psychiatry: A Comprehensive Textbook, Fifth Edition, and moonlighting pay from the Veterans Administration. None of these relationships is of direct relevance to the work described here. The other authors declare no competing interests. Funding Statement This research was supported by the National Institutes of Mental Health of the National Institutes of Health [under award numbers K08MH128665 to E.O., R01MH114927 to T.V.F.], the American Academy of Child and Adolescent Psychiatry (E.O.), and the Alan B. Slifka Foundation Riva Ariella Ritvo endowment (E.O.). S.R.G. was supported by CTSA Grant Number TL1 TR001864 from the National Center for Advancing Translational Science of the NIH. S.B.A. was supported by training grants from the National Institutes of Mental Health of the National Institutes of Health [T32 MH18268 and R25 MH077823]. I.M. was supported by the Interdepartmental Neuroscience Program NIH T32 Training Grant, 5T32NS041228-24. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board (IRB) of Yale School of Medicine (HIC 0301024156 and HIC 2000022993) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors.