De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism.
paper
Cited
Public
- Authors
- Cappi, Carolina; Oliphant, Melody E; Péter, Zsanett; Zai, Gwyneth; Conceição do Rosário, Maria; Sullivan, Catherine A W; Gupta, Abha R; Hoffman, Ellen J; Virdee, Manmeet; Olfson, Emily; Abdallah, Sarah B; Willsey, A Jeremy; Shavitt, Roseli G; Miguel, Euripedes C; Kennedy, James L; Richter, Margaret A; Fernandez, Thomas V
- Year
- 2020
- Journal
- Biological psychiatry
- PMID
- 31771860
- DOI
- 10.1016/j.biopsych.2019.09.029
- PMCID
- PMC7160031
BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with a genetic risk component, yet identification of high-confidence risk genes has been challenging. In recent years, risk gene discovery in other complex psychiatric disorders has been achieved by studying rare de novo (DN) coding variants. METHODS: We performed whole-exome sequencing in 222 OCD parent-child trios (184 trios after quality control), comparing DN variant frequencies with 777 previously sequenced unaffected trios. We estimated the contribution of DN mutations to OCD risk and the number of genes involved. Finally, we looked for gene enrichment in other datasets and canonical pathways. RESULTS: DN likely gene disrupting and predicted damaging missense variants are enriched in OCD probands (rate ratio, 1.52; p = .0005) and contribute to risk. We identified 2 high-confidence risk genes, each containing 2 DN damaging variants in unrelated probands: CHD8 and SCUBE1. We estimate that 34% of DN damaging variants in OCD contribute to risk and that DN damaging variants in approximately 335 genes contribute to risk in 22% of OCD cases. Furthermore, genes harboring DN damaging variants in OCD are enriched for those reported in neurodevelopmental disorders, particularly Tourette's disorder and autism spectrum disorder. An exploratory network analysis reveals significant functional connectivity and enrichment in canonical pathways, biological processes, and disease networks. CONCLUSIONS: Our findings show a pathway toward systematic gene discovery in OCD via identification of DN damaging variants. Sequencing larger cohorts of OCD parent-child trios will reveal more OCD risk genes and will provide needed insights into underlying disease biology.
Study summary.We performed whole exome sequencing on 222 OCD and 855 control parent-child trios. After quality control, 184 OCD and 777 control trios remained for subsequent analyses. Burden analyses compared the rates of de novo and inherited single nucleotide (SNVs) and insertion-deletion (indel) variants between cases and controls. Next, we used the TADA algorithm to assess the significance of gene-level recurrence of damaging variants in our OCD group, identifying two high-confidence risk genes. Exploratory network, pathway, and cross-disorder analyses were then performed using genes harboring de novo damaging variants in our OCD subjects. Finally, based on the number of de novo damaging variants in OCD versus controls, we estimated the number of genes contributing to OCD risk, and used this estimate to predict future risk gene discovery as additional OCD parent-child trios are studied by exome sequencing.
De novo damaging variants are associated with OCD risk.(A) Bar chart comparing the rates of de novo mutation types between OCD cases (red) and controls (blue). Comparisons are between per base pair (bp) mutation rates, considering only those “callable” loci in each family and cohort that meet required sequencing depth and quality scores to support high confidence de novo variant calling. Mutation rates were compared using a one-tailed rate ratio test. Statistically significant comparisons (p<0.05) are marked with asterisks. Error bars show 95% confidence intervals. (B) For the enriched classes of de novo variants, we quantified their contribution to OCD risk in two ways. First, we estimated the percentage of observed variants carrying risk by dividing the difference in rates (estimated coding variants per individual, see Table 1 and Methods) by the rate in OCD. Second, we estimated the percentage of cases with a mutation mediating risk by subtracting the proportion of controls carrying a mutation from the proportion in OCD probands carrying a mutation.
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| Name | Type |
|---|---|
| 1000 trios local | cohort |
| 2000 trios local | cohort |
| 3000 trios local | cohort |
| 500 trios local | cohort |
| 802 Tourette’s disorder parent-child trios local | cohort |
| 8100.p1 local | cohort |
| ADHD | phenotype |
| anxiety | phenotype |
| autism | phenotype |
| autism spectrum disorder | phenotype |
| autism spectrum disorders | phenotype |
| autistic disorder | phenotype |
| B cell receptor signaling local | drug |
| brain development | phenotype |
| CACNA1E | gene |
| cancer | phenotype |
| cases | cohort |
| central nervous system | anatomy |
| Centre for Addiction and Mental Health local | cohort |
| CHD8 | gene |
| Chd8 Haploinsufficient Mice local | cohort |
| comorbidity | phenotype |
| complement system | drug |
| Control cohort (855 trios) local | cohort |
| controls | cohort |
| Damaging de novo coding variants local | variant |
| damaging de novo mutation local | variant |
| De Novo Balanced Translocation local | variant |
| de novo damaging coding variants local | variant |
| de novo LGD mutation local | variant |
| de novo Mis-D mutation local | variant |
| De novo missense damaging variants local | variant |
| de novo variant | variant |
| depression | phenotype |
| developmental disorders | phenotype |
| Dlgap1 | gene |
| DLGAP1 de novo damaging variant local | variant |
| DLGAP1 nearby SNP (p=2.67e-4) local | variant |
| DLGAP1 paternally-inherited duplication local | variant |
| DLGAP1 SNP (p=2.49e-6) local | variant |
| DLGAP1 SNP (p=3.44e-6) local | variant |
| DLGAP3 | gene |
| focal adhesion kinase signaling local | drug |
| Frederick W. Thompson Anxiety Disorders Centre at Sunnybrook Health Sciences Centre local | cohort |
| GeNets algorithm local | drug |
| GeNets Metanetwork v1.0 local | drug |
| GM-CSF signaling local | drug |
| high-confidence risk genes local | gene |
| Illumina HiSeq 2000 | drug |
| immune response | phenotype |
| inherited mutations local | variant |
| Inherited variants local | variant |
| input gene list local | cohort |
| intellectual disability | phenotype |
| International OCD Foundation Genetic Collaborative (IOCDF-GC) local | cohort |
| LGD | variant |
| MedExome local | drug |
| Mis-D local | variant |
| mortality | phenotype |
| neurodevelopmental disorder | phenotype |
| neurological disorders | phenotype |
| neuropsychiatric disorders | phenotype |
| neurotrophin/tyrosine kinase signaling local | drug |
| NimbleGen SeqCap EZExomeV2 local | drug |
| obsessive-compulsive disorder | phenotype |
| OCD | phenotype |
| OCD8015.p1 local | cohort |
| OCD8134.p1 local | cohort |
| OCD8141.p1 local | cohort |
| OCD cohort (222 trios) local | cohort |
| OCD Collaborative Genetics Study (OCGAS) local | cohort |
| OCD parent-child trios local | cohort |
| OCD proband dataset local | cohort |
| OCD probands | cohort |
| OCD risk genes | gene |
| OCD trios local | cohort |
| OCD trios (ongoing) local | cohort |
| parent-child trios | cohort |
| Pervasive developmental disorder not otherwise specified local | phenotype |
| Pervasive Developmental Disorder Not Otherwise Specified local | phenotype |
| platelet activation local | phenotype |
| Polyphen2 | drug |
| probable risk genes local | gene |
| pro-inflammatory markers local | drug |
| quality of life | phenotype |
| rare de novo mutations local | variant |
| rare genetic sequence variation local | variant |
| repetitive behaviors | phenotype |
| risk genes | cohort |
| schizoaffective disorder | phenotype |
| schizophrenia | phenotype |
| SCUBE1 local | gene |
| sensorimotor gating | phenotype |
| separation anxiety disorder | phenotype |
| Simons Simplex Collection | cohort |
| Simplex OCD trios local | cohort |
| sodium ion homeostasis local | phenotype |
| SSC | cohort |
| synonymous variant | variant |
| TIC Genetics | cohort |
| tics | phenotype |
| Tourette's disorder local | phenotype |
| Tourette’s disorder local | phenotype |
| Tourette syndrome | phenotype |
| treatment-refractory disease local | phenotype |
| Treatment-refractory disease local | phenotype |
| trichotillomania | phenotype |
| tri-methylated histone H3 lysine 4 local | drug |
| TTN local | gene |
| Unaffected trios local | cohort |
| University of Sao Paulo School of Medicine Obsessive-Compulsive Spectrum Disorders Program local | cohort |
| whole exome sequencing | drug |
| Yale Center for Genomic Analysis local | cohort |
| Yale University School of Medicine | cohort |
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| Editorial: Exploring Rare Genetic Variation in Pediatric-Onset Obsessive-Compulsive Disorder: Some Excitement and Some Uncertainty. | Grice DE | — | 2025 | → |
| Genetic advances and translational phenotypes in rodent models for Tourette disorder. | Kowalski TF et al. | — | 2025 | → |
| Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder. | Strom NI et al. | — | 2025 | → |
| New Agents in the Treatment of Psychiatric Disorders: What Innovations and in What Areas of Psychopathology? | Bozzatello P et al. | — | 2025 | → |
| Psychiatric genetics in the diverse landscape of Latin American populations. | Bruxel EM et al. | — | 2025 | → |
| Review: Child Psychiatry in the Era of Genomics: The Promise of Translational Genetics Research for the Clinic. | Fitzpatrick SE et al. | — | 2025 | → |
| Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders. | Cunningham JL et al. | — | 2025 | → |
| Clinical characteristics of probands with obsessive-compulsive disorder from simplex and multiplex families. | Lima MO et al. | — | 2024 | → |
| Genomics of severe and treatment-resistant obsessive-compulsive disorder treated with deep brain stimulation: A preliminary investigation. | Chen LL et al. | — | 2024 | → |
| Latin American Trans-ancestry INitiative for OCD genomics (LATINO): Study protocol. | Crowley JJ et al. | — | 2024 | → |
| Neurobiology of Obsessive-Compulsive Disorder from Genes to Circuits: Insights from Animal Models. | Zhang YD et al. | — | 2024 | → |
| Obsessive-Compulsive Disorder in Children and Adolescents. | Stiede JT et al. | — | 2024 | → |
| Psilocybin in pharmacotherapy of obsessive-compulsive disorder. | Owe-Larsson M et al. | — | 2024 | → |
| Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes. | Olfson E et al. | — | 2024 | → |
| The genetics of trichotillomania and excoriation disorder: A systematic review. | Reid M et al. | — | 2024 | → |
| An updated catalog of <i>CTCF</i> variants associated with neurodevelopmental disorder phenotypes. | Price E et al. | — | 2023 | → |
| Genomics of Obsessive-Compulsive Disorder and Related Disorders: What the Clinician Needs to Know. | Crowley JJ | — | 2023 | → |
| Mechanisms of pathogenesis and environmental moderators in preclinical models of compulsive-like behaviours. | Wilson C et al. | — | 2023 | → |
| Phenotypic expansion of KCNH1-associated disorders to include isolated epilepsy and its associations with genotypes and molecular sub-regional locations. | Tian MQ et al. | — | 2023 | → |
| Primary complex motor stereotypies are associated with de novo damaging DNA coding mutations that identify KDM5B as a risk gene. | Fernandez TV et al. | — | 2023 | → |
| Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD. | Wang S et al. | — | 2023 | → |
| Relating pathogenic loss-of-function mutations in humans to their evolutionary fitness costs. | Agarwal I et al. | — | 2023 | → |
| The biology of SCUBE. | Lin YC et al. | — | 2023 | → |
| The genomics of visuospatial neurocognition in obsessive-compulsive disorder: A preliminary GWAS. | Alemany-Navarro M et al. | — | 2023 | → |
| The molecular genetics of nELAVL in brain development and disease. | Mulligan MR et al. | — | 2023 | → |
| The shared genetic risk factors between Tourette syndrome and obsessive-compulsive disorder. | Khoodoruth MAS et al. | — | 2023 | → |
| Tourette syndrome: clinical features, pathophysiology, and treatment. | Johnson KA et al. | — | 2023 | → |
| A rigorous <i>in silico</i> genomic interrogation at 1p13.3 reveals 16 autosomal dominant candidate genes in syndromic neurodevelopmental disorders. | Ben-Mahmoud A et al. | — | 2022 | → |
| Current understanding of the genetics of tourette syndrome. | Lin WD et al. | — | 2022 | → |
| De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia. | Van de Vondel L et al. | — | 2022 | → |
| De novo mutations identified by whole-genome sequencing implicate chromatin modifications in obsessive-compulsive disorder. | Lin GN et al. | — | 2022 | → |
| Early intervention in obsessive-compulsive disorder: From theory to practice. | Fontenelle LF et al. | — | 2022 | → |
| Gene-based therapeutics for rare genetic neurodevelopmental psychiatric disorders. | Davidson BL et al. | — | 2022 | → |
| Implications of Dosage Deficiencies in CTCF and Cohesin on Genome Organization, Gene Expression, and Human Neurodevelopment. | Cummings CT et al. | — | 2022 | → |
| Putting Genetics to Work in the Psychiatric Clinic. | McMahon FJ | — | 2022 | → |
| Revisiting the seven pillars of RDoC. | Morris SE et al. | — | 2022 | → |
| The prefrontal cortex and OCD. | Ahmari SE et al. | — | 2022 | → |
| Whole-exome DNA sequencing in childhood anxiety disorders identifies rare de novo damaging coding variants. | Olfson E et al. | — | 2022 | → |
| A dimensional perspective on the genetics of obsessive-compulsive disorder. | Strom NI et al. | — | 2021 | → |
| Animal Models for OCD Research. | Chamberlain BL et al. | — | 2021 | → |
| Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes. | Markenscoff-Papadimitriou E et al. | — | 2021 | → |
| Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms. | Manoli DS et al. | — | 2021 | → |
| Bidirectional Behavioral Selection in Mice: A Novel Pre-clinical Approach to Examining Compulsivity. | Mitra S et al. | — | 2021 | → |
| Cross-Disorder Analysis of De Novo Variants Increases the Power of Prioritising Candidate Genes. | Li K et al. | — | 2021 | → |
| DECO: a framework for jointly analyzing de novo and rare case/control variants, and biological pathways. | Nguyen TH et al. | — | 2021 | → |
| Developmental Considerations in Obsessive Compulsive Disorder: Comparing Pediatric and Adult-Onset Cases. | Geller DA et al. | — | 2021 | → |
| Dissection of the Genetic Association between Anorexia Nervosa and Obsessive-Compulsive Disorder at the Network and Cellular Levels. | Song W et al. | — | 2021 | → |
| Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants. | Halvorsen M et al. | — | 2021 | → |
| Genetics of obsessive-compulsive disorder. | Mahjani B et al. | — | 2021 | → |
| Genomics of Obsessive-Compulsive Disorder-Toward Personalized Medicine in the Era of Big Data. | Szejko N et al. | — | 2021 | → |
| Genotype-phenotype correlation in Phelan-McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes. | Ricciardello A et al. | — | 2021 | → |
| Pharmacotherapeutic Strategies and New Targets in OCD. | Pittenger C | — | 2021 | → |
| Pleiotropy and Cross-Disorder Genetics Among Psychiatric Disorders. | Lee PH et al. | — | 2021 | → |
| What Have We Learned About the Genetics of Obsessive-Compulsive and Related Disorders in Recent Years? | Mattheisen M et al. | — | 2021 | → |
| Xenopus leads the way: Frogs as a pioneering model to understand the human brain. | Exner CRT et al. | — | 2021 | → |
| Cutting-edge genetics in obsessive-compulsive disorder. | Saraiva LC et al. | — | 2020 | → |
| mTADA is a framework for identifying risk genes from de novo mutations in multiple traits. | Nguyen TH et al. | — | 2020 | → |
| The polygenic risk for obsessive-compulsive disorder is associated with the personality trait harm avoidance. | Bey K et al. | — | 2020 | → |
| Tourette syndrome research highlights from 2019 | Hartmann A et al. | — | 2020 | — |
| Tourette syndrome research highlights from 2019. | Hartmann A et al. | — | 2020 | → |
| De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis. | Wang S et al. | — | 2018 | → |
| The Psychiatric Cell Map Initiative: A Convergent Systems Biological Approach to Illuminating Key Molecular Pathways in Neuropsychiatric Disorders. | Willsey AJ et al. | — | 2018 | → |
| Integrated Bayesian analysis of rare exonic variants to identify risk genes for schizophrenia and neurodevelopmental disorders. | Nguyen HT et al. | — | 2017 | → |