De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism

Autor(es):Mostrar menos -

Cappi, Carolina ^[1] ; Oliphant, Melody E. ^[2] ; Peter, Zsanett ^[2] ; Zai, Gwyneth ^{[3, 4]} ; do Rosario, Maria Conceicao ^[5] ; Sullivan, Catherine A. W. ^[6] ; Gupta, Abha R. ^{[6, 2]} ; Hoffman, Ellen J. ^[2] ; Virdee, Manmeet ^[2] ; Olfson, Emily ^[2] ; Abdallah, Sarah B. ^[2] ; Willsey, A. Jeremy ^[7] ; Shavitt, Roseli G. ^[1] ; Miguel, Euripedes C. ^[1] ; Kennedy, James L. ^{[3, 4]} ; Richter, Margaret A. ^{[3, 8]} ; Fernandez, Thomas V. ^{[9, 2]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Psychiat, Sch Med, Sao Paulo - Brazil

^[2] Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT - USA

^[3] Univ Toronto, Dept Psychiat, Toronto, ON - Canada

^[4] Ctr Addict & Mental Hlth, Campbell Family Mental Hlth Res Inst, Mol Brain Sci Dept, Neurogenet Sect, Toronto, ON - Canada

^[5] Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo - Brazil

^[6] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 - USA

^[7] Univ Calif San Francisco, Dept Psychiat, UCSF Weill Inst Neurosci, San Francisco, CA - USA

^[8] Sunnybrook Hlth Sci Ctr, Sunnybrook Res Inst, Frederick W Thompson Anxiety Disorders Ctr, Toronto, ON - Canada

^[9] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT - USA

• Tipo de documento: Artigo Científico
• Fonte: BIOLOGICAL PSYCHIATRY; v. 87, n. 12, p. 1035-1044, JUN 15 2020.
• Citações Web of Science: 1

Resumo

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. (AU)

• Processo FAPESP: 14/01585-5 - Variações raras de novo e hereditárias no genoma de pacientes com transtorno obsessivo-compulsivo
• Beneficiário: Carolina Cappi
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado