Human CRY1 variants associate with attention deficit/hyperactivity disorder
| العنوان: | Human CRY1 variants associate with attention deficit/hyperactivity disorder |
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| المؤلفون: | I Halil Kavaklı, Arianna Goracci, Yuval Itan, Ayse Ozhan, Chiara Fallerini, Jean-Laurent Casanova, Cihan Aydin, M Ece Kars, O Emre Onat, Yiming Wu, Cem Atbaşoğlu, A. Nazli Basak, Kaya Bilguvar, Alessandra Renieri, Tayfun Ozcelik, M Allegra Trusso, Meram Can Saka, Seref Gul |
| المساهمون: | Gül, Şeref, Aydın, Cihan (ORCID 0000-0003-0560-1895 & YÖK ID 214696), Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Kavaklı, İbrahim Halil (ORCID 0000-0001-6624-3505 & YÖK ID 40319), Onat, O. Emre, Kars, M. Ece, Bilguvar, Kaya, Wu, Yiming, Özhan, Ayşe, Trusso, M. Allegra, Goracci, Arianna, Fallerini, Chiara, Renieri, Alessandra, Casanova, Jean Laurent, Itan, Yuval, Atbaşoğlu, Cem E., Saka, Meram C., Özçelik, Tayfun, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), Graduate School of Sciences and Engineering, College of Engineering, College of Sciences, Department of Chemical and Biological Engineering, Department of Molecular Biology and Genetics, Başak, A. N. |
| المصدر: | Journal of Clinical Investigation J Clin Invest |
| بيانات النشر: | American Society for Clinical Investigation, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, Genetic diseases, Genetics, Monogenic diseases, Psychiatric diseases, CLOCK Proteins, Delayed sleep phase, Bioinformatics, ARNTL Transcription Factors, Attention Deficit Disorder with Hyperactivity, Cryptochromes, Female, Genetic Association Studies, HEK293 Cells, Humans, Sleep Disorders, Circadian Rhythm, Mutation, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Insomnia, Medicine, Attention deficit hyperactivity disorder, Circadian rhythm, Exome sequencing, Depression (differential diagnoses), business.industry, General Medicine, medicine.disease, Circadian Rhythm, Biology, 030104 developmental biology, 030220 oncology & carcinogenesis, Anxiety, Major depressive disorder, medicine.symptom, Sleep Disorders, business, Research Article |
| الوصف: | Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders. NIH Clinical and Translational Science Award (CTSA) Program; NIH; French National Research Agency (ANR) under the “Investments for the future” Program; Integrative Biology of Emerging Infectious Diseases Laboratoire d’Excellence; IEIHSEER Grant; SEAe-Host Factors Grant; PNEUMOID Project Grant; INCA/Cancéropole Ile-de-France; Turkish Academy of Sciences (TÜBA); National Center for Advancing Translational Sciences (NCAST); Rockefeller University, INSERM; HHMI, University of Paris; St. Giles Foundation; Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai |
| وصف الملف: | pdf; application/pdf |
| تدمد: | 1558-8238 0021-9738 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c26e34969651363455b6ea63aaffd9dd https://doi.org/10.1172/jci135500 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c26e34969651363455b6ea63aaffd9dd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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