| Title: |
Human CRY1 variants associate with attention deficit/hyperactivity disorder |
| Authors: |
Emre Onat O.; Ece Kars M.; Gul S.; Bilguvar K.; Wu Y.; Ozhan A.; Aydin C.; Nazli Basak A.; Allegra Trusso M.; Goracci A.; Fallerini C.; Renieri A.; Casanova J. -L.; Itan Y.; Atbasoglu C. E.; Saka M. C.; Halil Kavakli I.; Ozcelik T. |
| Contributors: |
Emre Onat, O.; Ece Kars, M.; Gul, S.; Bilguvar, K.; Wu, Y.; Ozhan, A.; Aydin, C.; Nazli Basak, A.; Allegra Trusso, M.; Goracci, A.; Fallerini, C.; Renieri, A.; Casanova, J. -L.; Itan, Y.; Atbasoglu, C. E.; Saka, M. C.; Halil Kavakli, I.; Ozcelik, T. |
| Publication Year: |
2020 |
| Collection: |
Università degli Studi di Siena: USiena air |
| Subject Terms: |
Genetic diseases; Genetics; Monogenic diseases; Psychiatric diseases; ARNTL Transcription Factors; Adult; Attention Deficit Disorder with Hyperactivity; CLOCK Proteins; Cryptochromes; Female; Genetic Association Studies; HEK293 Cells; Humans; Male; Sleep Disorders; Circadian Rhythm; Mutation |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
STAMPA |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/32538895; info:eu-repo/semantics/altIdentifier/wos/WOS:000579359700002; volume:130; issue:7; firstpage:3885; lastpage:3900; numberofpages:16; journal:THE JOURNAL OF CLINICAL INVESTIGATION; https://hdl.handle.net/11365/1133646; https://www.jci.org/articles/view/135500; https://pmc.ncbi.nlm.nih.gov/articles/PMC7324179/ |
| DOI: |
10.1172/JCI135500 |
| Availability: |
https://hdl.handle.net/11365/1133646; https://doi.org/10.1172/JCI135500; https://www.jci.org/articles/view/135500; https://pmc.ncbi.nlm.nih.gov/articles/PMC7324179/ |
| Rights: |
info:eu-repo/semantics/closedAccess |
| Accession Number: |
edsbas.81D3EB01 |
| Database: |
BASE |