Human CRY1 variants associate with attention deficit/hyperactivity disorder.

TitleHuman CRY1 variants associate with attention deficit/hyperactivity disorder.
Publication TypeJournal Article
Year of Publication2020
AuthorsO Onat, E, M Kars, E, Gül, Ş, Bilguvar, K, Wu, Y, Özhan, A, Aydın, C, A Başak, N, M Trusso, A, Goracci, A, Fallerini, C, Renieri, A, Casanova, J-L, Itan, Y, Atbaşoğlu, CE, Saka, MC, İ Kavaklı, H, Ozcelik, T
JournalJ Clin Invest
Date Published2020 07 01
KeywordsAdult, ARNTL Transcription Factors, Attention Deficit Disorder with Hyperactivity, CLOCK Proteins, Cryptochromes, Female, Genetic Association Studies, HEK293 Cells, Humans, Male, Mutation, Sleep Disorders, Circadian Rhythm

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.

Alternate JournalJ Clin Invest
PubMed ID32538895
PubMed Central IDPMC7324179
Grant ListUM1 HG006504 / HG / NHGRI NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
UL1 TR001866 / TR / NCATS NIH HHS / United States
R01 AI088364 / AI / NIAID NIH HHS / United States
R01 AI127564 / AI / NIAID NIH HHS / United States
R37 AI095983 / AI / NIAID NIH HHS / United States
P01 AI061093 / AI / NIAID NIH HHS / United States
/ HH / Howard Hughes Medical Institute / United States