Human CRY1 variants associate with attention deficit/hyperactivity disorder
O. Emre Onat, M. Ece Kars, Şeref Gül, Kaya Bilguvar, Yiming Wu, Ayşe Özhan, Cihan Aydın, A. Nazlı Başak, M. Allegra Trusso, Arianna Goracci, Chiara Fallerini, Alessandra Renieri, Jean-Laurent Casanova, Yuval Itan, Cem E. Atbaşoğlu, Meram C. Saka, İ. Halil Kavaklı, Tayfun Özçelik
O. Emre Onat, M. Ece Kars, Şeref Gül, Kaya Bilguvar, Yiming Wu, Ayşe Özhan, Cihan Aydın, A. Nazlı Başak, M. Allegra Trusso, Arianna Goracci, Chiara Fallerini, Alessandra Renieri, Jean-Laurent Casanova, Yuval Itan, Cem E. Atbaşoğlu, Meram C. Saka, İ. Halil Kavaklı, Tayfun Özçelik
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Research Article Genetics

Human CRY1 variants associate with attention deficit/hyperactivity disorder

Abstract

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.

Authors

O. Emre Onat, M. Ece Kars, Şeref Gül, Kaya Bilguvar, Yiming Wu, Ayşe Özhan, Cihan Aydın, A. Nazlı Başak, M. Allegra Trusso, Arianna Goracci, Chiara Fallerini, Alessandra Renieri, Jean-Laurent Casanova, Yuval Itan, Cem E. Atbaşoğlu, Meram C. Saka, İ. Halil Kavaklı, Tayfun Özçelik

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Figure 1

Reverse phenotyping.

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Reverse phenotyping. Schematic of the phenotype-first (green) versus the...
Schematic of the phenotype-first (green) versus the genotype-first (also referred to as reverse phenotyping, blue) approaches for identification of causal gene mutations. The phenotype-first approach relies on identification of patients and families, collection of clinical data, accurate research diagnosis, and, finally, collection of genotype data steps. In the genotype-first approach, the process is reversed and starts with the analysis of genomic data and selection of candidate variants followed by comprehensive clinical phenotyping of patients and families to make accurate genotype-phenotype correlations.