Human CRY1 variants associate with attention deficit/hyperactivity disorder.

The Journal of Clinical Investigation
Onur Emre OnatTayfun Özçelik

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 anxi...Continue Reading

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Citations

Oct 9, 2020·The Journal of Biological Chemistry·Seref GulIbrahim Halil Kavakli
Jan 18, 2021·The Journal of Biological Chemistry·Seref GulIbrahim Halil Kavakli
Aug 2, 2021·Kidney International·Lina K SciesielskiChristof Dame
Nov 23, 2021·Frontiers in Psychiatry·José Ramón Gutiérrez-CasaresCarmen Montoto

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Datasets Mentioned

BETA
PRJNA624188

Methods Mentioned

BETA
coronary artery bypass
genotyping
dissect
PCR
electrophoresis
Assay
transfection
pull down

Software Mentioned

EIGENSTRAT
Burrows Aligner ( BWA )
GnomAD
GATK VariantRecalibrator VariantRecalibrator
ENSEMBL
house Perl scripts
EIGENSOFT
RF
LDlink
SKAT

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