Search

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, CRY1[DELTA]11 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 CRY1[DELTA]11. Also, we identified a variant, CRY1[DELTA]6 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 CRY1[DELTA]11 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., Introduction Sleep is genetically regulated by the circadian rhythm. Disruption of this rhythm leads to aberrant sleep patterns (1-4). Sleep is also frequently disturbed in individuals with psychiatric disorders. For [...]

The Slit-Robo family of axon guidance molecules works in concert, playing important roles in organ development and cancer. Expressions of individual Slit-Robo genes have been used in calculating univariable hazard ratios (HR uni ) for predicting cancer prognosis in the literature. However, Slit-Robo members do not act independently; hence, hazard ratios from multivariable Cox regression (HR multi ) on the whole gene set can further lead to identification of cancer-specific, novel, and independent prognostic gene pairs or modules. Herein, we obtained mRNA expressions of the Slit-Robo family consisting of four Robos ( ROBO1 / 2 / 3 / 4 ) and three Slits ( SLIT1 / 2 / 3 ), along with four types of survival outcome across cancers found in the Cancer Genome Atlas (TCGA). We used cluster heat maps to visualize closely associated pairs/modules of prognostic genes across 33 different cancers. We found a smaller number of significant genes in HR multi than in HR uni , suggesting that the former analysis was less redundant. High ROBO4 expression emerged as relatively protective within the family, in both types of HR analyses. Multivariable Cox regression, on the other hand, revealed significantly more HR signatures containing Slit-Robo pairs acting in opposing directions than those containing Slit-Slit or Robo-Robo pairs for disease-specific survival. Furthermore, we discovered, through the online app SmulTCan's lasso regression, Slit-Robo gene subsets that significantly differentiated between high- versus low-risk prognosis patient groups, particularly for renal cancers and low-grade glioma. The statistical pipeline reported herein can help test independent and significant pairs/modules within a codependent gene family for cancer prognostication, and thus should also prove useful in personalized/precision medicine research.