Circadian Disruption Is Associated with Elevated Whole-Semen mtDNA Copy Number and Implicates CRY1 as a Candidate Regulator in Humans and Mice

Mood and Psychosis Risk-Associated Genes Regulate Neuronal Circadian Rhythms Across the Transcriptome.

BACKGROUND Mood and psychotic disorders are associated with disrupted circadian rhythms in sleep and activity. While mood and psychosis risk-associated genes (MPRGs) have been linked with sleep and circadian phenotypes, their contributions to molecular clock pathways and cellular circadian rhythms remain unknown. METHODS To understand how MPRGs affect temporal dynamics and contribute to circadian rhythms in transcription across the genome, we knocked down expression of ARNTL, ANK3, CACNA1C, or TCF4 in human iPSC-derived neuronal precursor cells (NPCs) from healthy donors. Gene expression was examined serially over 24 h using whole-transcriptome RNA sequencing. Rhythm and pathway analyses were performed to identify rhythmic genes, and gene sets impacted by MPRG knockdown using small interfering RNA (siRNA). RESULTS Each siRNA distinctly altered phase and/or amplitude of rhythmic genes. Knockdown of ARNTL resulted in widespread loss of rhythms in core clock and other genes but also caused unexpected gains in rhythm. CACNA1C knockdown increased the number of rhythmic genes. ANK3 and TCF4 knockdown had modest effects on gain/loss of rhythm, but caused significant phase shifts. Functional analyses revealed widespread changes in rhythmic genes previously implicated in mood and psychotic disorders, including synaptic transmission, cellular stress response, and gated ion channels. CONCLUSIONS Our findings are the first to indicate MPRGs contribute widely to neuronal circadian rhythms across the transcriptome. Altered rhythms may disrupt biological pathways implicated across a range of psychiatric disorders.

Cross-species variant-to-function analyses implicate MEIS1 in conferring sleep abnormalities and impaired cerebellar development.

Genome-wide association studies (GWAS) have identified numerous loci for insomnia, yet functional validation of effector genes remains limited because most risk variants lie in noncoding regions, and the true causal gene is not known. Here, we use prior human cell-based variant-to-gene mapping to nominate six insomnia effector genes and test them in zebrafish, a tractable diurnal vertebrate model well-suited for sleep phenotyping. Our CRISPR-based behavioral screening identifies the MEIS1 ortholog, meis1b, as a regulator of sleep maintenance, with crispants displaying impaired nighttime-specific sleep maintenance and increased sleep latency. Comparative chromatin analyses reveal conserved regulatory architecture spanning the human insomnia-associated locus and selectively implicate meis1b, whereas the duplicated ohnolog meis1a was dispensable. Developmental profiling further shows that meis1b is expressed in cerebellar granule progenitors, paralleling human MEIS1 expression, and that its disruption impairs cerebellar development. Together, these findings establish zebrafish as an efficient vertebrate platform for functional interrogation of GWAS candidates and support an evolutionarily conserved cerebellar role for MEIS1 in sleep maintenance.

Genetic evidence linking circadian rhythm genes and hypertension: A two-sample Mendelian randomization study

It is found that PHOSPHO1, BAIAP3, OSGIN2, and ZDHHC18 demonstrated statistically significant associations with hypertension risk after false discovery rate correction and should be prioritized for follow-up.

Integrated Analysis of CRY1 Gene Expression and InDel Polymorphism Reveals Associations with Ovarian Morphological Traits in Chinese Holstein Dairy Cattle

Clock genes, such as cryptochrome 1 (CRY1), exhibit rhythmic expression in the reproductive organs. This gene is a key component of the circadian clock and is involved in various physiological processes, including reproduction, suggesting that it may be linked to ovarian activity via neuroendocrine pathways. However, the association between CRY1 variants and ovarian traits in dairy cows is unclear. In this study we used qRT-PCR to assay the mRNA expression of this gene, and found that CRY1 expression was highest in oocytes in several tissues; subsequently, we found that CRY1 expression was highest in the ovary in Chinese Holstein dairy cattle, followed by muscle and spleen tissues (p < 0.01). Next, we identified a six bp insertion/deletion (indel) locus within the CRY1 gene in Chinese Holstein dairy cattle. Only two genotypes were detected: II (n = 854, 83.7%) and ID (n = 166, 16.3%). Association analysis revealed that the identified indel was significantly associated with dominant follicle and corpus albicans diameters (p < 0.05) during metestrus. Specifically, individuals with the ID genotype exhibited smaller dominant follicles and corpus albicans than those with the II genotype. Our preliminary findings suggest that CRY1 is associated with specific ovarian morphological traits and may serve as a basis for further investigation of its potential role in bovine reproductive function.

Sperm Mitochondrial DNA Copy Number and Nuclear DNA Methylation Across Clinical and Non-Clinical Preconception Cohorts.

BACKGROUND Sperm mitochondrial DNA copy number is an emerging marker of male fertility, with elevated mtDNAcn associated with poor semen quality across various populations. Sperm DNA methylation has also been previously demonstrated to be negatively correlated with semen parameters in IVF cohorts. OBJECTIVE To determine whether mtDNAcn is associated with nuclear DNA methylation across three population-based and clinical fertility cohorts. DESIGN The association between sperm mtDNAcn and genome-wide DNA methylation was investigated in 748 men from a general population cohort (LIFE; n = 379) and two infertility cohorts (SEEDS; n = 170 and EARTH; n = 199). Sperm DNA methylation and mtDNAcn were quantified by the Illumina EPIC (v1) array and triplex probe-based digital PCR, respectively. Covariate-adjusted linear regressions were conducted within each cohort and then meta-analyzed using METAL. Gene ontology analyses explored the biological relevance of differentially methylated CpGs (DMCs) and regions (DMRs). RESULTS Using a Holm-Bonferroni significance threshold, our analyses identified 1351, 224, and 258 DMCs and 2582, 1536, and 1284 DMRs in LIFE, SEEDS, and EARTH, respectively, indicating that higher sperm mtDNAcn was associated with DNA hypermethylation. In meta-analysis, 576 DMCs were associated with mtDNAcn. Notably, the genes corresponding with DMCs and DMRs are known critical regulators of male fertility and were enriched in the regulation of male meiosis, germline protection, spermatogenesis pathways, and early embryonic development. DISCUSSION AND CONCLUSION Our results, observed across three independent cohorts and supported by meta-analysis, indicate a consistent association between the sperm mitochondrial genome and nuclear DNA methylation, suggesting that mtDNAcn and methylation patterns may be linked during spermatogenesis. Further research is warranted to elucidate the mechanisms underlying these associations and to evaluate their relevance for reproductive outcomes.

CLOCK rs1801260 and MTNR1B rs10830963 Polymorphisms Modulate the Association between Cholesterol Levels and Circadian Rhythms in Arctic Residents