Biology subjects

Tchio, C.

Publications and source records attributed to Tchio, C..

4 recordsLinked to original sources

bioRxiv2025

ADCY3 Ser107Pro links difficulty awakening in the morning to adiposity through circadian regulation of adipose thermogenesis

Modern lifestyles often disturb circadian rhythms, yet the genetic circuits that convert this stress into metabolic dysfunction remain poorly defined. Here, we identify a missense variant in ADCY3 (rs11676272; Ser107Pro) as a pleiotropic regulator of circadian preference and adiposity. Using genome-wide pleiotropy analysis in [~]480,000 UK Biobank participants, we show that the G risk allele (Pro107) increases morningness, BMI, and fat mass in European (N=451,324) and African (N=8,738) ancestry groups, with behavioral amplification by morning difficulty awakening observed in Europeans, power limited interaction modeling in other populations. Structural modeling and transcriptomic analysis suggest this allele destabilizes ADCY3 and alters adipose-specific splicing and expression. In mice, Adcy3 is rhythmically expressed in adipose tissue, with the conserved Pro107 site showing BMAL1 binding and cold-inducible activation. Human adipose ADCY3 expression also increases after weight loss. Together, these findings reveal a genotype-dependent, behaviorally modifiable axis linking difficulty awakening to adipose thermogenesis and obesity risk.

genomics↗

bioRxiv2024

An integrative approach prioritizes the orphan GPR61 genomic region in tissue-specific regulation of chronotype

ObjectivesChronotype, a manifestation of circadian rhythms, affects morning or evening preferences and ease of getting-up. This study explores the genetic basis of morning chronotype and ease of getting-up, focusing on the G protein-coupled receptor locus, GPR61. MethodsWe analyzed the genetic correlation between chronotype and ease of getting-up using linkage disequilibrium score regression with summary statistics from the UK Biobank (n=453,379). We prioritized shared signals between chronotype and ease of getting-up using the Human Genetic Evidence (HuGE) score. We assessed the significance of GPR61 and the lead variant rs12044778 through colocalization and in-silico analyses from ENCODE, Genotype-Tissue Expression, Hi-C, and Knockout Mouse Project databases to explore potential regulatory roles of causal genes. ResultsWe identified a strong genetic correlation (Rg=0.80, P=4.9 x10324) between chronotype and ease of getting-up. Twenty-three genes, including three circadian core clock components, had high HuGE scores for both traits. Lead variant rs12044778 in GPR61 was prioritized for its high HuGE score (45) and causal pleiotropy (posterior probability=0.98). This morningness variant influenced gene expression in key tissues: decreasing GPR61 in tibial nerve, increasing AMIGO1 in subcutaneous adipose, and increasing ATXN7L2 in the cerebellum. Functional knockout models showed GPR61 knockout increased fat mass and activity, AMIGO1 knockout increased activity, and ATXN7L2 knockout reduced body weight without affecting activity. ConclusionsOur findings reveal pleiotropic genetic factors influencing chronotype and ease of getting-up, emphasizing GPR61s rs12044778 and nearby genes like AMIGO1 and ATXN7L2. These insights advance understanding of circadian preferences and suggest potential therapeutic interventions. SIGNIFICANCEThis study investigates the genetic underpinnings of chronotype preferences and ease of getting up, with a focus on the orphan G protein-coupled receptor GPR61 and the locus lead variant rs12044778. By combining genomic data with in silico functional analysis, we provide mechanistic insight into a locus for morning chronotype and ease of getting in the morning. We identified the variant rs12044778 as a key regulator of GPR61 and nearby genes AMIGO1 and ATXN7L2 influencing circadian and metabolic traits. Our findings shed light on the intricate genetic networks governing circadian rhythms, suggesting potential therapeutic targets for disorders of the circadian rhythm.

genomics↗

bioRxiv2023

Identifying novel links between cardiovascular disease and insomnia by Drosophila modeling of genes from a pleiotropic GWAS locus

Insomnia symptoms have been associated with cardiovascular disease (CVD), doubling the risk of incident CVD, but specific shared pathways remain poorly understood. Recently, genome-wide association studies (GWAS) identified genetic loci significantly associated with insomnia symptoms, including one locus (near ATP5G1, UBE2Z, SNF8, IGF2BP1, and GIP) that was previously linked with CVD in an independent GWAS. To evaluate the cell-autonomous role of genes within the 17q21 insomnia and CVD locus, we used Drosophila melanogaster models to perform tissue-specific RNAi knockdown of four conserved orthologues (ATPSynC, Lsn, Bruce, and Imp) in neurons and in the heart. To identify non-cell-autonomous mechanisms, we also assessed heart function in flies with neuronal-specific knockdown and sleep in flies with heart-specific knockdown. Neuronal and cardiac-specific RNAi knockdown of several of the genes conserved in Drosophila led to compromised sleep quality and impaired cardiac performance. Neuronal-specific knockdown of ATPSynC, Imp, and Lsn led to disruptions in sleep quantity and quality. Knockdown of ATPSynC and Lsn in the heart led to significantly reduced cardiac performance without and with cardiac dilation, respectively. Furthermore, Lsn and ATPSynC-suppressed hearts showed disruption in the actin-containing myofibrillar organization and led to a significantly shortened lifespan. Non-cell-autonomous effects were seen both from neurons to heart (Imp), and heart to neurons (ATPSynC and Lsn). Specifically, Imp neuronal knockdown led to a significantly compromised cardiac function, whereas knockdown of ATPSynC and Lsn in the heart led to compromised sleep characterized by increased sleep fragmentation, both accompanied by an increase in inflammation through Upd3, an inflammatory cytokine, in the heart or head, respectively. We also demonstrate disrupted cardiac function or sleep upon cardiac-specific or neuronal-specific overexpression of Upd3, respectively, showing a direct link between cardiac dysfunction and sleep disruption through inflammation. Our study reveals tissue-specific and cross-tissue consequences of Drosophila knockdown of multiple genes at this locus, providing novel insights into potential genetic mechanisms linking CVD and insomnia. Our study also highlights the key role of these four conserved genes in both sleep and cardiac function.

physiology↗

bioRxiv2022

Multi-ancestry genome-wide analysis identifies common genetic variants for self-reported sleep duration and shared genetic effects

Both short and long sleep duration are associated with increased risk of chronic diseases, but the genetic determinants of sleep duration are largely unknown outside of European populations. Here we report transferability of a polygenic score of 78 European ancestry sleep duration SNPs to an African (n=7,288; p=0.003), a South Asian (n=7,485; p=0.025), and a Japanese (n=13,618; p=6x10-4) cohort, but not to a cohort of Hispanic/Latino (n- XXX; p=0.71) participants. Furthermore, in a pan-ancestry (N = 483,235) meta-analysis of genome-wide association studies (GWAS) for habitual sleep duration, 5 novel and 68 known loci are associated with genome-wide significance. For the novel loci, sleep duration signals colocalize with expression-QTLs for PRR12 and COG5 in brain tissues, and pleiotropic associations are observed with cardiovascular and neuropsychiatric traits. Overall, our results suggest that the genetic basis of sleep duration is at least partially shared across diverse ancestry groups.

genomics↗