ADCY3 Ser107Pro links difficulty awakening in the morning to adiposity through circadian regulation of adipose thermogenesis
Tchio, C.; Maher, M.; Moth, C.; Meiler, J.; Lane, J.; Taylor, H.; Williams, J.; Saxena, R.
Show abstract
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.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes 96%
- Whole Genome Sequencing Analysis Of Body Mass Index Identifies Novel African Ancestry-Specific Risk Allele 95%
- Comprehensive genomic analysis of dietary habits in UK Biobank identifies hundreds of genetic loci and establishes causal relationships between educational attainment and healthy eating 95%
Similar papers in this journal
- Diet-induced loss of adipose Hexokinase 2 triggers hyperglycemia 95%
- 3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity 95%
- A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion 95%
Similar papers in this journal
Similar papers in this journal
- The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity 95%
- Systematic cell-type resolved transcriptomes of 8 tissues in 8 lab and wild-derived mouse strains captures global and local expression variation 94%
- Analysis across Taiwan Biobank, Biobank Japan and UK Biobank identifies hundreds of novel loci for 36 quantitative traits 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.