Identification of novel loci regulating circulating melatonin and its causal relationship with hypertension

Identifying causal genetic variants for high-altitude adaptation through blood eQTL analysis in plateau populations

A substantial number of genetic variants have been associated with high-altitude adaptation (HAA), yet most of them are located in non-coding genomic regions, leaving their specific functions and underlying mechanisms largely unknown. In this study, we analyze whole-genome and transcriptome sequencing data from a self-established cohort comprising 61 native highlanders (NHs) and 164 acclimatized newcomers (ANs), identifying 6,586 cis- and 34,203 trans-expression quantitative trait loci (eQTLs), along with 130 cell type-specific eQTLs. By further combining these data with a large East Asia (~30% Tibetan) genome-wide association study (GWAS) cohort, we employ colocalization and causal inference analyses to prioritize 85 cis-eQTLs associated with HAA and identify several novel candidate causal genes, including EXOC8 , which is experimentally confirmed to regulate erythroid differentiation. Additionally, network analysis of these causal genes uncovers multiple regulatory pathways, mainly involving energy metabolism, autophagy, ubiquitination and inflammation. Our study offers a comprehensive eQTL map and reveals causal chains of “variant-gene-phenotype” for HAA-related traits, which provides new insights into potential regulatory mechanisms and targets for prevention and treatment of altitude sickness.

Hypertension-associated DNA methylation signatures and multi-generational epigenetic clocks in Korean adults.

Genetic evidence for a causal relationship between melatonin metabolism and depression.

To investigate the causal relevance of melatonin metabolism, which provides the biological basis for circulating melatonin levels, to specific depression symptom subtypes, we performed a targeted systematic review of melatonin metabolism pathways in the human brain and liver. Using two-sample Mendelian randomization (MR), we assessed the causal effects of metabolism pathways and/or individual genes on major depressive disorder (MDD) and nine symptom subtypes derived from Patient Health Questionnaire-9 (PHQ-9). Instrumental variables (IVs) were expression quantitative trait loci (eQTL) for eight individual genes, one synthesis route, and three degradation routes. Results were assessed using Bayesian colocalization and phenome-wide association analyses. At the pathway-level, the genetically proxied synthesis-route signal was associated with PHQ-9 Assessment 5 (PHQ9A5, OR: 0.89, 95% CI: 0.85-0.93), but sensitivity analyses suggested this association was primarily driven by TPH1 and may reflect serotonin-related biology. In contrast, higher brain melatonin degradation raised the risk of both PHQ9A1 (OR: 1.03, 95% CI: 1.02-1.04) and PHQ9A7 (OR: 1.03, 95% CI: 1.02-1.03). Within degradation, up-regulation of the kynurenine sub-pathway increased the odds of PHQ9A3 (OR: 1.05, 95% CI: 1.02-1.07), PHQ9A4 (OR = 1.04, 95% CI: 1.02-1.06) and PHQ9A7 (OR: 1.05, 95% CI: 1.02-1.07). Gene-level analyses were largely concordant, except for SULT1A1, whose higher expression was genetically protective for PHQ9A3 but risk-increased for PHQ9A1 and PHQ9A4. Overall, these results demonstrate that melatonin metabolism exerts symptom-specific and pathway-specific causal effects on depression. A stratified view of melatonin's role may help optimize the application of exogenous melatonin supplementation.

Discovery of functional variants regulating lipid metabolism in an East Asian population.

BACKGROUND Recent genome-wide association studies have identified more than 900 lipid-related loci; however, the specific genes and mechanisms that regulate blood lipid levels remain incompletely understood. This study aimed to identify lipid-associated variants in Koreans and to investigate their potential functional and regulatory mechanisms. METHODS We performed a genome-wide association study of triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels in 72,298 Korean participants. Genotype data were imputed using the Northeast Asian Reference Database, version 2. We then conducted conditional analysis, statistical fine-mapping, and functional variant-to-gene mapping, and further evaluated the associations of lipid-associated variants with coronary artery disease. Significant variants were subsequently examined using a luciferase reporter assay in HepG2 cells. RESULTS Our analyses identified 182 independent lipid-associated signals, including 64 previously unreported signals. Integrative fine-mapping and variant-to-gene mapping prioritized 24 variants with evidence of transcriptional regulatory effects and 40 linked genes, including potential lipid metabolism regulators PIP5KL1 and UBE4A. Reporter assays further supported allele-specific regulatory activity for rs10987803 and rs5130. Several low-frequency protein-altering variants implicated established lipid metabolism pathways. Notably, a Korean-enriched ANGPTL3 missense variant (rs753849210; p.W338C) was associated with markedly lower triglyceride levels. Lipid effects were directionally concordant with coronary artery disease associations for variants in PCSK9 (rs564427867; p.E32K and rs151193009; p.R93C), HIST1H1C (rs12111009; p.G124A), and CELSR2 (rs77619489; p.A2806V). CONCLUSIONS These findings refine the genetic architecture of lipid traits and nominate candidate genes and regulatory variants for future studies of lipid-related cardiometabolic disease.

Multi-omic characterization of the Hispanic/Latino blood lipidome reveals an additional locus and attenuated genetic prediction.

While lipids have been extensively investigated, genetic regulation of the circulating lipidome in diverse populations remains poorly understood. We conducted a lipidome-wide GWAS of 830 lipid species in 2,287 Hispanic/Latino participants and performed predictive modeling across omics layers. We identified 7,593 genome-wide significant SNPs mapping to 208 genes. Conditional analysis disentangled the long-range linkage disequilibrium artifacts from the pleiotropic FADS1/2/3 cluster. Separately, we discovered an association at the GPLD1 locus for a circulating ceramide. Colocalization revealed shared genetic architecture with conventional lipids alongside distinct, species-specific pathways. Incorporating Native/Indigenous American eQTLs within a multi-omic framework uncovered 62 likely regulatory genes missed by European-centric gene expression models. Finally, genetically regulated predictive models demonstrated performance declining from transcriptomics to proteomics to lipidomics, reflecting increased distance from gene action along the molecular cascade. Our study provides a genetic landscape of lipid metabolism in a highly burdened population and highlights the challenges in predicting lipid abundance.

A Functional SNP in the Promoter Region of Ovine IDO2 Associated With Melatonin Levels via Affecting Transcription Activity by CLOCK.

Sheep seasonal reproduction is regulated by photoperiod via melatonin. Indoleamine 2,3-dioxygenase 2 (IDO2), an enzyme involved in tryptophan metabolism through the kynurenine pathway and belonging to the IDO family, may contribute to melatonin homeostasis, but its role in reproductive seasonality remains unclear. In this study, genome-wide selection analyses combining Z(FST) and XP-EHH between seasonal and non-seasonal sheep identified a selection signature encompassing the IDO2 region and revealed g.-809T>C as a functional candidate variant within this region. Experiments employing electrophoretic mobility shift assay (EMSA) and luciferase assays revealed that this site lies within the CLOCK transcription factor binding domain. The -809C variant reduced promoter activity compared to -809T (p < 0.05). Sheep with the CC genotype had higher plasma melatonin levels than TC/TT counterparts (p < 0.05). These findings suggest that the g.-809C allele decreases IDO2 transcription by reducing CLOCK binding affinity, thereby potentially affecting IDO2-associated tryptophan/melatonin metabolism and increasing melatonin levels, which may contribute to photoperiodic responses in sheep. This IDO2 variation provides new insights into the genetic regulation of melatonin-mediated reproductive seasonality and represents a potential marker for genetic improvement of reproductive seasonal traits in sheep.