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.
Chenghui Zhao, Jia-Wei Guan, Jun-Hua Liu et al.· Communications Biology· 0 citations
These exploratory findings indicate that hypertension-associated epigenetic changes are captured by multi-generational epigenetic clocks and may implicate inflammation-related pathways, warranting confirmation in longitudinal studies.
Jangho Lee, S. Park, Jin-Taek Hwang et al.· GeroScience· 0 citations
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.
Yuanbi Wang, Wen Wen, Hansheng Chen et al.· Journal of Affective Disorde...· 0 citations
The findings refine the genetic architecture of lipid traits and nominate candidate genes and regulatory variants for future studies of lipid-related cardiometabolic disease.
Sungji Moon, Young Jun Park, Jaeyong Choi et al.· Metabolism: Clinical and Exp...· 0 citations
A lipidome-wide GWAS of 830 lipid species in 2,287 Hispanic/Latino participants and predictive modeling across omics layers provided a genetic landscape of lipid metabolism in a highly burdened population and highlights the challenges in predicting lipid abundance.
Wanying Zhu, Hung-Hsin Chen, H. Highland et al.· HGG advances· 0 citations
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.
Xunping Jiang, Shaxuan Chi, Xiaodong Wang et al.· Animal Genetics· 0 citations