Tibetans have lived at high altitudes for thousands of years and have developed unique physiological traits to adapt to hypoxia. This study identifies genes involved in high-altitude adaptation through genome-wide scans showing positive selection in regions containing genes related to hypoxia response. EGLN1 and PPARA haplotypes are significantly associated with decreased hemoglobin (Hb) levels in Tibetans. These findings support previous hypotheses about high-altitude adaptation and highlight the complexity of hypoxia response pathways. The Tibetan highlands are one of the most extreme human environments. Tibetans have distinct physiological traits compared to lowland populations, including lower Hb concentration. High-altitude Tibetans maintain normal aerobic metabolism despite severe hypoxia, possibly through changes in the oxygen transport system. These traits suggest unique adaptation to high-altitude conditions. The study used two criteria to identify genes involved in high-altitude adaptation: a priori candidates based on known functions and genome-wide scans for regions with positive selection. A list of Gene Ontology categories associated with hypoxia traits was merged with a pathway related to hypoxia response. The resulting 247 functional candidate loci were analyzed for positive selection. Genome-wide scans identified 10 genes associated with high-altitude adaptation, including EGLN1, EPAS1, EDNRA, PTEN, PPARA, ANGPTL4, CYP17A1, CYP2E1, HMOX2, and CAMK2D. These genes are involved in hypoxia response pathways and lipid metabolism. The study found significant negative correlations between Hb concentration and advantageous haplotypes of EGLN1 and PPARA. The results suggest that high-altitude adaptation in Tibetans is due to local positive selection on several genes. The study also found that the selection signals correspond to 200kb genome regions rather than individual genes. Additional analyses localized the selection signals within these regions. The study tested the statistical significance of the observed pattern using a randomization test. The results showed that the observed number of genes associated with Hb concentration was significantly higher than expected by chance. The strong association between Hb concentration and haplotype variation at EGLN1 and PPARA provides evidence of a genetic contribution to high-altitude adaptation in Tibetans. The study also found that EGLN1 and PPARA are involved in regulating HIF and its target genes. EGLN1 targets HIF alpha proteins for degradation, decreasing the transcription of HIF-regulated genes. PPARA interacts with components of the HIF pathway and its expression is inhibited by HIF1 during hypoxia. A PPARA agonist resulted in decreased Hb levels in clinical trials, consistent with the association found in this study. The study concludes that the genetic basis of high-altitude adaptation in Tibetans is complex and involves multiple genes. Understanding these genetic adaptations can improve our understandingTibetans have lived at high altitudes for thousands of years and have developed unique physiological traits to adapt to hypoxia. This study identifies genes involved in high-altitude adaptation through genome-wide scans showing positive selection in regions containing genes related to hypoxia response. EGLN1 and PPARA haplotypes are significantly associated with decreased hemoglobin (Hb) levels in Tibetans. These findings support previous hypotheses about high-altitude adaptation and highlight the complexity of hypoxia response pathways. The Tibetan highlands are one of the most extreme human environments. Tibetans have distinct physiological traits compared to lowland populations, including lower Hb concentration. High-altitude Tibetans maintain normal aerobic metabolism despite severe hypoxia, possibly through changes in the oxygen transport system. These traits suggest unique adaptation to high-altitude conditions. The study used two criteria to identify genes involved in high-altitude adaptation: a priori candidates based on known functions and genome-wide scans for regions with positive selection. A list of Gene Ontology categories associated with hypoxia traits was merged with a pathway related to hypoxia response. The resulting 247 functional candidate loci were analyzed for positive selection. Genome-wide scans identified 10 genes associated with high-altitude adaptation, including EGLN1, EPAS1, EDNRA, PTEN, PPARA, ANGPTL4, CYP17A1, CYP2E1, HMOX2, and CAMK2D. These genes are involved in hypoxia response pathways and lipid metabolism. The study found significant negative correlations between Hb concentration and advantageous haplotypes of EGLN1 and PPARA. The results suggest that high-altitude adaptation in Tibetans is due to local positive selection on several genes. The study also found that the selection signals correspond to 200kb genome regions rather than individual genes. Additional analyses localized the selection signals within these regions. The study tested the statistical significance of the observed pattern using a randomization test. The results showed that the observed number of genes associated with Hb concentration was significantly higher than expected by chance. The strong association between Hb concentration and haplotype variation at EGLN1 and PPARA provides evidence of a genetic contribution to high-altitude adaptation in Tibetans. The study also found that EGLN1 and PPARA are involved in regulating HIF and its target genes. EGLN1 targets HIF alpha proteins for degradation, decreasing the transcription of HIF-regulated genes. PPARA interacts with components of the HIF pathway and its expression is inhibited by HIF1 during hypoxia. A PPARA agonist resulted in decreased Hb levels in clinical trials, consistent with the association found in this study. The study concludes that the genetic basis of high-altitude adaptation in Tibetans is complex and involves multiple genes. Understanding these genetic adaptations can improve our understanding