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Indigenous Tibetan people have lived on the Tibetan Plateau for millennia. There is a long-standing question about the genetic basis of high-altitude adaptation in Tibetans. We conduct a genome-wide study of 7.3 million genotyped and imputed SNPs of 3,008 Tibetans and 7,287 non-Tibetan individuals of Eastern Asian ancestry. Using this large dataset, we detect signals of high-altitude adaptation at nine genomic loci, of which seven are unique. The alleles under natural selection at two of these loci [methylenetetrahydrofolate reductase (MTHFR) and EPAS1] are strongly associated with blood-related phenotypes, such as hemoglobin, homocysteine, and folate in Tibetans. The folate-increasing allele of rs1801133 at the MTHFR locus has an increased frequency in Tibetans more than expected under a drift model, which is probably a consequence of adaptation to high UV radiation. These findings provide important insights into understanding the genomic consequences of high-altitude adaptation in Tibetans.high-altitude adaptation | Tibetans | genome-wide association study | mixed linear model | polygenic selection G enetic adaptation to a novel environment is a fundamental process for the survival and adaptation of a species. In humans, one of the most recent examples is adaptation to high altitude, such as the Tibetan highlands. The Tibetan Plateau (TP; also known as the Qinghai-Tibet Plateau in China) has an average elevation of ∼4,000 m above sea level, where the oxygen concentration is ∼40% lower (1) and UV radiation is ∼30% stronger (2) than at sea level. The indigenous Tibetan people have developed a distinctive set of physiological characteristics to adapt to the extreme environmental conditions in the highlands (1). Previous population-based genetic studies have reported evidence that genetic variants at the EPAS1 and EGLN1 loci have been under positive natural selection (3-7). These genetic variants are associated with phenotypic variation of hemoglobin concentration (HGB) in Tibetans (3-5). The EPAS1 gene, which encodes the hypoxia inducible factor-2α (HIF-2α) subunit of HIF complex, is a transcription factor involved in body response to hypoxia (8, 9). EGLN1 encodes PHD2, which is a major oxygen-dependent negative regulator of HIFs (10, 11). Apart from these two known genes that have biological relevance to hypoxia adaptation (3-7, 12), several other candidate gene loci (e.g., PPARA and HBB) have been highlighted in recent studies (3,4,(13)(14)(15). Genetic adaptation to high altitude, however, is likely to be a complex process, with a large number of genes involved in response to not only hypoxia but also, other extreme environmental conditions, such as low temperature, high UV radiation, and insufficient food supply. If the strength of natural selection at these gene loci has been small to moderate, these loci would not be detected in previous studies (3-7) of small sample size (typically n < 150). In this study, we perform a largescale genome-wide study to detect genetic signals of high-altitude adaptation in 3...