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Tibetan goat is an ancient breed, which inhabits the adverse conditions of the plateaus in China. To investigate the role of selection in shaping its genomes, we genotyped Tibetan goats (Nagqu Prefecture, above 4500 m) and three lowland populations (Xinjiang goats, Taihang goats and Huanghuai goats). The result of PCA, neighbor-joining (N-J) tree and model-based clustering showed that the genetic structure between the Tibetan goat and the three lowland populations has significant difference. As demonstrated by the <i>di</i> statistic, we found that some genes were related to the high-altitude adaptation of Tibetan goats. Functional analysis revealed that these genes were enriched in the VEGF (vascular endothelial growth factor) signaling pathway and melanoma, suggesting that nine genes (<i>FGF2</i>, <i>EGFR</i>, <i>AKT1</i>, <i>PTEN</i>, <i>MITF</i>, <i>ENPEP</i>, <i>SIRT6</i>, <i>KDR</i>, and <i>CDC42</i>) might have important roles in the high-altitude adaptation of Nagqu Tibetan goats. We also found that the <i>LEPR</i> gene was under the strongest selection (<i>di</i> value = 16.70), and it could induce upregulation of the hypoxic ventilatory response. In addition, five genes (<i>LEPR</i>, <i>LDB1</i>, <i>EGFR</i>, <i>NOX4</i> and <i>FGF2</i>) with high <i>di</i> values were analyzed using q-PCR. Among them, we found that <i>LEPR</i>, <i>LDB1</i> and <i>FGF2</i> exhibited higher expression in the lungs of the Tibetan goats; <i>LEPR</i>, <i>EGFR</i> and <i>LDB1</i> exhibited higher expression in the hearts of the Huanghuai goat. Our results suggest that <i>LEPR</i>, <i>LDB1</i>, <i>EGFR</i> and <i>FGF2</i> genes may be related to the high-altitude adaptation of the goats. These findings improve our understanding of the selection of the high-altitude adaptability of the Nagqu Tibetan goats and provide new theoretical knowledge for the conservation and utilization of germplasm resources.