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Here, we related HA adaptive genetic variants in three gene loci (<jats:italic>EGLN1<\/jats:italic>, <jats:italic>EPAS1<\/jats:italic>, and <jats:italic>PPARA<\/jats:italic>) to interindividual variance in a set of physiological characteristics, neuropsychological tests, and topological attributes of large\u2010scale structural and functional brain networks in 135 indigenous Tibetan highlanders. Analyses of individual HA adaptive single\u2010nucleotide polymorphisms (SNPs) revealed that specific SNPs selectively modulated physiological characteristics (erythrocyte level, ratio between forced expiratory volume in the first second to forced vital capacity, arterial oxygen saturation, and heart rate) and structural network centrality (the left anterior orbital gyrus) with no effects on neuropsychology or functional brain networks. Further analyses of genetic adaptive scores, which summarized the overall degree of genetic adaptation to HA, revealed significant correlations only with structural brain networks with respect to local interconnectivity of the whole networks, intermodule communication between the right frontal and parietal module and the left occipital module, nodal centrality in several frontal regions, and connectivity strength of a subnetwork predominantly involving in intramodule edges in the right temporal and occipital module. Moreover, the associations were dependent on gene loci, weight types, or topological scales. Together, these findings shed new light on genotype\u2013phenotype interactions under HA hypoxia and have important implications for developing new strategies to optimize organism and tissue responses to chronic hypoxia induced by extreme environments or diseases.<\/jats:p>","DOI":"10.1002\/hbm.24954","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T09:43:18Z","timestamp":1583314998000},"page":"2406-2430","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Neural network correlates of high\u2010altitude adaptive genetic variants in Tibetans: A pilot, exploratory study"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8104-398X","authenticated-orcid":false,"given":"Zhiyue","family":"Guo","sequence":"first","affiliation":[{"name":"Institute of Brain Diseases and Cognition School of Medicine, Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cunxiu","family":"Fan","sequence":"additional","affiliation":[{"name":"Institute of Brain Diseases and Cognition School of Medicine, Xiamen University  Xiamen Fujian China"},{"name":"Department of Neurology Shanghai Changhai Hospital, Navy Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Brain Diseases and Cognition School of Medicine, Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luobu","family":"Gesang","sequence":"additional","affiliation":[{"name":"Institute of High Altitude Medicine, Tibet Autonomous Region People's Hospital  Lhasa, Tibet Autonomous Region China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Radiology Tibet Autonomous Region People's Hospital  Lhasa, Tibet Autonomous Region China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningkai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Psychology Hangzhou Normal University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuchu","family":"Weng","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, South China Normal University Institute for Brain Research and Rehabilitation  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5912-4871","authenticated-orcid":false,"given":"Qiyong","family":"Gong","sequence":"additional","affiliation":[{"name":"Huaxi Magnetic Resonance Research Center West China Hospital, Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0452-1885","authenticated-orcid":false,"given":"Jiaxing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Brain Diseases and Cognition School of Medicine, Xiamen University  Xiamen Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, South China Normal University Institute for Brain Research and Rehabilitation  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,3,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1006108107"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2017.04.014"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1089\/ham.2015.0118"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-53884-0.00029-4"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2007.01.019"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmrb.1996.0086"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1018985108"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajpa.1330950303"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1002443107"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajpa.1330730404"},{"key":"e_1_2_10_12_1","first-page":"597","article-title":"Quantitative genetic analysis of arterial oxygen saturation in Tibetan highlanders","volume":"69","author":"Beall C. 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