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It is generally considered that the interplay between genes and the environment is important in the onset and\/or development of SCZ. Although several whole-exome sequencing studies have revealed rare risk variants of SCZ, no rare coding variants have been strongly replicated. Assessing isolated populations under extreme conditions might lead to the discovery of variants with a recent origin, which are more likely to have a higher frequency than chance to reflect gene-environment interactions. Following this approach, we examined a unique cohort of Tibetans living at an average altitude above 4500 meters. Whole-exome sequencing of 47 SCZ cases and 53 controls revealed 275 potential novel risk variants and two known variants (<jats:italic>12:46244485: A\/G and 22:18905934: A\/G<\/jats:italic>) associated with SCZ that were found in existing databases. Only one gene (<jats:italic>C5orf42<\/jats:italic>) in the gene-based statistics surpassed the exome-wide significance in the cohort. Metascape enrichment analysis suggested that novel risk genes were strongly enriched in pathways relevant to hypoxia, neurodevelopment, and neurotransmission. Additionally, 47 new risk genes were followed up in Han sample of 279 patients with SCZ and 95 controls, only <jats:italic>BAI2<\/jats:italic> variant appearing in one case. Our findings suggest that SCZ patients living at high altitudes may have a unique risk gene signature, which may provide additional information on the underlying biology of SCZ, which can be exploited to identify individuals at greater risk of exposure to hypoxia.<\/jats:p>","DOI":"10.1038\/s41398-024-02984-y","type":"journal-article","created":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T20:32:09Z","timestamp":1719865929000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Whole-exome sequencing of individuals from an isolated population under extreme conditions implicates rare risk variants of schizophrenia"],"prefix":"10.1038","volume":"14","author":[{"given":"Lei","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue-Song","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuewen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7529-4408","authenticated-orcid":false,"given":"Yong","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,6,29]]},"reference":[{"key":"2984_CR1","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1177\/0269881112467089","volume":"27","author":"WR Keller","year":"2013","unstructured":"Keller WR, Kum LM, Wehring HJ, Koola MM, Buchanan RW, Kelly DL. 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