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Recent genome-wide association studies (GWAS) on common variants increase our understanding of MDD; however, the underlying genetic basis remains largely unknown. Many studies have been proposed to explore the genetics of complex diseases from a viewpoint of the \u201cmissing heritability\u201d by considering low-frequency and rare variants, copy-number variations, and other types of genetic variants. Here we developed a novel computational and statistical strategy to investigate the \u201cmissing heritability\u201d of MDD. We applied Hamming distance on common, low-frequency, and rare single-nucleotide polymorphism (SNP) sets to measure genetic distance between two individuals, and then built the multi-dimensional scaling (MDS) pictures. Whole-exome genotyping data from a Los Angeles Mexican-American cohort (203 MDD and 196 controls) and a European-ancestry cohort (473 MDD and 497 controls) were examined using our proposed methodology. MDS plots showed very significant separations between MDD cases and healthy controls for low-frequency SNP set (<jats:italic>P<\/jats:italic>value\u2009&lt;\u20092.2e\u221216) and rare SNP set (<jats:italic>P<\/jats:italic>value\u2009=\u20097.681e\u221212). Our results suggested that low-frequency and rare variants may play more significant roles in the genetics of MDD.<\/jats:p>","DOI":"10.1038\/s41398-018-0117-7","type":"journal-article","created":{"date-parts":[[2018,4,4]],"date-time":"2018-04-04T02:16:57Z","timestamp":1522808217000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Low-frequency and rare variants may contribute to elucidate the genetics of major depressive disorder"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3248-8421","authenticated-orcid":false,"given":"Chenglong","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"Arcos-Burgos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6548-426X","authenticated-orcid":false,"given":"Bernhard T.","family":"Baune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Arolt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udo","family":"Dannlowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma-Li","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Licinio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,3,27]]},"reference":[{"key":"117_CR1","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1001\/archpsyc.1994.03950010008002","volume":"51","author":"RC Kessler","year":"1994","unstructured":"Kessler, R. 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