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Model\u2010free linkage analysis was performed using genotypes for 392 highly informative polymorphisms with an average spacing of 9 cM. The highest maximum LOD score observed, 8.19 (genome\u2010wide adjusted <jats:italic>P<\/jats:italic>\u2009\u226a\u20090.0001), occurred for Recurrent Major Depressive Disorder (R\u2010MDD) at D2S2321 (205 cM), located 121 kb proximal to <jats:italic>CREB1<\/jats:italic>. Nineteen chromosomal regions contained linkage peaks that reached genome\u2010wide statistical significance (genome\u2010wide adjusted <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) and ten of these were \u201chighly significant\u201d (adjusted <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). Six of the 19 linkage peaks were revealed only when the analysis included covariates to control for the effects of sex and linkage to <jats:italic>CREB1.<\/jats:italic> Sex\u2010specific susceptibility loci were common and preferentially affected the vulnerability of women to developing unipolar Mood Disorders. Five loci revealed evidence of interaction with the <jats:italic>CREB1<\/jats:italic> locus in determining susceptibility (epistasis). A systematic candidate gene analysis is presented and potential overlaps of the linkage regions for unipolar Mood Disorders with those reported for other psychiatric disorders are discussed. The findings suggest that genes whose products participate in cellular signaling pathways that converge on CREB, as well as the target genes whose expression they regulate, may also harbor alleles that affect the development of Mood Disorders and related conditions. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.b.20073","type":"journal-article","created":{"date-parts":[[2003,10,23]],"date-time":"2003-10-23T13:19:40Z","timestamp":1066915180000},"page":"1-18","source":"Crossref","is-referenced-by-count":154,"title":["Genome\u2010wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early\u2010onset, major depression"],"prefix":"10.1002","volume":"123B","author":[{"given":"George S.","family":"Zubenko","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brion","family":"Maher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"Hugh B.","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy N.","family":"Zubenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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