title: Duplication of the SLIT3 locus on 5q35.1 predisposes to major depressive disorder.
abstract: Major depressive disorder (MDD) is a common psychiatric and behavioral disorder. To discover novel variants conferring risk to MDD, we conducted a whole-genome scan of copy number variation (CNV), including 1,693 MDD cases and 4,506 controls genotyped on the Perlegen 600K platform. The most significant locus was observed on 5q35.1, harboring the SLIT3 gene (P = 2×10(-3)). Extending the controls with 30,000 subjects typed on the Illumina 550 k array, we found the CNV to remain exclusive to MDD cases (P = 3.2×10(-9)). Duplication was observed in 5 unrelated MDD cases encompassing 646 kb with highly similar breakpoints. SLIT3 is integral to repulsive axon guidance based on binding to Roundabout receptors. Duplication of 5q35.1 is a highly penetrant variation accounting for 0.7% of the subset of 647 cases harboring large CNVs, using a threshold of a minimum of 10 SNPs and 100 kb. This study leverages a large dataset of MDD cases and controls for the analysis of CNVs with matched platform and ethnicity. SLIT3 duplication is a novel association which explains a definitive proportion of the largely unknown etiology of MDD.
authors.affiliation: Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Patrick M A
authors.initials: PM
authors.lastname: Sleiman
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.forename: James H
authors.initials: JH
authors.lastname: Flory
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.forename: Marcin
authors.initials: M
authors.lastname: Imielinski
authors.forename: Edward C
authors.initials: EC
authors.lastname: Frackelton
authors.forename: Haijun
authors.initials: H
authors.lastname: Qiu
authors.forename: Frank
authors.initials: F
authors.lastname: Mentch
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D000328:Adult; D000368:Aged; D001369:Axons / Q000378:metabolism; D002895:Chromosomes, Human, Pair 5; D003865:Major Depressive Disorder / Q000235:genetics*; D004200:Diseases in Twins; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D012306:Risk
chemical_list: D008565:Membrane Proteins; C498990:SLIT3 protein, human