title: Copy number variants in attention-deficit hyperactive disorder: identification of the 15q13 deletion and its functional role.
abstract: OBJECTIVE
  Evidence has supported a role for rare copy number variants in the etiology of attention-deficit hyperactivity disorder (ADHD), in particular, the region 15q13, which is also a hot spot for several neuropsychiatric disorders. This region spans several genes, but their role and the biological implications remain unclear.
  
  
  METHODS
  We carried out, for the first time, an analysis of the 15q13 region in an Italian cohort of 117 ADHD patients and 77 controls using the MLPA method, confirmed by a genome single-nucleotide polymorphism array. In addition, we probed for downstream effects of the 15q13 deletions on gene expression by carrying out a transcriptomic analysis in blood.
  
  
  RESULTS
  We found 15q13 deletions in two ADHD patients and identified 129 genes as significantly dysregulated in the blood of the two ADHD patients carrying 15q13 deletions compared with ADHD patients without 15q13 deletions. As expected, genes in the deleted region (KLF13, MTMR10) were downregulated in the two patients with deletions. Moreover, a pathway analysis identified apoptosis, oxidation reduction, and immune response as the mechanisms that were altered most significantly in the ADHD patients with 15q13 deletions. Interestingly, we showed that deletions in KLF13 and CHRNA7 influenced the expression of genes belonging to the same immune/inflammatory and oxidative stress signaling pathways.
  
  
  CONCLUSIONS
  Our findings are consistent with the presence of 15q13 deletions in Italian ADHD patients. More interestingly, we show that pathways related to immune/inflammatory response and oxidative stress signaling are affected by the deletion of KFL13 and CHRNA7. Because the phenotypic effects of 15q13 are pleiotropic, our findings suggest that there are shared biologic pathways among multiple neuropsychiatric conditions.
authors.affiliation: aGenetics Unit bNeuropsychopharmacology Unit, IRCCS 'Centro S. Giovanni di Dio' Fatebenefratelli cDepartment of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia dChildhood and Adolescent Neuropsychiatry Unit of Fatebenefratelli and Oftalmico, Milan, Italy eDepartments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA fStress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College London, London, United Kingdom gDepartment of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Stefano
authors.initials: S
authors.lastname: Valbonesi
authors.forename: Chiara
authors.initials: C
authors.lastname: Magri
authors.forename: Michele
authors.initials: M
authors.lastname: Traversa
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Annamaria
authors.initials: A
authors.lastname: Cattaneo
authors.forename: Elena
authors.initials: E
authors.lastname: Milanesi
authors.forename: Vera
authors.initials: V
authors.lastname: Valenti
authors.forename: Massimo
authors.initials: M
authors.lastname: Gennarelli
authors.forename: Catia
authors.initials: C
authors.lastname: Scassellati
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15; D056915:DNA Copy Number Variations; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis