title: Investigating the contribution of common genetic variants to the risk and pathogenesis of ADHD.
abstract: OBJECTIVE
  A major motivation for seeking disease-associated genetic variation is to identify novel risk processes. Although rare copy number variants (CNVs) appear to contribute to attention deficit hyperactivity disorder (ADHD), common risk variants (single-nucleotide polymorphisms [SNPs]) have not yet been detected using genome-wide association studies (GWAS). This raises the concern as to whether future larger-scale, adequately powered GWAS will be worthwhile. The authors undertook a GWAS of ADHD and examined whether associated SNPs, including those below conventional levels of significance, influenced the same biological pathways affected by CNVs.
  
  
  METHODS
  The authors analyzed genome-wide SNP frequencies in 727 children with ADHD and 5,081 comparison subjects. The gene sets that were enriched in a pathway analysis of the GWAS data (the top 5% of SNPs) were tested for an excess of genes spanned by large, rare CNVs in the children with ADHD.
  
  
  RESULTS
  No SNP achieved genome-wide significance levels. As previously reported in a subsample of the present study, large, rare CNVs were significantly more common in case subjects than comparison subjects. Thirteen biological pathways enriched for SNP association significantly overlapped with those enriched for rare CNVs. These included cholesterol-related and CNS development pathways. At the level of individual genes, CHRNA7, which encodes a nicotinic receptor subunit previously implicated in neuropsychiatric disorders, was affected by six large duplications in case subjects (none in comparison subjects), and SNPs in the gene had a gene-wide p value of 0.0002 for association in the GWAS.
  
  
  CONCLUSIONS
  Both common and rare genetic variants appear to be relevant to ADHD and index-shared biological pathways.
authors.affiliation: MRC Centre in Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, Wales. stergiakouliE@cardiff.ac.uk
authors.forename: Evangelia
authors.initials: E
authors.lastname: Stergiakouli
authors.forename: Marian
authors.initials: M
authors.lastname: Hamshere
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Kate
authors.initials: K
authors.lastname: Langley
authors.forename: Irina
authors.initials: I
authors.lastname: Zaharieva
authors.forename: Ziarah
authors.initials: Z
authors.lastname: Hawi
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kent
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Nigel
authors.initials: N
authors.lastname: Williams
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Michael
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Anita
authors.initials: A
authors.lastname: Thapar
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D002648:Child; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D018570:Risk Assessment; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor