title: Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study.
abstract: Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.
authors.affiliation: School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences (MICCN), Monash University, Melbourne, VIC, Australia.
authors.forename: Z
authors.initials: Z
authors.lastname: Hawi
authors.affiliation: School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences (MICCN), Monash University, Melbourne, VIC, Australia.
authors.forename: T D R
authors.initials: TD
authors.lastname: Cummins
authors.affiliation: School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences (MICCN), Monash University, Melbourne, VIC, Australia.
authors.forename: J
authors.identifier: 0000-0002-3269-1438
authors.initials: J
authors.lastname: Tong
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Arcos-Burgos
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Q
authors.identifier: 0000-0002-6341-0416
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Matthews
authors.affiliation: School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences (MICCN), Monash University, Melbourne, VIC, Australia.
authors.forename: D P
authors.initials: DP
authors.lastname: Newman
authors.affiliation: School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences (MICCN), Monash University, Melbourne, VIC, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Academic Child Psychiatry Unit, Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Vance
authors.affiliation: Mater Research Institute, University of Queensland, Brisbane, QLD, Australia.
authors.forename: H S
authors.initials: HS
authors.lastname: Heussler
authors.affiliation: School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.|Child and Family East, Prince of Wales Hospital, Randwick, NSW, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Levy
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Easteal
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: N R
authors.identifier: 0000-0001-7421-3357
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: E
authors.initials: E
authors.lastname: Kenny
authors.affiliation: Department of Biochemistry, National University of Ireland Galway, Galway, Ireland.
authors.forename: D
authors.identifier: 0000-0002-3413-570X
authors.initials: D
authors.lastname: Morris
authors.affiliation: School of Medicine, University of St Andrews, St Andrews, Scotland, UK.
authors.forename: L
authors.initials: L
authors.lastname: Kent
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: M
authors.identifier: 0000-0003-0206-5337
authors.initials: M
authors.lastname: Gill
authors.affiliation: School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences (MICCN), Monash University, Melbourne, VIC, Australia.|Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Bellgrove
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D004247:DNA; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007494:Ireland; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C579455:BDNF protein, human; D004247:DNA