Separating the wheat from the chaff: systematic identification of functionally relevant noncoding variants in ADHD.
Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.
School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia.
J H S
JH
Tong
School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia.
Z
Z
Hawi
School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia.
C
C
Dark
School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia.
T D R
TD
Cummins
School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia.
B P
BP
Johnson
School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia.
D P
DP
Newman
School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia.
R
R
Lau
Academic Child Psychiatry Unit, Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC, Australia.
A
A
Vance
Mater Research Institute, University of Queensland, Brisbane, QLD, Australia.
H S
HS
Heussler
Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
N
N
Matthews
School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia.
M A
MA
Bellgrove
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.|Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.|Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia.|Murdoch Children's Research Institute, Parkville, VIC, Australia.
K C
KC
Pang
D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000503:physiopathology; D019295:Computational Biology / Q000379:methods*; D057890:Epigenomics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors