Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder.
Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for <5% of ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. © 2017 Wiley Periodicals, Inc.
Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.|Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan.
Daniel Seung
DS
Kim
Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Amber A
AA
Burt
Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Jane E
JE
Ranchalis
Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, Oregon.
Beth
B
Wilmot
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington.
Joshua D
JD
Smith
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington.
Karynne E
KE
Patterson
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington.
Bradley P
BP
Coe
Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan.
Yatong K
YK
Li
Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Michael J
MJ
Bamshad
Department of Psychology, University of Iowa, Iowa City, Iowa.
Molly
M
Nikolas
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington.
Evan E
EE
Eichler
Department of Psychiatry, University of California-Irvine, Irvine, California.|Department of Epidemiology, University of California-Irvine, Irvine, California.
James M
JM
Swanson
Department of Psychiatry, Oregon Health and Science University, Portland, Oregon.
Joel T
JT
Nigg
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington.
Deborah A
DA
Nickerson
Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.|Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington.
Gail P
GP
Jarvik
D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000473:pathology; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000473:pathology; D015415:Biomarkers / Q000032:analysis*; D002648:Child; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype
D015415:Biomarkers
attention deficit hyperactivity disorder (ADHD); autism spectrum disorder (ASD); exome sequencing; intellectual disability (ID); molecular inversion probe (MIP) sequencing; sporadic ADHD