Journal article
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
American journal of medical genetics. Part B, Neuropsychiatric genetics, Vol.174(4), pp.381-389
06/2017
DOI: 10.1002/ajmg.b.32527
PMCID: PMC5467442
PMID: 28332277
Abstract
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.
Details
- Title: Subtitle
- 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
- Creators
- Daniel Seung Kim - Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MichiganAmber A Burt - Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WashingtonJane E Ranchalis - Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WashingtonBeth Wilmot - Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OregonJoshua D Smith - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WashingtonKarynne E Patterson - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WashingtonBradley P Coe - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WashingtonYatong K Li - Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MichiganMichael J Bamshad - Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WashingtonMolly Nikolas - Department of Psychology, University of Iowa, Iowa City, IowaEvan E Eichler - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WashingtonJames M Swanson - Department of Epidemiology, University of California-Irvine, Irvine, CaliforniaJoel T Nigg - Department of Psychiatry, Oregon Health and Science University, Portland, OregonDeborah A Nickerson - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WashingtonGail P Jarvik - Department of Genome Sciences, University of Washington School of Medicine, Seattle, WashingtonUniversity of Washington Center for Mendelian Genomics
- Resource Type
- Journal article
- Publication Details
- American journal of medical genetics. Part B, Neuropsychiatric genetics, Vol.174(4), pp.381-389
- DOI
- 10.1002/ajmg.b.32527
- PMID
- 28332277
- PMCID
- PMC5467442
- NLM abbreviation
- Am J Med Genet B Neuropsychiatr Genet
- ISSN
- 1552-4841
- eISSN
- 1552-485X
- Grant note
- T32 HL007312 / NHLBI NIH HHS U54 HG006493 / NHGRI NIH HHS U01 HG008657 / NHGRI NIH HHS UM1 HG006493 / NHGRI NIH HHS F31 MH101905 / NIMH NIH HHS RC2 HG005608 / NHGRI NIH HHS R01 MH099064 / NIMH NIH HHS R01 MH101221 / NIMH NIH HHS T32 HG000040 / NHGRI NIH HHS
- Language
- English
- Date published
- 06/2017
- Academic Unit
- Psychological and Brain Sciences; Injury Prevention Research Center
- Record Identifier
- 9984214751202771
Metrics
19 Record Views