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.
| Original language | English (US) |
|---|---|
| Journal | American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics |
| DOIs | |
| State | Accepted/In press - 2017 |
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Keywords
- Attention deficit hyperactivity disorder (ADHD)
- Autism spectrum disorder (ASD)
- Exome sequencing
- Intellectual disability (ID)
- Molecular inversion probe (MIP) sequencing
- Sporadic ADHD
ASJC Scopus subject areas
- Genetics(clinical)
- Cellular and Molecular Neuroscience
- Psychiatry and Mental health
Cite this
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. / Kim, Daniel Seung; Burt, Amber A.; Ranchalis, Jane E.; Wilmot, Beth; Smith, Joshua D.; Patterson, Karynne E.; Coe, Bradley P.; Li, Yatong K.; Bamshad, Michael J.; Nikolas, Molly; Eichler, Evan E.; Swanson, James M.; Nigg, Joel; Nickerson, Deborah A.; Jarvik, Gail P.
In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, 2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Kim, Daniel Seung
AU - Burt, Amber A.
AU - Ranchalis, Jane E.
AU - Wilmot, Beth
AU - Smith, Joshua D.
AU - Patterson, Karynne E.
AU - Coe, Bradley P.
AU - Li, Yatong K.
AU - Bamshad, Michael J.
AU - Nikolas, Molly
AU - Eichler, Evan E.
AU - Swanson, James M.
AU - Nigg, Joel
AU - Nickerson, Deborah A.
AU - Jarvik, Gail P.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Attention deficit hyperactivity disorder (ADHD)
KW - Autism spectrum disorder (ASD)
KW - Exome sequencing
KW - Intellectual disability (ID)
KW - Molecular inversion probe (MIP) sequencing
KW - Sporadic ADHD
UR - http://www.scopus.com/inward/record.url?scp=85016069857&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016069857&partnerID=8YFLogxK
U2 - 10.1002/ajmg.b.32527
DO - 10.1002/ajmg.b.32527
M3 - Article
C2 - 28332277
AN - SCOPUS:85016069857
JO - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
JF - American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
SN - 1552-4841
ER -