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Cited by 83Attention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on BehaviorAutism Spectrum Disorder Research

Common and specific genes and peripheral biomarkers in children and adults with attention-deficit/hyperactivity disorder

Open access
Bonvicini, Cristian, Faraone, Stephen V., Scassellati, Catia·2018·The World Journal of Biological Psychiatry
DOI 10.1080/15622975.2017.1282175PMC PMC5568996
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Abstract

OBJECTIVES: Elucidating the biological mechanisms involved in attention-deficit/hyperactivity disorder (ADHD) has been challenging. Relatively unexplored is the fact that these mechanisms can differ with age. METHODS: We present an overview on the major differences between children and adults with ADHD, describing several studies from genomics to metabolomics performed in ADHD children and in adults (cADHD and aADHD, respectively). A systematic search (up until February 2016) was conducted. RESULTS: From a PRISMA flow-chart, a total of 350 and 91 genomics and metabolomics studies were found to be elligible for cADHD and aADHD, respectively. For children, associations were found for genes belonging to dopaminergic (SLC6A3, DRD4 and MAOA) and neurodevelopmental (LPHN3 and DIRAS2) systems and OPRM1 (Yates corrected P = 0.016; OR = 2.27 95%CI: 1.15-4.47). Studies of adults have implicated circadian rhythms genes, HTR2A, MAOB and a more generic neurodevelopmental/neurite outgrowth network (BCHE, SNAP25, BAIAP2, NOS1/NO, KCNIP4 and SPOCK3; Yates corrected P = 0.007; OR = 3.30 95%CI: 1.33-8.29). In common among cADHD and aADHD, the most significant findings are for oxidative stress proteins (MAD, SOD, PON1, ARES, TOS, TAS and OSI), and, in the second level, DISC1, DBH, DDC, microRNA and adiponectin. CONCLUSIONS: Through a convergent functional genomics, this review contributes to clarification of which genetic/biological mechanisms differ with age. The effects of some genes do not change throughout the lifetime, whereas others are linked to age-specific stages. Additional research and further studies are needed to generate firmer conclusions that might someday be useful for predicting the remission and persistence of the disorder. Despite the limitations, some of these genes/proteins could be potential useful biomarkers to discriminate cADHD from aADHD.

AI snapshot

Written from the paper’s full text.

TL;DR

This review uses convergent functional genomics to compare genetic and peripheral biomarker findings between children and adults with ADHD. It reports age-specific gene/protein sets and a smaller common set, suggesting partly differential etiological pathways across the lifespan.

Key findings

  • In children with ADHD (cADHD), specific associations were reported for dopaminergic and neurodevelopmental genes: SLC6A3, DRD4, MAOA, LPHN3, DIRAS2, and OPRM1 (Yates Corrected p=0.016; OR=2.27, 95%CI:1.15–4.47).
  • In adults with ADHD (aADHD), specific associations were reported for circadian rhythm genes, HTR2A, MAOB, and a neurodevelopmental/neurite outgrowth network including BCHE, SNAP25, BAIAP2, NOS1/NO, KCNIP4, and SPOCK3 (Yates Corrected p=0.007; OR=3.30, 95%CI:1.33–8.29).
  • Findings common to cADHD and aADHD were most significant for oxidative stress proteins (MAD, SOD, PON1, ARES, TOS, TAS, OSI), followed at a second level by DISC1, DBH, DDC, microRNA, and adiponectin.
  • The PRISMA flow-chart identified 350 eligible genomics and metabolomics studies for cADHD and 91 for aADHD; one aADHD pilot combining SLC6A3, DRD5, TPH1, and SNAP25 expression reported sensitivity and specificity over 80%.

Methods

  • Design: review/overview of genomics (linkage, candidate gene association, SNP/CNV GWAS, expression) and metabolomics studies in children and adults with ADHD.
  • Data: systematic search up until February 2016; eligibility yielded 350 studies for cADHD and 91 for aADHD.
  • Analysis: convergent functional genomics with summary of positive/negative findings and statistical results for common and specific pathways, reported in Tables S1 and S2; detailed search strategy, inclusion/exclusion criteria, and statistical analyses are in supplementary material.

Limitations

  • The paper states that meta-analyses were divided into single studies to give the same weight to different findings; that more genes were associated with aADHD because SNP/CNV GWAS studies available for a gene mostly showed negative results in children; and that several genes/proteins require replication (OPRM1, adiponectin, KCNIP4, SPOCK3, microRNA, DIRAS2, DISC1, ZNF804A, ASTN2, GPC5/6, kynurenine pathway, CTNNA2, MAP1B, ITGAE/ITGA11).
  • The paper also states that all genetic studies in childhood and/or adulthood ADHD so far lack power and have not provided a genome-wide association hit or robust candidate gene, and that future analyses of hyperactive/impulsive symptoms across age ranges could be useful.
  • Evident from the text: this is a review of published studies rather than new primary data, and key methodological details and full statistical tables are relegated to supplementary material not included in the provided text.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1080/15622975.2017.1282175

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 18 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    In aADHD, MAOB, which encodes the enzyme that metabolizes dopamine, was more strongly associated.

    “In aADHD MAOB, which encodes the enzyme that metabolizes dopamine, was more strongly associated.”
    Quote in the paperSubstantial claim
  • Findingcitation

    The oxidative stress system is a major actor involved in both cADHD and aADHD.

    “The involvement of the oxidative stress system as major actor followed by some dopamine metabolism enzymes (DBH, DDC), DISC1, microRNA and adiponectin in cADHD and in aADHD strengthens the hypothesis that dysregulation of oxidative stress mechanisms as well as of dopamine metabolism are implicated in ADHD independently of age.”
    Quote in the paperSubstantial claim
  • Findingown data

    Circadian rhythms genes, MAOB, HTR2A, BCHE, SNAP25, BAIAP2, NOS1, KCNIP4, SPOCK3 are specific for aADHD.

    “whereas circadian rhythms genes, MAOB, HTR2A, BCHE, SNAP25, BAIAP2, NOS1, KCNIP4, SPOCK3 are specific for aADHD (p=0.007; OR=3.30 95%CI:1.33–8.29, Table S2).”
    Quote in the paperSubstantial claim
  • Findingreasoning

    Our results confirm the involvement of this system throughout lifespan.

    “Our results confirm the involvement of this system throught lifespan.”
    Quote in the paperSubstantial claim
  • Findingown data

    The systematic search identified 350 eligible studies from genomics and metabolomics for cADHD and 91 for aADHD.

    “From a PRISMA flow-chart, a total of eligibility 350 studies from genomics and metabolomics were found for cADHD and 91 for aADHD.”
    • Also stated in: § Results · plain
      “As indicated in the PRISMA flow-chart, a total of eligibility was 350 studies from genomics and metabolomics for cADHD and 91 for aADHD (Figure 1).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Findingnone given

    SNPs-CNVs-GWAS studies available for a gene showed mostly negative results for children, and more genes resulted in associations with aADHD.

    “Moreover, as the SNPs-CNVs-GWAS studies available for a gene showed mostly negative results for children, more genes resulted in associations with aADHD”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In common among cADHD and aADHD, the most significant findings are for oxidative stress proteins (MAD, SOD, PON1, ARES, TOS, TAS, OSI), and, in the second level, DISC1, DBH, DDC, microRNA and adiponectin.

    “In common among cADHD and aADHD, the most significant findings are for oxidative stress proteins (MAD, SOD, PON1, ARES, TOS, TAS, OSI), and, in the second level, DISC1, DBH, DDC, microRNA and adiponectin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For cADHD, associations were found for genes belonging to dopaminergic (SLC6A3, DRD4, MAOA) and neurodevelopmental (LPHN3, DIRAS2) systems and OPRM1 (Yates corrected p=0.016; OR=2.27 95%CI 1.15-4.47).

    “For children, associations were found for genes belonging to dopaminergic (SLC6A3, DRD4, MAOA) and neurodevelopmental (LPHN3, DIRAS2) systems and OPRM1 (Yates Corrected p=0.016; OR=2.27 95%CI:1.15–4.47).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Fewer studies were performed for KCNIP4, SPOCK3, and DIRAS2 genes.

    “Fewer studies were performed for KCNIP4, SPOCK3, and DIRAS2 genes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    All genetic studies performed in childhood and/or adulthood ADHD so far are characterized by a lack of power and their results have not provided genome-wide association hit or robust candidate gene.

    “all genetic studies performed in childhood and/or adulthood ADHD so far are characterized by a lack of power and their results have not provided genome-wide association hit or robust candidate gene”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For aADHD, studies implicated circadian rhythms genes, HTR2A, MAOB and a more generic neurodevelopmental/neurite outgrowth network (BCHE, SNAP25, BAIAP2, NOS1/NO, KCNIP4, SPOCK3; Yates corrected p=0.007; OR=3.30 95%CI 1.33-8.29).

    “Studies of adults have implicated circadian rhythms genes, HTR2A, MAOB and a more generic neurodevelopmental/neurite outgrowth network (BCHE, SNAP25, BAIAP2, NOS1/NO, KCNIP4, SPOCK3; Yates Corrected p=0.007; OR= 3.30 95%CI:1.33–8.29).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The 9R allele of the 40bp SLC6A3 VNTR is associated with aADHD, although not significant after Bonferroni correction.

    “One associates, even though not significant after Bonferroni correction, the 9R allele of the 40bp SLC6A3 VNTR with aADHD (Bonvicini, Faraone, Scassellati 2016)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bonvicini, Faraone, Scassellati 2016

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The review found some divergence in findings between cADHD and aADHD, which suggests differential etiological pathways for different age ranges.

    “Consistently with a developmental twin study where different sources of additive genetic variance accounted for the expression of ADHD in childhood and adulthood (Chang et al. 2013), our review found some divergence in findings between cADHD and aADHD, which suggests differential etiological pathways for different age ranges.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Chang et al. 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A systematic search up until February 2016 was conducted.

    “A systematic search (up until February, 2016) was conducted.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both stimulants have been shown to stimulate neurite outgrowth and directly or indirectly regulate the expression and/or function of several genes/proteins implicated in this network.

    “Both stimulants have been shown to stimulate neurite outgrowth and directly or indirectly regulate the expression and/or funtion of several genes/proteins implicated in this network.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poelmans et al. (2011)

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There are some genes whose effects do not differ throughout lifetime, whereas others are linked to age specific stages.

    “There are some genes whose effects do not differ throughout lifetime, whereas others are linked to age specific stages.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: SNAP25 plays an important role in axonal growth, synaptic plasticity and neurotransmitter release, acting in essential steps for wiring the nervous system.
    • Rests on an assumption: NOS1 influences cadherin systems and plays a direct role in neurite outgrowth.

  • May combine two claims.

    Premisecitation

    The DRD4 7R allele is associated with cortical thickness trajectories in early development, but this association was no longer found around 16-18 years of age.

    “Moreover, the DRD4 7R allele is associated with cortical thickness trajectories in early development but this association was no longer found around 16–18 years of age (Shaw et al. 2007; Shaw et al. 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Shaw et al. 2007

      Not checked in the free run.

    • cites Shaw et al. 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A hypothetical signature of genetic and biochemical markers that might someday be useful for diagnosing ADHD in childhood includes SLC6A3, DRD4 and MAOA.

    “This signature includes SLC6A3, DRD4 and MAOA, which is consistent with our conclusions.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Faraone, Bonvicini, Scassellati 2014

      Not checked in the free run.

    • cites Scassellati and Bonvicini 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To give the same weight to the different findings (single study and meta-analysis), each meta-analysis available for a certain gene or protein was divided into single studies.

    “to give the same weight to the different findings (single study and meta-analysis), we divided each meta-analysis available for a certain gene or protein, into single studies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oxidative stress predisposes to a diverse range of psychiatric conditions, including ADHD.

    “Research suggests that oxidative stress predispones to a diverse range of psychiatric conditions, including ADHD (Joseph et al. 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Joseph et al. 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    These mechanisms could be linked to a potential differential effect in the developing (LPHN3 and DIRA2) and adult (BCHE, SNAP25, BAIAP2, NOS1, KCNIP4, SPOCK3) brain.

    “These mechanisms, which are believed to underpin processes relevant for ADHD such as cognitive performance, attention, learning and memory formation, could be linked to a potential differential effect in the developing (LPHN3 and DIRA2) and adult (BCHE, SNAP25, BAIAP2, NOS1, KCNIP4, SPOCK3) brain.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The neurite outgrowth, synaptic plasticity and neuronal proliferation/differentiation mechanisms underpin processes relevant for ADHD such as cognitive performance, attention, learning and memory formation.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    These specific associations could reflect a certain versatility of these genes throughout the lifespan, first with a less significant role on early brain development and a larger role later in the lifecycle.

    “These specific associations could reflect a certain versatility of these genes throughout the lifespan, first with a less significant role on early brain development and a larger role later in the lifecycle.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Differential effects exist for dopaminergic and neurodevelopmental/neurite outgrowth systems in cADHD (SLC6A3, DRD4, MAOA, LPHN3, DIRAS2) and in aADHD (MAOB, BCHE, SNAP25, BAIAP2, NOS1, KCNIP4, SPOCK3).

    “In summary, these data suggest that specific genetic and biological mechanisms can differ with age and suggest differential effects for dopaminergic and neurodevelopmental/neurite outgrowth systems in cADHD (SLC6A3, DRD4, MAOA, LPHN3, DIRAS2) and in aADHD (MAOB, BCHE, SNAP25, BAIAP2, NOS1, KCNIP4, SPOCK3).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: SNAP25 plays an important role in axonal growth, synaptic plasticity and neurotransmitter release, acting in essential steps for wiring the nervous system.
    • Rests on an assumption: NOS1 influences cadherin systems and plays a direct role in neurite outgrowth.

  • May combine two claims.

    Interpretationreasoning

    The effects of some genes do not change throughout lifetime, whereas others are linked to age specific stages.

    “The effects of some genes do not change throughout lifetime, whereas others are linked to age specific stages.”
    Quote in the paperSubstantial claim
19 of 19

  • The paper relies on this without support.

    The identification of biomarkers may facilitate the differential diagnosis of ADHD.

    “The identification of biomarkers may facilitate the differential diagnosis of ADHD.”

  • The paper relies on this without support.

    Peripheral biomarkers reflect the central biological mechanisms of ADHD.

    “The results of a recent meta-analysis of childhood ADHD studies identified some potential peripheral biomarkers linked to monoaminergic pathways and to the HPA axis (Scassellati et al. 2012).”

  • The paper relies on this without support.

    The neurite outgrowth, synaptic plasticity and neuronal proliferation/differentiation mechanisms underpin processes relevant for ADHD such as cognitive performance, attention, learning and memory formation.

    “These mechanisms, which are believed to underpin processes relevant for ADHD such as cognitive performance, attention, learning and memory formation”

  • The paper relies on this without support.

    SNAP25 plays an important role in axonal growth, synaptic plasticity and neurotransmitter release, acting in essential steps for wiring the nervous system.

    “SNAP25 plays an important role in axonal growth, synaptic plasticity and neurotransmitter release, acting in essential steps for wiring the nervous system.”

  • The paper relies on this without support.

    NOS1 influences cadherin systems and plays a direct role in neurite outgrowth.

    “NOS1 influences cadherin systems and plays a direct role in neurite outgrowth.”

  • The paper relies on this without support.

    DISC1 is implicated in neuronal migration, neurite outgrowth and axon targeting during brain development.

    “More findings should be carried out on DISC1, a gene implicated in neuronal migration, neurite outgrowth and axon targeting during brain development.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Familial history has been found to be the most significant risk factor for the emergence and persistence of ADHD.

    “As reviewed above, familial history has been found to be the most significant risk factor for the emergence and persistence of ADHD (Chang et al., 2013; Bonvicini et al., 2018; Uchida et al., 2018).”

    From A Review of Heterogeneity in Attention Deficit/Hyperactivity Disorder (ADHD) (2019) · cites this paper as Bonvicini et al., 2018

    The Introduction (page unavailable) discusses substantial ADHD heritability and reports that 65% of affected children continue to have symptoms into adulthood. It does not identify family history as a risk factor for persistence or rank it as the most significant risk factor for ADHD’s emergence. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

  • While child and adult aggression are genetically similar, some genetic factors underlying ADHD in children and later life may be different.

    “suggesting that while child and adult aggression are genetically similar, it is conceivable that some genetic factors underlying ADHD in children and later life may be different [32]”

    From Genetics of child aggression, a systematic review (2024) · cites this paper as [32]

    The Discussion (page not provided) reports different genetic findings for childhood and adult ADHD and suggests that their etiological pathways may differ. It does not address whether child and adult aggression are genetically similar, so that part of the cited sentence is unsupported by this source. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • BCHE is called adult-specific despite a childhood association

    Major

    The paper describes BCHE as the stronger association among genes affected by a deletion in childhood ADHD, but subsequently calls BCHE specific to adult ADHD.

1 of 1

The citation lists haven’t been fetched yet

References 116 · Cited by 83

Research works printed but not linked: 4

  1. Corominas-Roso M, 2013, Int J Neuropsychopharmacol, 30, 1
  2. Drtilkova I, 2008, Neuro Endocrinol Lett, 29, 320
  3. Gao Q, 2014, Shanghai Arch Psychiatry, 26, 194
  4. Kayyal M, 2015, Pak J Med Sci, 31, 1162

Authors
Bonvicini, C., Faraone, S. V., & Scassellati, C.
Affiliations
  • Centro San Giovanni di Dio Fatebenefratelli (IT)
  • SUNY Upstate Medical University (US)
Corresponding author
Scassellati, Catia
ORCID
Venue
The World Journal of Biological Psychiatry
Publisher
Informa UK Limited
Published
2017-02-24
Volume
19
Issue
2
Pages
80-100
ISSN
  • 1562-2975 (ISSN-L)
  • 1814-1412
DOI
10.1080/15622975.2017.1282175
PMC
PMC5568996
OpenAlex
W2574544988
Semantic Scholar
e1e231d2bdbb5f9e9c2e1dd0fabd0ed60283e23c
Cited by
83
References
116
Citations by year
2026: 2 · 2025: 7 · 2024: 11 · 2023: 11 · 2022: 10 · 2021: 13 · 2020: 12 · 2019: 7 · 2018: 5 · 2017: 5
FWCI
1.20
Type
journal article
Language
en
Open access
Locations
  • The World Journal of Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Figshare (submittedVersion, cc-by)
  • Figshare (cc-by)
Funders
  • Italian Ministry of Health
  • K.G. Jebsen Centre for Research on Neuropsychiatric Disorders
  • European Union’s Seventh Framework Programme for research (602805)
  • NIMH (R01MH094469)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
attention deficit hyperactivity disorder, childhood ADHD, adult ADHD, genetic biomarkers, peripheral biomarkers, dopaminergic genes, dopamine transporter, DRD4, monoamine oxidase A, LPHN3, OPRM1, circadian rhythm genes, HTR2A, monoamine oxidase B, neurodevelopmental genes, oxidative stress, microRNA, adiponectin, metabolomics, functional genomics
MeSH terms
Adult, Attention Deficit Disorder with Hyperactivity, Child, Humans, Biomarkers, Genomics, Metabolomics

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