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Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood.

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric disorder. Despite the high heritability, the unraveling of specific genetic factors related to ADHD is hampered by its considerable genetic complexity. Recent evidence suggests that gene-gene interactions can explain part of this complexity. We examined the impact of strongly supported interaction effects between the LPHN3 gene and the NTAD gene cluster (NCAM1-TTC12-ANKK1-DRD2) in a 7-year follow-up of a clinical sample of adults with ADHD, addressing associations with susceptibility, symptomatology and stability of diagnosis. The sample comprises 548 adults with ADHD and 643 controls. Entropy-based analysis indicated a potential interaction between the LPHN3-rs6551665 and TTC12-rs2303380 SNPs influencing ADHD symptom counts. Further analyses revealed significant interaction effects on ADHD total symptoms (p=0.002), and with hyperactivity/impulsivity symptom counts (p=0.005). In the group composed by predominantly hyperactive/impulsive and combined presentation, the presence of LPHN3-rs6551665 G allele was related to increased ADHD risk only in individuals carrying the TTC12-rs2303380 AA genotype (p=0.026). Also, the same allelic constellation is involved in maintenance of ADHD in a predominantly hyperactive/impulsive or combined presentation after a 7-year follow-up (p=0.008). These observations reinforce and replicate previous evidence suggesting that an interaction effect between the LPHN3 gene and the NTAD cluster may have a role in the genetic substrate associated to ADHD also in adults. Moreover, it is possible that the interactions between LPHN3 and NTAD are specific factors contributing to the development of an ADHD phenotype with increased hyperactivity/impulsivity that is maintained throughout adulthood.

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  • Authors+Show Affiliations

    ,

    Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

    ,

    Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

    ,

    Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

    ,

    Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

    ,

    Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

    ,

    Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

    ,

    ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

    ,

    ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

    ,

    ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

    ,

    ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Department of Psychiatry, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents, Brazil.

    ,

    Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Department of Psychiatry, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: claiton.bau@ufrgs.br.

    ,

    ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Department of Psychiatry, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

    ADHD Outpatient Program - Adult Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

    Source

    MeSH

    Adult
    Attention Deficit Disorder with Hyperactivity
    CD56 Antigen
    Disease Progression
    Female
    Follow-Up Studies
    Genetic Predisposition to Disease
    Humans
    Male
    Multigene Family
    Phenotype
    Polymorphism, Single Nucleotide
    Protein-Serine-Threonine Kinases
    Proteins
    Receptors, Dopamine D2
    Receptors, G-Protein-Coupled
    Receptors, Peptide
    Retrospective Studies

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    28624582

    Citation

    Kappel, Djenifer B., et al. "Further Replication of the Synergistic Interaction Between LPHN3 and the NTAD Gene Cluster On ADHD and Its Clinical Course Throughout Adulthood." Progress in Neuro-psychopharmacology & Biological Psychiatry, vol. 79, no. Pt B, 2017, pp. 120-127.
    Kappel DB, Schuch JB, Rovaris DL, et al. Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood. Prog Neuropsychopharmacol Biol Psychiatry. 2017;79(Pt B):120-127.
    Kappel, D. B., Schuch, J. B., Rovaris, D. L., da Silva, B. S., Cupertino, R. B., Winkler, C., ... Mota, N. R. (2017). Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood. Progress in Neuro-psychopharmacology & Biological Psychiatry, 79(Pt B), pp. 120-127. doi:10.1016/j.pnpbp.2017.06.011.
    Kappel DB, et al. Further Replication of the Synergistic Interaction Between LPHN3 and the NTAD Gene Cluster On ADHD and Its Clinical Course Throughout Adulthood. Prog Neuropsychopharmacol Biol Psychiatry. 2017 10 3;79(Pt B):120-127. PubMed PMID: 28624582.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood. AU - Kappel,Djenifer B, AU - Schuch,Jaqueline B, AU - Rovaris,Diego L, AU - da Silva,Bruna S, AU - Cupertino,Renata B, AU - Winkler,Cristina, AU - Teche,Stefania P, AU - Vitola,Eduardo S, AU - Karam,Rafael G, AU - Rohde,Luis A, AU - Bau,Claiton H D, AU - Grevet,Eugenio H, AU - Mota,Nina R, Y1 - 2017/06/15/ PY - 2017/03/15/received PY - 2017/05/30/revised PY - 2017/06/13/accepted PY - 2017/6/19/pubmed PY - 2018/5/31/medline PY - 2017/6/19/entrez KW - ADHD KW - Adults KW - Gene-gene interaction KW - Hyperactivity KW - LPHN3 KW - NTAD gene cluster SP - 120 EP - 127 JF - Progress in neuro-psychopharmacology & biological psychiatry JO - Prog. Neuropsychopharmacol. Biol. Psychiatry VL - 79 IS - Pt B N2 - Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric disorder. Despite the high heritability, the unraveling of specific genetic factors related to ADHD is hampered by its considerable genetic complexity. Recent evidence suggests that gene-gene interactions can explain part of this complexity. We examined the impact of strongly supported interaction effects between the LPHN3 gene and the NTAD gene cluster (NCAM1-TTC12-ANKK1-DRD2) in a 7-year follow-up of a clinical sample of adults with ADHD, addressing associations with susceptibility, symptomatology and stability of diagnosis. The sample comprises 548 adults with ADHD and 643 controls. Entropy-based analysis indicated a potential interaction between the LPHN3-rs6551665 and TTC12-rs2303380 SNPs influencing ADHD symptom counts. Further analyses revealed significant interaction effects on ADHD total symptoms (p=0.002), and with hyperactivity/impulsivity symptom counts (p=0.005). In the group composed by predominantly hyperactive/impulsive and combined presentation, the presence of LPHN3-rs6551665 G allele was related to increased ADHD risk only in individuals carrying the TTC12-rs2303380 AA genotype (p=0.026). Also, the same allelic constellation is involved in maintenance of ADHD in a predominantly hyperactive/impulsive or combined presentation after a 7-year follow-up (p=0.008). These observations reinforce and replicate previous evidence suggesting that an interaction effect between the LPHN3 gene and the NTAD cluster may have a role in the genetic substrate associated to ADHD also in adults. Moreover, it is possible that the interactions between LPHN3 and NTAD are specific factors contributing to the development of an ADHD phenotype with increased hyperactivity/impulsivity that is maintained throughout adulthood. SN - 1878-4216 UR - https://www.unboundmedicine.com/medline/citation/28624582/Further_replication_of_the_synergistic_interaction_between_LPHN3_and_the_NTAD_gene_cluster_on_ADHD_and_its_clinical_course_throughout_adulthood_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0278-5846(17)30211-7 DB - PRIME DP - Unbound Medicine ER -