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A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD.

Abstract

In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.

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  • Authors+Show Affiliations

    ,

    Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

    , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

    Source

    Molecular psychiatry 17:7 2012 Jul pg 741-7

    MeSH

    Aspartic Acid
    Attention Deficit Disorder with Hyperactivity
    Brain
    Case-Control Studies
    Choline
    Chromosomes, Human, Pair 11
    Genetic Linkage
    Genetic Predisposition to Disease
    Glutamine
    Humans
    Inositol
    Magnetic Resonance Spectroscopy
    Methylphenidate
    Polymorphism, Single Nucleotide
    Protons
    Receptors, G-Protein-Coupled
    Receptors, Peptide

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Intramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21606926

    Citation

    Jain, M, et al. "A Cooperative Interaction Between LPHN3 and 11q Doubles the Risk for ADHD." Molecular Psychiatry, vol. 17, no. 7, 2012, pp. 741-7.
    Jain M, Vélez JI, Acosta MT, et al. A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. Mol Psychiatry. 2012;17(7):741-7.
    Jain, M., Vélez, J. I., Acosta, M. T., Palacio, L. G., Balog, J., Roessler, E., ... Muenke, M. (2012). A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. Molecular Psychiatry, 17(7), pp. 741-7. doi:10.1038/mp.2011.59.
    Jain M, et al. A Cooperative Interaction Between LPHN3 and 11q Doubles the Risk for ADHD. Mol Psychiatry. 2012;17(7):741-7. PubMed PMID: 21606926.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD. AU - Jain,M, AU - Vélez,J I, AU - Acosta,M T, AU - Palacio,L G, AU - Balog,J, AU - Roessler,E, AU - Pineda,D, AU - Londoño,A C, AU - Palacio,J D, AU - Arbelaez,A, AU - Lopera,F, AU - Elia,J, AU - Hakonarson,H, AU - Seitz,C, AU - Freitag,C M, AU - Palmason,H, AU - Meyer,J, AU - Romanos,M, AU - Walitza,S, AU - Hemminger,U, AU - Warnke,A, AU - Romanos,J, AU - Renner,T, AU - Jacob,C, AU - Lesch,K-P, AU - Swanson,J, AU - Castellanos,F X, AU - Bailey-Wilson,J E, AU - Arcos-Burgos,M, AU - Muenke,M, Y1 - 2011/05/24/ PY - 2011/5/25/entrez PY - 2011/5/25/pubmed PY - 2012/11/14/medline SP - 741 EP - 7 JF - Molecular psychiatry JO - Mol. Psychiatry VL - 17 IS - 7 N2 - In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome. SN - 1476-5578 UR - https://www.unboundmedicine.com/medline/citation/21606926/A_cooperative_interaction_between_LPHN3_and_11q_doubles_the_risk_for_ADHD_ L2 - http://dx.doi.org/10.1038/mp.2011.59 DB - PRIME DP - Unbound Medicine ER -