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A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication.

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.

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  • Authors+Show Affiliations

    ,

    National Human Genome Research Institute, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA.

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

    Source

    Molecular psychiatry 15:11 2010 Nov pg 1053-66

    MeSH

    Adolescent
    Adult
    Attention Deficit Disorder with Hyperactivity
    Brain
    Cell Survival
    Central Nervous System Stimulants
    Child
    Child, Preschool
    Chromosome Mapping
    Female
    Genetic Linkage
    Genetic Predisposition to Disease
    Genotype
    Humans
    Magnetic Resonance Spectroscopy
    Male
    Polymorphism, Genetic
    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

    20157310

    Citation

    Arcos-Burgos, M, et al. "A Common Variant of the Latrophilin 3 Gene, LPHN3, Confers Susceptibility to ADHD and Predicts Effectiveness of Stimulant Medication." Molecular Psychiatry, vol. 15, no. 11, 2010, pp. 1053-66.
    Arcos-Burgos M, Jain M, Acosta MT, et al. A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol Psychiatry. 2010;15(11):1053-66.
    Arcos-Burgos, M., Jain, M., Acosta, M. T., Shively, S., Stanescu, H., Wallis, D., ... Muenke, M. (2010). A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Molecular Psychiatry, 15(11), pp. 1053-66. doi:10.1038/mp.2010.6.
    Arcos-Burgos M, et al. A Common Variant of the Latrophilin 3 Gene, LPHN3, Confers Susceptibility to ADHD and Predicts Effectiveness of Stimulant Medication. Mol Psychiatry. 2010;15(11):1053-66. PubMed PMID: 20157310.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. AU - Arcos-Burgos,M, AU - Jain,M, AU - Acosta,M T, AU - Shively,S, AU - Stanescu,H, AU - Wallis,D, AU - Domené,S, AU - Vélez,J I, AU - Karkera,J D, AU - Balog,J, AU - Berg,K, AU - Kleta,R, AU - Gahl,W A, AU - Roessler,E, AU - Long,R, AU - Lie,J, AU - Pineda,D, AU - Londoño,A C, AU - Palacio,J D, AU - Arbelaez,A, AU - Lopera,F, AU - Elia,J, AU - Hakonarson,H, AU - Johansson,S, AU - Knappskog,P M, AU - Haavik,J, AU - Ribases,M, AU - Cormand,B, AU - Bayes,M, AU - Casas,M, AU - Ramos-Quiroga,J A, AU - Hervas,A, AU - Maher,B S, AU - Faraone,S V, 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 - Vortmeyer,A, AU - Bailey-Wilson,J E, AU - Castellanos,F X, AU - Muenke,M, Y1 - 2010/02/16/ PY - 2010/2/17/entrez PY - 2010/2/17/pubmed PY - 2011/3/2/medline SP - 1053 EP - 66 JF - Molecular psychiatry JO - Mol. Psychiatry VL - 15 IS - 11 N2 - Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD. SN - 1476-5578 UR - https://www.unboundmedicine.com/medline/citation/20157310/A_common_variant_of_the_latrophilin_3_gene_LPHN3_confers_susceptibility_to_ADHD_and_predicts_effectiveness_of_stimulant_medication_ L2 - http://dx.doi.org/10.1038/mp.2010.6 DB - PRIME DP - Unbound Medicine ER -