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

Molecular Psychiatry volume 15, pages 1053–1066 (2010)Cite this article

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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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Acknowledgements

We are grateful to the families who participated in this research. This research was supported by the Division of Intramural Research, NHGRI, NIH and in part by COLCIENCIAS, Grants 1115-04-12010, 11150418083, and by the Deutsche Forschungsgemeinschaft (KFO 125/1-1, SFB 581). This study used the high-performance computational capabilities of the SGI Origin 2000 system at the Center for Information Technology, National Institutes of Health, Bethesda, MD and the services of the NHGRI Genomics Core under the supervision of Marypat S Jones and Chandra Settara. Darryl Leja provided graphical assistance to the figures. N Steigerwald provided technical assistance in the DNA German sample processing. Mahim Jain, Sharon B Shively and Sabina Domené are doctoral students in the NIH Graduate Partnerships Program, at Oxford University, George Washington University and the University of Buenos Aires, respectively. Some of this work is to be presented to the above programs in partial fulfillment of the requirements for the PhD degree. Authors from Spain are grateful to Anna Bielsa, Xavier Gastaminza, Rosa Bosch, Monica Fernandez Anguiano and Sílvia Rodríguez-Ben for their participation in the clinical assessment and to Cristina Sánchez-Mora for laboratory assistance. MR is a recipient of a Miguel de Servet contract from the ‘Ministerio de Sanidad y Política Social’, Spain. Financial support was received from ‘Instituto de Salud Carlos III-FIS’ (PI041267, PI042010, PI040524, PI080519) and ‘Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR’ (2009GR971). SNP genotyping of the Spanish samples was performed at the Barcelona node of the ‘Centro Nacional de Genotipado’ (CEGEN; www.cegen.org).

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Authors and Affiliations

  1. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    M Arcos-Burgos, M Jain, M T Acosta, S Shively, H Stanescu, D Wallis, S Domené, J I Vélez, J D Karkera, J Balog, K Berg, R Kleta, W A Gahl, E Roessler, R Long, J E Bailey-Wilson & M Muenke

  2. National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    S Shively, J Lie & A Vortmeyer

  3. Neurosciences Group, University of Antioquia, Medellín, Colombia

    D Pineda, A C Londoño, J D Palacio, A Arbelaez & F Lopera

  4. The Children's Hospital of Philadelphia, Philadelphia, PA, USA

    J Elia & H Hakonarson

  5. Department of Biomedicine, Section of Biochemistry and Molecular Biology, University of Bergen, Bergen, Norway

    S Johansson, P M Knappskog & J Haavik

  6. Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Catalonia, Spain

    M Ribases, M Casas & J A Ramos-Quiroga

  7. Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, CIBER-ER, IBUB, Barcelona, Catalonia, Spain

    B Cormand

  8. Genes and Disease Program, Center for Genomic Regulation (CRG), CIBER-ESP, Centro Nacional de Genotipado (CeGen), Barcelona, Catalonia, Spain

    M Bayes

  9. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Catalonia, Spain

    M Casas & J A Ramos-Quiroga

  10. Child and Adolescent Mental Health Unit, Hospital Mútua de Terrassa, Barcelona, Catalonia, Spain

    A Hervas

  11. Departments of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    B S Maher

  12. Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA

    S V Faraone

  13. Department of Child and Adolescent Psychiatry, Saarland University Hospital, Homburg, Saar, Germany

    C Seitz & C M Freitag

  14. Division of Neuro-Behavioral Genetics, Graduate School for Psychobiology, University of Trier, Trier, Germany

    H Palmason & J Meyer

  15. Department of Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany

    M Romanos, S Walitza, U Hemminger, A Warnke, T Renner & K-P Lesch

  16. Department of Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany

    J Romanos, T Renner, C Jacob & K-P Lesch

  17. Department of Molecular and Psychobiology, University of Würzburg, Würzburg, Germany

    T Renner & K-P Lesch

  18. UCI Child Development Center, University of California, Irvine, CA, USA

    J Swanson

  19. New York University Child Study Center, New York, NY, USA

    F X Castellanos

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Correspondence to M Muenke.

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None of the authors at the National Institutes of Health has any conflict of interest. Authors from other institutions contributed samples for replication studies only.

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Arcos-Burgos, M., Jain, M., Acosta, M. et al. A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol Psychiatry 15, 1053–1066 (2010). https://doi.org/10.1038/mp.2010.6

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