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

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. Lie, D. Pineda, A. C. Londõo, J. D. Palacio, A. Arbelaez & 31 others F. Lopera, J. Elia, H. Hakonarson, S. Johansson, P. M. Knappskog, J. Haavik, M. Ribases, B. Cormand, M. Bayes, M. Casas, J. A. Ramos-Quiroga, A. Hervas, Brion Maher, S. V. Faraone, C. Seitz, C. M. Freitag, H. Palmason, J. Meyer, M. Romanos, S. Walitza, U. Hemminger, A. Warnke, J. Romanos, T. Renner, C. Jacob, K. P. Lesch, J. Swanson, A. Vortmeyer, J. E. Bailey-Wilson, F. X. Castellanos, M. Muenke

Research output: Contribution to journalArticle

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 n6360, 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.

Original languageEnglish (US)
Pages (from-to)1053-1066
Number of pages14
JournalMolecular Psychiatry
Volume15
Issue number11
DOIs
StatePublished - Nov 2010
Externally publishedYes

Fingerprint

Attention Deficit Disorder with Hyperactivity
Genes
Neurobiology
alpha-latrotoxin receptor
Neuroimaging
Population
Genome
Brain

Keywords

  • ADHD
  • complex trait
  • gene
  • genetics
  • latrophilin
  • LPHN3

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

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), 1053-1066. https://doi.org/10.1038/mp.2010.6

A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. / Arcos-Burgos, M.; Jain, M.; Acosta, M. T.; Shively, S.; Stanescu, H.; Wallis, D.; Domené, S.; Vélez, J. I.; Karkera, J. D.; Balog, J.; Berg, K.; Kleta, R.; Gahl, W. A.; Roessler, E.; Long, R.; Lie, J.; Pineda, D.; Londõo, A. C.; Palacio, J. D.; Arbelaez, A.; Lopera, F.; Elia, J.; Hakonarson, H.; Johansson, S.; Knappskog, P. M.; Haavik, J.; Ribases, M.; Cormand, B.; Bayes, M.; Casas, M.; Ramos-Quiroga, J. A.; Hervas, A.; Maher, Brion; Faraone, S. V.; Seitz, C.; Freitag, C. M.; Palmason, H.; Meyer, J.; Romanos, M.; Walitza, S.; Hemminger, U.; Warnke, A.; Romanos, J.; Renner, T.; Jacob, C.; Lesch, K. P.; Swanson, J.; Vortmeyer, A.; Bailey-Wilson, J. E.; Castellanos, F. X.; Muenke, M.

In: Molecular Psychiatry, Vol. 15, No. 11, 11.2010, p. 1053-1066.

Research output: Contribution to journalArticle

Arcos-Burgos, M, Jain, M, Acosta, MT, Shively, S, Stanescu, H, Wallis, D, Domené, S, Vélez, JI, Karkera, JD, Balog, J, Berg, K, Kleta, R, Gahl, WA, Roessler, E, Long, R, Lie, J, Pineda, D, Londõo, AC, Palacio, JD, Arbelaez, A, Lopera, F, Elia, J, Hakonarson, H, Johansson, S, Knappskog, PM, Haavik, J, Ribases, M, Cormand, B, Bayes, M, Casas, M, Ramos-Quiroga, JA, Hervas, A, Maher, B, Faraone, SV, Seitz, C, Freitag, CM, Palmason, H, Meyer, J, Romanos, M, Walitza, S, Hemminger, U, Warnke, A, Romanos, J, Renner, T, Jacob, C, Lesch, KP, Swanson, J, Vortmeyer, A, Bailey-Wilson, JE, Castellanos, FX & Muenke, M 2010, '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, pp. 1053-1066. https://doi.org/10.1038/mp.2010.6
Arcos-Burgos, M. ; Jain, M. ; Acosta, M. T. ; Shively, S. ; Stanescu, H. ; Wallis, D. ; Domené, S. ; Vélez, J. I. ; Karkera, J. D. ; Balog, J. ; Berg, K. ; Kleta, R. ; Gahl, W. A. ; Roessler, E. ; Long, R. ; Lie, J. ; Pineda, D. ; Londõo, A. C. ; Palacio, J. D. ; Arbelaez, A. ; Lopera, F. ; Elia, J. ; Hakonarson, H. ; Johansson, S. ; Knappskog, P. M. ; Haavik, J. ; Ribases, M. ; Cormand, B. ; Bayes, M. ; Casas, M. ; Ramos-Quiroga, J. A. ; Hervas, A. ; Maher, Brion ; Faraone, S. V. ; Seitz, C. ; Freitag, C. M. ; Palmason, H. ; Meyer, J. ; Romanos, M. ; Walitza, S. ; Hemminger, U. ; Warnke, A. ; Romanos, J. ; Renner, T. ; Jacob, C. ; Lesch, K. P. ; Swanson, J. ; Vortmeyer, A. ; Bailey-Wilson, J. E. ; Castellanos, F. X. ; Muenke, M. / A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. In: Molecular Psychiatry. 2010 ; Vol. 15, No. 11. pp. 1053-1066.
@article{c03e869b432b4e09be3991c594d2d0a5,
title = "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 n6360, 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.",
keywords = "ADHD, complex trait, gene, genetics, latrophilin, LPHN3",
author = "M. Arcos-Burgos and M. Jain and Acosta, {M. T.} and S. Shively and H. Stanescu and D. Wallis and S. Domen{\'e} and V{\'e}lez, {J. I.} and Karkera, {J. D.} and J. Balog and K. Berg and R. Kleta and Gahl, {W. A.} and E. Roessler and R. Long and J. Lie and D. Pineda and Lond{\~o}o, {A. C.} and Palacio, {J. D.} and A. Arbelaez and F. Lopera and J. Elia and H. Hakonarson and S. Johansson and Knappskog, {P. M.} and J. Haavik and M. Ribases and B. Cormand and M. Bayes and M. Casas and Ramos-Quiroga, {J. A.} and A. Hervas and Brion Maher and Faraone, {S. V.} and C. Seitz and Freitag, {C. M.} and H. Palmason and J. Meyer and M. Romanos and S. Walitza and U. Hemminger and A. Warnke and J. Romanos and T. Renner and C. Jacob and Lesch, {K. P.} and J. Swanson and A. Vortmeyer and Bailey-Wilson, {J. E.} and Castellanos, {F. X.} and M. Muenke",
year = "2010",
month = "11",
doi = "10.1038/mp.2010.6",
language = "English (US)",
volume = "15",
pages = "1053--1066",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "11",

}

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 - Londõo, 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, Brion

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.

PY - 2010/11

Y1 - 2010/11

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 n6360, 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.

AB - 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 n6360, 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.

KW - ADHD

KW - complex trait

KW - gene

KW - genetics

KW - latrophilin

KW - LPHN3

UR - http://www.scopus.com/inward/record.url?scp=77954902187&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954902187&partnerID=8YFLogxK

U2 - 10.1038/mp.2010.6

DO - 10.1038/mp.2010.6

M3 - Article

VL - 15

SP - 1053

EP - 1066

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 11

ER -