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

被引：220

作者：

Arcos-Burgos, M. ^{[1
]}

Jain, M. ^{[1
]}

Acosta, M. T. ^{[1
]}

Shively, S. ^{[1
,2
]}

Stanescu, H. ^{[1
]}

Wallis, D. ^{[1
]}

Domene, S. ^{[1
]}

Velez, J. I. ^{[1
]}

Karkera, J. D. ^{[1
]}

Balog, J. ^{[1
]}

Berg, K. ^{[1
]}

Kleta, R. ^{[1
]}

Gahl, W. A. ^{[1
]}

Roessler, E. ^{[1
]}

Long, R. ^{[1
]}

Lie, J. ^{[2
]}

Pineda, D. ^{[3
]}

Londono, A. C. ^{[3
]}

Palacio, J. D. ^{[3
]}

Arbelaez, A. ^{[3
]}

Lopera, F. ^{[3
]}

Elia, J. ^{[4
]}

Hakonarson, H. ^{[4
]}

Johansson, S. ^{[5
]}

Knappskog, P. M. ^{[5
]}

Haavik, J. ^{[5
]}

Ribases, M. ^{[6
]}

Cormand, B. ^{[7
]}

Bayes, M. ^{[8
]}

Casas, M. ^{[6
,9
]}

Ramos-Quiroga, J. A. ^{[6
,9
]}

Hervas, A. ^{[10
]}

Maher, B. S. ^{[11
,12
]}

Faraone, S. V. ^{[13
]}

Seitz, C. ^{[14
]}

Freitag, C. M. ^{[14
]}

Palmason, H. ^{[15
]}

Meyer, J. ^{[15
]}

Romanos, M. ^{[16
]}

Walitza, S. ^{[16
]}

Hemminger, U. ^{[16
]}

Warnke, A. ^{[16
]}

Romanos, J. ^{[17
]}

Renner, T. ^{[16
,17
,18
]}

Jacob, C. ^{[17
]}

Lesch, K-P ^{[16
,17
,18
]}

Swanson, J. ^{[19
]}

Vortmeyer, A. ^{[2
]}

Bailey-Wilson, J. E. ^{[1
]}

Castellanos, F. X. ^{[20
]}

机构：

[1] NHGRI, NIH, Bethesda, MD 20892 USA

[2] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA

[3] Univ Antioquia, Neurosci Grp, Medellin, Colombia

[4] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[5] Univ Bergen, Dept Biomed, Sect Biochem & Mol Biol, Bergen, Norway

[6] Hosp Univ Vall dHebron, Dept Psychiat, Barcelona, Catalonia, Spain

[7] Univ Barcelona, Fac Biol, Dept Genet, CIBER ER,IBUB, Barcelona, Catalonia, Spain

[8] Ctr Nacl Genotipado CeGen, Genes & Dis Program, CRG, CIBER ESP, Barcelona, Catalonia, Spain

[9] Univ Autonoma Barcelona, Dept Psychiat & Legal Med, Catalonia, Spain

[10] Hosp Mutua de Terrassa, Child & Adolescent Mental Hlth Unit, Barcelona, Catalonia, Spain

[11] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA USA

[12] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Human Genet, Richmond, VA USA

[13] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA

[14] Saarland Univ Hosp, Dept Child & Adolescent Psychiat, Homburg, Saar, Germany

[15] Univ Trier, Grad Sch Psychobiol, Div Neurobehav Genet, Trier, Germany

[16] Univ Wurzburg, Dept Child & Adolescent Psychiat & Psychotherapy, Wurzburg, Germany

[17] Univ Wurzburg, Dept Psychiat & Psychotherapy, Wurzburg, Germany

[18] Univ Wurzburg, Dept Mol & Psychobiol, Wurzburg, Germany

[19] Univ Calif Irvine, UCI Child Dev Ctr, Irvine, CA USA

[20] NYU, Ctr Child Study, New York, NY USA

来源：

MOLECULAR PSYCHIATRY | 2010年 / 15卷 / 11期

关键词：

ADHD; complex trait; gene; LPHN3; genetics; latrophilin; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; GENOME-WIDE ASSOCIATION; ALPHA-LATROTOXIN RECEPTOR; LINKAGE DISEQUILIBRIUM; CHILDREN; RISK; POLYMORPHISM; METAANALYSIS; STATISTICS;

D O I：

10.1038/mp.2010.6

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. Molecular Psychiatry (2010) 15, 1053-1066; doi:10.1038/mp.2010.6; published online 16 February 2010

引用

页码：1053 / 1066

页数：14

共 59 条

[21] Attention-deficit/hyperactivity disorder and comorbid disruptive behavior disorders:: Evidence of pleiotropy and new susceptibility loci [J].