ADHDgene Database

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Large-scale studies

Data Summary

Published Variant
- SNP: 1391
- CNV: 398
- Others: 173
Published Gene: 359
Published Region: 128
Pathway by PBA: 8
Study: 361

Study Report

Basic Info

Reference	Arcos-Burgos M, 201020157310
Citation	Arcos-Burgos M., Jain M., Acosta M. T., Shively S., Stanescu H., Wallis D., Domene S., Velez J. I., Karkera J. D., Balog J., Berg K., Kleta R., Gahl W. A., Roessler E., Long R., Lie J., Pineda D., Londono 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 B. S., 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. and Muenke M. (2010) "A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication." Mol Psychiatry, 15(11): 1053-66.
Study Design	pedigree and case-control
Study Type	Linkage study and Candidate-gene association study
Sample Size	18 extended families with 433 individuals, and 137 nuclear families with 527 individuals
Predominant Ethnicity	Caucasian
Population	Paisa, USA, Germany, Norway, Spain

Detail Info

Summary	They used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. 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.
Total Sample	used 18 extended Paisa families with 433 individuals, and 137 nuclear Paisa families with 527 individuals for linkage study; samples used for replication were ascertained from disparate regions of the world, namely from the United States (two independent samples, US1 and US2), Germany, Norway and Spain. A total of 1410 families with 6360 individuals were evaluated.
Replication Size	1255 families with 5400 individuals
Sample Collection	the Paisa population in Antioquia, Colombia for linkage study, samples from the United States, Germany, Norway and Spain for replication
Diagnosis Description	Structured diagnostic interview -Vanderbilt, -SWAN, and -DICA-IV-P; Structured diagnostic interview I, II, WURS, CAARS, K-SADS-PL, CBCL; Structured diagnostic interview. ASRS, WURS; Structured diagnostic interview (K-SADS-PL)- Conners' Parent and Teacher Rating Scale: (CPRS-R: L, CTRS-R:L)
Technique	The Illumina genotyping service was used for genotyping, except for the sample from Norway that was genotyped using Sequenom's MassARRAY iPLEX System; also sequenced using Surveyor
Analysis Method	family-based association tests were applied by comparing allele frequencies for transmitted and untransmitted alleles using PLINK; linkage disequilibrium via cladistic analysis; haplotypes test for association; family-based odds ratios from the TDT tests were combined with the case-control odds ratio using a meta-analytical approach; the random-effects method was used when significant heterogeneity was present and the fixed-effects method otherwise.
Result Description	The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3); the region of association is located on chromosome 4 at 62.4-62.7Mb within the LPHN3 gene encompassing exons 4 through 19; three markers passed a test of heterogeneity and were significant after adjusting for multiple tests; identified two SNPs (in the haplotype block associated with ADHD and are located at splice sites) of potential significance for the expression profile of LPHN3.

SNPs reported by this study (count: 5)

SNP	Allele Change	Risk Allele	Statistical Values	Author Comments	Result of Statistical Analysis
rs2345039	C:G		fixed-effects meta-analysis P-value= 8.97E-04, OR=1.21	reaching significance at the meta-analysis after 10 000 perm...... reaching significance at the meta-analysis after 10 000 permutations More...	Significant
rs2305339	A >G		mutation, no P-value	in the haplotype block associated with ADHD and located at ...... in the haplotype block associated with ADHD and located at splice sites, potential significance for the expression profile of LPHN3 More...	Trend
rs1947274	C:A		fixed-effects meta-analysis P-value= 5.41E-04, OR=1.23	reaching significance at the meta-analysis after 10 000 perm...... reaching significance at the meta-analysis after 10 000 permutations More...	Significant
rs1397548	G>A		mutation, no p-value	in the haplotype block associated with ADHD and located at ...... in the haplotype block associated with ADHD and located at splice sites, potential significance for the expression profile of LPHN3 More...	Trend
rs6551665	G:A		fixed-effects meta-analysis P-value=3.46E-04, OR=1.23	reaching significance at the meta-analysis after 10 000 perm...... reaching significance at the meta-analysis after 10 000 permutations More...	Significant

Genes reported by this study (count: 1)

Regions reported by this study (count: 1)