TY  - JOUR
A1  - Jain, M.
A1  - Vélez, J. I.
A1  - Acosta, M. T.
A1  - Palacio, L. G.
A1  - Balog, J.
A1  - Roessler, E.
A1  - Pineda, D.
A1  - Londoño, A. C.
A1  - Palacio, J. D.
A1  - Arbelaez, A.
A1  - Lopera, F.
A1  - Elia, J.
A1  - Hakonarson, H.
A1  - Seitz, C.
A1  - Freitag, C. M.
A1  - Palmason, H.
A1  - Meyer, J.
A1  - Romanos, M.
A1  - Walitza, S.
A1  - Hemminger, U.
A1  - Warnke, A.
A1  - Romanos, J.
A1  - Renner, T.
A1  - Jacob, C.
A1  - Lesch, K.-P.
A1  - Swanson, J.
A1  - Castellanos, F. X.
A1  - Bailey-Wilson, J. E.
A1  - Arcos-Burgos, M.
A1  - Muenke, M.
T1  - A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD
JF  - Molecular Psychiatry
N2  - In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10−8) and 11q and 17p (P<1 × 10−6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q–11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.
KW  - ADHD
KW  - genetic interaction
KW  - LPHN3
KW  - NCAM1
KW  - DRD2
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125128
VL  - 17
ER  - 
TY  - JOUR
A1  - Jarick, I.
A1  - Volckmar, A. L.
A1  - Pütter, C.
A1  - Pechlivanis, S.
A1  - Nguyen, T. T.
A1  - Dauvermann, M. R.
A1  - Beck, S.
A1  - Albayrak, Ö.
A1  - Scherag, S.
A1  - Gilsbach, S.
A1  - Cichon, S.
A1  - Hoffmann, P.
A1  - Degenhardt, F.
A1  - Nöthen, M. M.
A1  - Schreiber, S.
A1  - Wichmann, H. E.
A1  - Jöckel, K. H.
A1  - Heinrich, J.
A1  - Tiesler, C. M. T.
A1  - Faraone, S. V.
A1  - Walitza, S.
A1  - Sinzig, J.
A1  - Freitag, C.
A1  - Meyer, J.
A1  - Herpertz-Dahlmann, B.
A1  - Lehmkuhl, G.
A1  - Renner, T. J.
A1  - Warnke, A.
A1  - Romanos, M.
A1  - Lesch, K. P.
A1  - Reif, A.
A1  - Schimmelmann, B. G.
A1  - Hebebrand, J.
A1  - Scherag, A.
A1  - Hinney, A.
T1  - Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder
JF  - Molecular Psychiatry
N2  - Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls \((P=2.8 × 10^{-4})\) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients \((P=1.2 × 10^{-3})\) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control \((P=4.3 × 10^{-2})\). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
KW  - children
KW  - ADHD
KW  - CNVs
KW  - GWAS
KW  - PARK2
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121131
VL  - 19
IS  - 19
ER  -