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  - Neufang, S.
A1  - Akhrif, A.
A1  - Herrmann, C.G.
A1  - Drepper, C.
A1  - Homola, G.A.
A1  - Nowak, J.
A1  - Waider, J.
A1  - Schmitt, A.G.
A1  - Lesch, K.-P.
A1  - Romanos, M.
T1  - Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans
JF  - Translational Psychiatry
N2  - In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies.
KW  - Clinical Genetics
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164418
IS  - 6
ER  -