title: COMT x DRD4 epistasis impacts prefrontal cortex function underlying response control.
abstract: The prefrontal cortex plays a major role in cognitive control, but it is unclear how single genes and gene-gene interactions (genetic epistasis) impact neural and behavioral phenotypes. Both dopamine (DA) availability ("inverted U-model") and excitatory versus inhibitory DA receptor stimulation ("dual-state theory") have been linked to important principles of prefrontal processing. Catechol-O-methyltransferase (COMT; Val158Met) and DA D4-receptor (DRD4; 48 bp VNTR) genotypes were analyzed for effects on behavioral and neural correlates of prefrontal response control (NoGo-anteriorization, NGA) using a Go-NoGo task and electroencephalography (114 controls and 181 patients with attention-deficit/hyperactivity disorder).  DRD4 and COMT epistatically interacted on the NGA, whereas single genes and diagnosis showed no significant impact. Subjects with presumably relatively increased D4-receptor function (DRD4: no 7R-alleles) displayed an inverted U-relationship between the NGA and increasing COMT-dependent DA levels, whereas subjects with decreased D4-sensitivity (7R) showed a U-relationship. This interaction was supported by 7R-allele dose effects and mirrored by reaction time variability (non-significant after multiple testing correction). Combining previous theories of prefrontal DA functioning, neural stability at intermediate DA levels may be accompanied by the risk of overly decreased neural flexibility if inhibitory DA receptor function is additionally decreased. Our findings might help to disentangle the genetic basis of dopaminergic mechanisms underlying prefrontal (dys)function.
authors.affiliation: Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Würzburg, 97080 Würzburg, Germany. sebastian.heinzel@med.uni-tuebingen.de
authors.forename: Sebastian
authors.initials: S
authors.lastname: Heinzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Dresler
authors.forename: Christina G
authors.initials: CG
authors.lastname: Baehne
authors.forename: Monika
authors.initials: M
authors.lastname: Heine
authors.forename: Andrea
authors.initials: A
authors.lastname: Boreatti-Hümmer
authors.forename: Christian P
authors.initials: CP
authors.lastname: Jacob
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Renner
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Fallgatter
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Ehlis
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000473:pathology*; D001931:Brain Mapping; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003657:Decision Making / Q000502:physiology; D004569:Electroencephalography; D004843:Epistasis, Genetic / Q000235:genetics*; D005071:Evoked Potentials / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics; D009483:Neuropsychological Tests; D011110:Polymorphism, Genetic / Q000235:genetics; D017397:Prefrontal Cortex / Q000473:pathology*; D011930:Reaction Time / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D014825:Vocabulary; D055815:Young Adult
chemical_list: C493599:DRD4 protein, human; D050638:Receptors, Dopamine D4; D002394:Catechol O-Methyltransferase