Why Some People Discount More than Others: Baseline Activation in the Dorsal PFC Mediates the Link between COMT Genotype and Impatient Choice

Individuals differ widely in how steeply they discount future rewards. The sources of these stable individual differences in delay discounting (DD) are largely unknown. One candidate is the COMT Val158Met polymorphism, known to modulate prefrontal dopamine levels and affect DD. To identify possible neural mechanisms by which this polymorphism may contribute to stable individual DD differences, we measured 73 participants' neural baseline activation using resting electroencephalogram (EEG). Such neural baseline activation measures are highly heritable and stable over time, thus an ideal endophenotype candidate to explain how genes may influence behavior via individual differences in neural function. After EEG-recording, participants made a series of incentive-compatible intertemporal choices to determine the steepness of their DD. We found that COMT significantly affected DD and that this effect was mediated by baseline activation level in the left dorsal prefrontal cortex (DPFC): (i) COMT had a significant effect on DD such that the number of Val alleles was positively correlated with steeper DD (higher numbers of Val alleles means greater COMT activity and thus lower dopamine levels). (ii) A whole-brain search identified a cluster in left DPFC where baseline activation was correlated with DD; lower activation was associated with steeper DD. (iii) COMT had a significant effect on the baseline activation level in this left DPFC cluster such that a higher number of Val alleles was associated with lower baseline activation. (iv) The effect of COMT on DD was explained by the mediating effect of neural baseline activation in the left DPFC cluster. Our study thus establishes baseline activation level in left DPFC as salient neural signature in the form of an endophenotype that mediates the link between COMT and DD.

Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinson's disease.

BACKGROUND Catecholamine-O-methyl-tranferase (COMT) initiates dopamine degradation. Its activity is mainly determined by a single nucleotide polymorphism in the COMT gene (Val158Met, rs4680) separating high (Val/Val, COMT(HH)), intermediate (Val/Met, COMT(HL)) and low metabolizers (Met/Met, COMT(LL)). We investigated dopaminergic denervation in the striatum in PD patients according to COMT rs4680 genotype. METHODS Patients with idiopathic PD were assessed for motor severity (UPDRS-III rating scale in OFF-state), dopaminergic denervation using [123I]-FP-CIT SPECT imaging, and genotyped for the COMT rs4680 enzyme. [123I]-FP-CIT binding potential (BP) for each voxel was defined by the ratio of tracer-binding in the region of interest (striatum, caudate nucleus and putamen) to that in a region of non-specific activity. Genotyping was performed using TaqMan(®) SNP genotyping assay. We used a regression model to evaluate the effect of COMT genotype on the BP in the striatum and its sub-regions. RESULTS Genotype distribution was: 11 (27.5%) COMT(HH), 26 (65%) COMT(HL) and 3 (7.5%) COMT(LL). There were no significant differences in disease severity, treatments, or motor scores between genotypes. When adjusted to clinical severity, gender and age, low and intermediate metabolizers showed significantly higher rates of striatal denervation (COMT(HL+LL) BP = 1.32 ± 0.04) than high metabolizers (COMT(HH), BP = 1.6 ± 0.08; F(1.34) = 9.0, p = 0.005). Striatal sub-regions showed similar results. BP and UPDRS-III motor scores (r = 0.44, p = 0.04) (p < 0.001) were highly correlated. There was a gender effect, but no gender-genotype interaction. CONCLUSIONS Striatal denervation differs according to COMT-Val158Met polymorphism. COMT activity may play a role as a compensatory mechanism in PD motor symptoms.

Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia

Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Val108/158 Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups (n = 11–16) assayed with functional MRI. Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.

Histoire des Ariégeois (Comté de Foix, Vicomté de Couserans, [etc.]) De l'esprit et de la force intellectuelle et morale dans l'Ariège et les Pyrénées centrales.

[1. ptie.] Les poètes.--[2. ptie.] Les militaires. [t.1.] Depuis le commencement du Comte de Foix jusqu'à la Révolution française. [t.2.] Depuis la Révolution française jusqu'à nos jours.--[3. ptie.] Administrateurs et hommes scientifiques.--[4. ptie.] Archéologues. t.1. Descripteurs du sol, géologues, historiens. t.2. Suite des hommes scientifiques, orateurs, moralistes, pédagogues, publicistes, etc. t.3. suite et fin des hommes scientifiques. Compléments sur les hommes et les choses.

Coutumes des pays et comté de Flandre. Quartier de Furnes.

Vol. 2, 1896.

Les chroniques de l'Ardennes et des Woëpvres, ou Revue et examen des traditions locales antérieures au xie siècle, pour servir à l'histoire de l'ancien comté de Chiny.

Mode of access: Internet.

Nobiliaire toulousain; inventaire général des titres probants de noblesse et de dignités nobiliaires; lettres patentes d'anoblissement, jugements de confirmantion ou de maintenue de noblesse, érections de terres en baronnie, vicomté, comté, marquisat, description héraldique des blasons, actes d'hommages, de reconnaissances, de dénombrements, devises, cris, etc., etc.

Mode of access: Internet.

Le comté de Clermont en Beauvoisis; études pour servir à son histoire.

Vol.[1] is reprinted from Bulletin de la Société académique de l'Oise, t.15, 1.ptie.

Recherches sur les incursions des Anglais et des Grandes Compagnies dans le duché et le comté de Bourgogne à la fin du XIVe siècle, précédées de considérations sur l'origine des Grandes Compagnies, leur diverses dénominations, leur influence au point de vue politique et militaire, etc.

"Pièces justificatives": p. 121-136.

Auguste Castan et la Franche-Comté.

"Extrait des Annales franc-comtoises.- Janvier-février 1894."