Impaired Executive Control Is Associated with a Variation in the Promoter Region of the Tryptophan Hydroxylase 2 Gene Martin Reuter1, Ulrich Ott2,3, Dieter Vaitl2,3, and Ju¨rgen Hennig2 Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/19/3/401/1756580/jocn.2007.19.3.401.pdf by guest on 18 May 2021 Abstract & Current models of attention describe attention not as a catechol-O-methyltransferase (COMT ) VAL158MET and the homogenous entity but as a set of neural networks whose tryptophan hydroxylase 2 (TPH2) À703 G/T promoter poly- measurement yields a set of three endophenotypes—alerting, morphism, were tested for possible associations with attention. orienting, and executive control. Previous findings revealed dif- COMT is involved in the catabolism of dopamine, and TPH is the ferent neuroanatomical regions for these subsystems, and data rate-limiting enzyme for serotonin synthesis. Results showed no from twin studies indicate differences in their heritability. The effect of the COMT polymorphism on attention performance. present study investigated the molecular genetic basis of at- However, the TT genotype of TPH2 À703 G/T was significantly tention in a sample of 100 healthy subjects. Attention per- associated with more errors (a possible indicator of impaired formance was assessed with the attention network test that impulse control; p = .001) and with decreased performance in distinguishes alerting, orienting, and executive control (con- executive control ( p = .001). This single-nucleotide poly- flict) using a simple reaction time paradigm with different morphism on the TPH2 gene explained more than 10% of the cues and congruent and incongruent flankers. Two gene loci on variance in both indicators of attention stressing the role of the candidate genes for cognitive functioning, the functional serotonergic system for cognitive functions. & INTRODUCTION studies have produced contradicting results, which can Intelligence is one of the most heritable psychological be accounted for by stratification effects, small sample phenotypes known, and because of its importance for sizes, or different phenotype definitions, yet with re- academic achievement and job performance ( Jensen, spect to cognitive functioning a line of evidence exists 1998), the search for its biological basis is one of the pointing unequivocally to the hypothesis that the func- greatest scientific challenges. Twin and adoption studies tional VAL158MET polymorphism of the catechol-O- have demonstrated that about 70% of the variance in methyltransferase (COMT, an enzyme that degrades intelligence is determined by genes (Bouchard, Lykken, monoamines such as dopamine in the synaptic cleft) McGue, Segal, & Tellegen, 1990); however, the search gene is a promising candidate gene (for a review, see for specific candidate genes of intelligence has so far Goldberg & Weinberger, 2004). A single-nucleotide been rather unsuccessful (Reuter, Roth, Hove, & Hennig, polymorphism (SNP), a G!A transition in codon 158 2006). One of the reasons for this is the complexity of the COMT gene located at the q11 band of human of the phenotype. Therefore, newer strategies prefer chromosome 22, results in a three- to fourfold difference analyzing so-called endophenotypes of intelligence, in COMT enzyme activity by coding for the synthesis of which are distinct subcomponents of general cognitive the amino acid methionine (MET; lower enzyme activ- ability, like memory, attention, vigilance, or executive ity) instead of valine (VAL). Heterozygotes (VAL/MET control (Posthuma, Mulder, Boomsma, & De Geus, genotype) have intermediate levels of COMT activity 2002; te Nijenhuis & van der Flier, 2002; Bowden, (Lachman et al., 1996). Other dopaminergic candidate Carstairs, & Shores, 1999). These endophenotypes are genes have less successfully been tested for associations less complex than general cognitive ability and, there- with cognitive functioning (e.g., Perry et al., 1997). fore, presumably determined by a smaller amount of There is evidence that the serotonergic (5-HT) system genes (Reuter et al., 2005). Various genetic association is also involved in cognitive functioning; however the ra- tionale for the implication of the 5-HT system in cog- nitive functions is less understood, and support from the 1University of Bonn, 2University of Giessen, 3Bender Institute literature is scarcer than for dopamine. Cuccaro, Wright, of Neuroimaging Abramson, Marsteller, and Valentine (1993) reported a D 2007 Massachusetts Institute of Technology Journal of Cognitive Neuroscience 19:3, pp. 401–408 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.2007.19.3.401 by guest on 01 October 2021 significantly negative correlation between whole-blood serious evidence underlining the involvement of the 5-HT and cognitive–intellectual abilities in a sample 5-HT system in higher cognitive functions (Reuter, of autistic patients and their first-degree relatives. By Roth, Holve, & Hennig, 2006). means of tryptophan depletion, an elegant method to Moreover, Walther et al. (2003) identified a second investigate the involvement of 5-HT in brain functions, TPH isoform—referred to as TPH2—in mice, that is impairment in cognitive functioning could be demon- predominantly expressed in the brain stem, whereas strated in both animal and healthy human subjects the classical TPH gene—now labeled TPH1—is ex- studies (Evers et al., 2005; Mazer et al., 1997). Further pressed in the gut, pineal gland, spleen, and thymus. evidence emerges from clinical studies showing the The authors also identified a human TPH2 ortholog on Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/19/3/401/1756580/jocn.2007.19.3.401.pdf by guest on 18 May 2021 beneficial effects of substances increasing central 5-HT human chromosome 12p21.1. SNPs in the TPH2 gene activity. For example, Poyurovsky et al. (2003) showed have now been detected, and first studies have demon- in a double-blind placebo controlled study in a sam- strated associations between TPH2 gene variations and ple of schizophrenic patients that the 5-HT2a antago- depression, ADHD, autism, and suicide (Coon et al., nist mianserin improved performance in neurocognitive 2005; Walitza et al., 2005; Zhou et al., 2005; Zill et al., tasks. In the same line, Harvey (2003) reported that the 2004). Moreover, functional studies emphasize the im- combined dopamine and serotonin receptor antagonist pact of the TPH2 À703 G/T SNP on amygdala responses ziprasidone significantly improves multiple cognitive do- to emotional stimuli (Canli, Congdon, Gutknecht, mains such as attention/vigilance, episodic memory, Constable, & Lesch, 2005). Recent findings from two executive function, and visuomotor speed in schizo- independent research units show that the TT genotype phrenic patients. Results indicate that the preponder- is associated with low anxiety and high extraversion ance of 5-HT2a antagonism over dopamine D2 blockade (Reuter, Kuepper, & Hennig, in press; Gutknecht et al., exerted by atypical antipsychotics may contribute to their in press), which is an indicator of low impulse control. cognitive-enhancing effects. All these findings underpin Moreover, in another ongoing study of our own group, the role of the 5-HT system in cognitive functioning, the prevalence of the TT genotype is significantly higher although there is abundant evidence for a more salient in drug addicted subjects than in controls. Because a role of the dopaminergic system. It is also possible that lack of impulse control is associated with a higher risk some of the 5-HT effects on cognitive functioning are for drug addiction, the TT genotype of the À703 G/T SNP mediated via an indirect pathway by influencing the ac- is likely to be related to worse performance in cognitive tivity of the dopaminergic system. It is known that the tasks measuring prefrontal executive control. 5-HT system exerts an inhibitory effect on dopamine The development of valid and reliable paradigms is release (e.g., Porras et al., 2002). the essential prerequisite for the investigation of the The tryptophan hydroxylase (TPH) gene is a promis- biological basis of endophenotypes of cognitive ability. ing candidate gene for cognitive functioning because it is Fan, McCandliss, Sommer, Raz, and Posner (2002) devel- the rate-limiting enzyme of 5-HT synthesis. In numerous oped an attention network test (ANT) designed to eval- independent studies the TPH1 gene has been reported uate the processing efficiency of the three attentional to be associated with aggression, suicidal behavior, networks involved in the three subcomponents of nicotine addiction, and other psychopathologies (e.g., attention proposed by Posner and Dehaene (1994), Hennig, Reuter, Netter, Burk, & Landt, 2005; Reuter & namely, alerting, orienting, and executive control. Alert- Hennig, 2005a; Nielsen et al., 1998). However, these ing is defined as achieving and maintaining an alert positive findings have been criticized as the TPH1 gene state; orienting is the selection of information from is primarily expressed in the periphery and polymor- sensory input; and executive control is defined as phisms of the TPH1 gene that showed positive associa- resolving conflict among responses. The functional effi- tions with the phenotypes under investigation were ciency of these three attentional networks is assessed by located in intron 7. Alternative mechanisms making gene reaction time (RT) differences between conditions pre- expression from an intronic sequence possible