Serotonin and early cognitive development: variation in the tryptophan hydroxylase 2 gene is associated with visual attention in 7-month-old infants Jukka M. Leppa ¨nen, 1 Mikko J. Peltola, 1 Kaija Puura, 2 Mirjami Ma ¨ntymaa, 2 Nina Mononen, 3 and Terho Lehtima ¨ki 3 1 Department of Psychology, University of Tampere, Finland; 2 Department of Child Psychiatry, Tampere University Hospital, Finland; 3 Department of Clinical Chemistry, Medical School, University of Tampere and Tampere University Hospital, Finland Background: Allelic variation in the promoter region of a gene that encodes tryptophan hydroxylase isoform 2 (TPH2), a rate-limiting enzyme of serotonin synthesis in the central nervous system, has been associated with variations in cognitive function and vulnerability to affective spectrum disorders. Little is known about the effects of this gene variant on cognition during development and about possible intermediate developmental steps that lead to the adult phenotype. Here, we examined the hypothesis that the TPH2 -703 may act during early stages of development and bias the acquisition of elementary cognitive processes involved in attention and emotion regulation. Methods: Seven-month-old infants (n = 66) were genotyped for the TPH2 -703 G/T polymorphism (rs4570625) and tested for the efficiency of attention shifts from a stimulus at fixation to a new stimulus in the visual periphery. Results: Compared to TPH2 G/G homozygotes, infants with the T-carrier genotype exhibited a significantly higher number of missing attention shifts. This genotype effect tended to be particularly pronounced when infants had to disengage from an affectively salient stimulus before shifting attention to the peripheral stimulus. The results also showed that TPH2 genotype was indirectly associated, via its effect on attention disen- gagement, with temperamental emotion regulation (soothability). Conclusions: Together, these results implicate serotonin system genes in early cognitive development and suggest variations in the early- emerging cognitive capacities as a potential developmental precursor of individual differences in emotion regulation and vulnerability to affective disorders. Keywords: Attention, cognition, development, emotion, infancy, serotonin. Considerable recent interest has focused on poly- morphisms in serotonin system genes, their effects on brain and cognitive function, and their potential role in the causation of emotional and behavioral disorders. One of these polymorphisms is a G to T base substitution in the regulatory promoter region of a gene that encodes tryptophan hydroxylase iso- form 2 (TPH2), a rate-limiting enzyme of serotonin synthesis in the central nervous system (Walther et al., 2003). The exact functional significance of the TPH2 -703 polymorphisms (rs4570625) remains undetermined (Scheuch et al., 2007), but recent studies suggest that the G allele as compared to the T allele is associated with relative loss of mRNA expression and may thereby be associated with lower serotonin concentrations (Chen, Vallender, & Miller, 2008; Lin et al., 2007). These differences may have widespread functional consequences on brain func- tion and behavior given that the TPH2 gene is expressed in various regions of the human brain, including serotonergic raphe nuclei and their pro- jection areas in the neocortex (Lin et al., 2007), and given the established role of serotonin in brain development (Gaspar, Cases, & Maroteaux, 2003) as well as direct modulation of brain processes for cognition, emotion, and behavior (Lucki, 1998). Consistent with this scenario, recent studies have linked TPH2 -703 G/T with a variety of cognitive and affective processes. Compared to individuals homo- zygous for the more common G allele of the TPH2 - 703, individuals with one or two copies of the less common T allele exhibit generally lower level of per- formance in tasks that are sensitive to attention regulation and cognitive control processes (Reuter, Ott, Vaitl, & Hennig, 2007; Strobel et al., 2007), exaggerated activation in the amygdala and con- nected brain regions at rest and in response to emotional stimuli (Brown et al., 2005; Canli, Cong- don, Constable, & Lesch, 2008; Canli, Congdon, Gutknecht, Constable, & Lesch, 2005; Furmark et al., 2008), and enhanced attention-sensitive event- related brain responses to affectively and behavior- ally relevant stimuli (Baehne et al., 2008; Herrmann et al., 2007). There is also evidence linking the T allele with disorders of emotion regulation (Gutknecht et al., 2007). Conflict of interest statement: No conflicts declared. Journal of Child Psychology and Psychiatry 52:11 (2011), pp 1144–1152 doi:10.1111/j.1469-7610.2011.02391.x Ó 2011 The Authors. Journal of Child Psychology and Psychiatry Ó 2011 Association for Child and Adolescent Mental Health. Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA