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  • The heterogeneity among studies that investigated the


    The heterogeneity among studies that investigated the association of COMT Val158Met with alexithymia was also significant (Ham et al., 2005; Min et al., 2016; Swart et al., 2011; Zekioglu et al., 2014). The healthy status, drug effect, and other demographic variables also influenced one's ability of emotion identifying and describing. For example, the findings in Min's study (Koh et al., 2016) showing the Val allele of COMT Val158Met polymorphism associating with high alexithymia was replicated in the current meta-analyses. However, the study was conducted with 224 patients of obsessive-compulsive disorder. The patients took selective serotonin reuptake inhibitors during alexithymia assessment. The association might be influenced by the individual differences in adverse drug effect among the genotypes of COMT Val158Met (Arias et al., 2006; Benedetti et al., 2009; Ji et al., 2012). Therefore, it was possible that some of previous findings could not really reflect the relation between the polymorphism and alexithymia. The limitations should be noted as well. Firstly, the TAS-20 scale used in the study is a self-rating instrument. This scale may be not suitable for the high alexithymic subjects given that they show impaired memory to recall their emotional memories for emotional stimuli (Takahashi et al., 2015). In future study, task-related assessment should be adopted. Secondly, life events such as childhood maltreatments also impact the characteristics of alexithymia. Therefore, the genetic-environmental paradigm should be considered when examining the roles of BML-277 synthesis in alexithymia. Thirdly, our sample is heterogeneous. The subjects represent a highly homogeneous group (same ethnic background and very limited age range), while other studies included in the meta-analysis were mixed Caucasian and Asian. The available data was insufficient for meta-analysis with different ethnities and healthy conditions. The lack of a sensitivity analysis for different backgrounds reduced the generalizability of our findings.
    Conclusion The replicated study and meta-analyses indicated that the 5-HTTLPR and COMT Val158Met polymorphisms are not associated with alexithymia. However, the lack of association should be viewed in the light of the heterogeneity for ethnicity and psychopathology.
    Author contributions
    Introduction Intra-subject variability (ISV) refers to within-person variations in performance over short periods of time. ISV of reaction times (RTs) is elevated in schizophrenia (Kaiser et al., 2008, Rentrop et al., 2010, Smyrnis et al., 2009), methamphetamine psychosis (Fassbender, Lesh, Ursu, & Salo, 2015), bipolar disorder (Brotman, Rooney, Skup, Pine, & Leibenluft, 2009), attention-deficit/hyperactivity disorder (ADHD; Klein, Wendling, Huettner, Ruder, & Peper, 2006) and Parkinson’s disease (Burton, Strauss, BML-277 synthesis Hultsch, Moll, & Hunter, 2006), which have all been associated with altered dopaminergic function. Contrastingly, for depression (Schwartz et al., 1989), obsessive-compulsive disorder (Damilou, Apostolakis, Thrapsanioti, Theleritis, & Smyrnis, 2016) or autism (Adamo et al., 2014), ISV was not found to be elevated. In ADHD literature, increased ISV of RTs is amongst the most consistent findings (Kofler et al., 2013) and considered to reflect underlying neural aetiology (Kuntsi & Klein, 2012). As ADHD patients demonstrated greatly elevated reaction time standard deviation (RTSD) after accounting for mean RT, but slower mean RT was no longer detectable after accounting for elevated RTSD (Klein et al., 2006), ISV is unlikely to be a consequence of response slowing and must be studied as an independent construct. ISV is considered to be modulated by catecholaminergic activity in the prefrontal cortex (PFC) (Winterer et al., 2006, Winterer et al., 2006). The action of dopamine (DA) released in the synaptic cleft is terminated either by DA transporters (DAT) reuptake, diffusion out of the synapse or by catabolism of the Val158Met polymorphism (rs4680) of the Catechol-O-methyl-transferase (COMT) enzyme (Slifstein et al., 2008). The COMT genotype plays a particularly important role in catabolism of extracellular DA in the PFC (Turnbridge, Bannerman, Sharp, & Harrison, 2004) due to that lower concentration of DAT here than in the striatum (Lewis et al., 2001, Sesack et al., 1998). The substitution of the Met allele by the Val allele leads to a three-to-four-fold increase in enzymatic activity, resulting in lower DA signalling (Lachman et al., 1996). COMT is therefore a promising gene for the study of mechanisms underlying differences in ISV.