Candidate gene associations with withdrawn behavior.

Social withdrawal is an observable, dimensional and core neuropsychiatric phenomenon in developmental psychopathology. Rarely associated with disruptive behavior, social withdrawal receives delayed clinical attention in the community, with a parallel underrepresentation in scientific literature. Earlier identification and characterization of withdrawn behavior (WB) has profound implications for predicting psychopathology across many domains, including depression (Goodwin, Fergusson, & Horwood, 2004; K. H. Rubin, Chen, McDougall, Bowker, & McKinnon, 1995), psychosis (Miller, Byrne, Hodges, Lawrie, & Johnstone, 2002), autism (Ooi, Rescorla, Ang, Woo, & Fung, 2010), anxiety (Aschenbrand, Angelosante, & Kendall, 2005; Kasius et al., 1997) and suicide (Ferdinand & Verhulst, 1995). WBs are heritable Hoekstra, Bartels, Hudziak, Van Beijsterveldt, & Boomsma, 2008) and longitudinal data have established that social withdrawal persists and worsens over time (Hofstra, Van der Ende, & Verhulst, 2000). This study proposes to expand the biological basis of this powerful and compelling trait through dimensional psychometric and genetic analysis of a substantial patient sample. A biological basis for WBs such as shyness, inhibition and introversion has long been recognized. 10-15% of children as young as age two could be characterized by a shy, inhibited response to novelty, and those reaction patterns are preserved over time, correlated with autonomic activity, and serve as risk factors for social anxiety and avoidance in later life (Kagan, Reznick, & Snidman, 1988). Genetic factors have proven to be primary in the influence of WB in early childhood (Hoekstra et al., 2008) and adolescence. Estimates of heritability increase with age, reaching 45% by age 16 for both genders (Lamb et al., 2010). However, individual gene association with shyness or behavioral inhibition in children remains elusive. The strongest associations have been found in serotonin transporter 5-HTT and the dopamine receptors D4 and D2. The short allele variant of the serotonin transporter, 5-HTTLPR, has already been associated with depression, anxiety, neuroticism and harm avoidance (Lesch et al., 1996). Homozygosity for 5-HTTLPR was found to have a significant effect on WBs in children with ADHD (Zhao et al., 2005). The dopamine receptor D4 is functionally important in the inhibition of passive avoidance (Tarazi & Baldessarini, 1999). Three alleles, DRD4/48bp-repeat, 7-repeat and A1 have shown a statistical trend for association and linkage with WB (Marino et al., 2004). The D2 receptor also has potential to affect WB, as it is strongly implicated by animal models in the development of social attachments (Gingrich, Liu, Cascio, Wang, & Insel, 2000). The DRD2/Taq1 A1 allele has previously been discovered in association with schizoid and avoidant personality components (Blum et al., 1997). Within developmental psychopathology, hopes of simpler, direct gene-trait correlations are gone. The absence of large and significant results in genome-wide association studies examining known heritable phenotypes such as behavioral inhibition, has posed the problem of “missing heritability”. Neuropsychiatric phenotypes may be particularly vulnerable due to a preference for categorical definitions, with dimensional approaches used rarely. This study offers the potential to reproduce previous findings and identify new genes’ importance by examining a discreet number of known psychiatric candidate genes in a large sample measured by the Withdrawn Behavior Subscale Score (WBS) of the Adult Self-Report (ASR) and Child Behavior Checklist (CBCL), a dimensional measure of behavioral inhibition with established persistence (Hofstra et al., 2000), heritability (Hoekstra et al., 2008) and cross-culture generalizability (Heubeck, 2000). We anticipated associations between catecholaminergic genes and WB.