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Early-Onset Bipolar Disorder 325affect these neurobiological circuits or directly increase risk for BD could serveas other factors in this set.Genetic Markers for Bipolar Disorder RiskTwo potential BD gene candidates code for the serotonin transporter (5-HTT) andfor brain-derived neurotrophic growth factor (BDNF). Polymorphisms of thesegenes have been associated with depression and BD (Caspi et al., 2003; Geller etal., 2004; Neves-Pereira et al., 2002). However, because these polymorphisms arerelatively common in the population, these genes likely lead to a gross effect onthe brain (such as general changes in serotonergic functioning) and thus carry onlya small effect by themselves in creating risk for BD. Perhaps due to these smalleffects and the complexity of human behavior, polymorphisms in genes such asthese have not been well linked to behavioral outcomes such as BD on a consistent,replicated basis. As genes do not encode for behavior, a more direct effect ofgenes to study may be the effect on brain structure and function (Hariri & Weinberger,2003). Here we will discuss the effects of these two candidate genes onincreasing risk for mood disorders and on brain regions involved in BD.Role of Serotonin Transporter GenePolymorphisms in Mood DisordersThe serotonin transporter protein is involved with regulating the concentration ofavailable synaptic serotonin and thus may have widespread effect on mood andmood regulation (Smith et al., 2004). The serotonin transporter (5-HTT) genecontains a common polymorphism: a 44-base-pair (bp) insertion/deletion polymorphismin the promoter region (5-HTTLPR). This polymorphism results in twocommonly found functional alleles at the 5-HTTPLR, a short (s)-allele and a long(l)–allele. The s-allele contains a shorter promoter segment and results in reducedtranscription and functionality of the protein compared to the l-allele. This is arelatively common polymorphism, as the frequency of the s-allele in people ofEuropean descent is approximately 40% (Hariri & Weinberger, 2003). A recentmeta-analysis of 14 studies investigating association of these polymorphisms withBD or major depressive disorder (MDD) found a significant association for BDwith the 5-HTT s-allele (Lasky-Su, Faraone, Glatt, & Tsuang, 2004). The oddsratio (OR) was 1.13, indicating a small but significant effect. No associations werefound between either polymorphism and MDD. However, presence of the s-allelemay confer increased risk for depression when combined with stressful lifeevents (Caspi et al., 2003). This finding has been replicated in children with historiesof maltreatment (Kaufman et al., 2004). Therefore, the s-allele of 5-HTTmay confer risk for development of mood disorders, including BD, particularlyin the context of psychosocial stress.