Identifying genetic variants associated with the personality trait Neuroticism, a marker for depression.
Sen, Srijan
2005
Abstract
Evidence from epidemiological studies indicates that genetic factors play a substantial role in determining our risk for depression. Unfortunately, no specific genes have been definitively identified to date. One promising approach is to determine whether genetic variants are associated not with disease per se, but with trait markers that are themselves associated with risk for the disease. The personality trait Neuroticism, characterized by anxiety, low mood vulnerability, is one such trait marker for depression. In this dissertation, we explore potential associations between polymorphisms in neurotransmitter genes and Neuroticism in a large community sample. Numerous lines of evidence implicate Brain Derived Neurotrophic Factor (BDNF) in the pathophysiology of depression via hippocampal mechanisms. In our sample, we find an association between the valine allele at a BDNF coding polymorphism (Val66Met) and increased Neuroticism (p = 0.005). In a subsequent analysis, we find an association between the same BDNF valine allele and decreased hippocampal volume (p = 0.009). The GABA (A) receptor alpha6 subunit gene has been associated with benzodiazepine and alcohol sensitivity, but has not been investigated in Neuroticism or depression risk. In our sample we find an association between a GABA (A) alpha6 coding variant (Pro385Ser) and Neuroticism (p = 0.003). The serotonin transporter promoter polymorphism (5-HTTLPR) is known to affect the strength of the promoter of the serotonin transporter gene. Lesch and colleagues initially reported that 5-HTTLPR is associated Neuroticism. Multiple replication attempts have produced conflicting results. In our sample we confirmed the association between 5-HTTLPR and Neuroticism (p = 0.008). Moreover, we performed a meta-analysis on 23 studies investigating this association to explain the contradictions in the literature. We found strong evidence for an association between 5-HTTLPR and Neuroticism as measured by the NEO personality inventory (p = 0.000016). Studies that did not replicate this association either had too small sample size, or used alternate personality inventories. Polymorphisms in two other candidate genes, monoamine oxidase A and the serotonin receptor 2A, showed no association with Neuroticism. In total, the three associated variants account for approximately 25% of the Neuroticism genetic variance in our sample. In a separate analysis, we find an association between a dopamine receptor 4 polymorphism (DRD4-IL3) and both systolic (p = 0.031) and diastolic (p = 0.034) blood pressure. Furthermore, we find evidence that the effects of DRD4-IL3 on blood pressure increase with age (p = 0.009).Subjects
Associated Depression Genetic Variants Identifying Marker Neuroticism Personality Trait
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