Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.

https://science.sciencemag.org/content/sci/274/5292/1527.full.pdf

Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region

https://lsa.umich.edu/psych/research&labs/berridge/publications/Berridge&RobinsonBrResRev1998.pdf

What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?

Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5'-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.

Allelic Variation of Human Serotonin Transporter Gene Expression

Extraversion has two central characteristics: (1) interpersonal engagement, which consists of affiliation (enjoying and valuing close interpersonal bonds, being warm and affectionate) and agency (being socially dominant, enjoying leadership roles, being assertive, being exhibitionistic, and having a sense of potency in accomplishing goals) and (2) impulsivity, which emerges from the interaction of extraversion and a second, independent trait (constraint). Agency is a more general motivational disposition that includes dominance, ambition, mastery, efficacy, and achievement. Positive affect (a combination of positive feelings and motivation) is closely associated with extraversion. Extraversion is accordingly based on positive incentive motivation. Parallels between extraversion (particularly its agency component) and a mammalian behavioral approach system based on positive incentive motivation implicate a neuroanatomical network and modulatory neurotransmitters in the processing of incentive motivation. A corticolimbic-striatal-thalamic network (1) integrates the salient incentive context in the medial orbital cortex, amygdala, and hippocampus; (2) encodes the intensity of incentive stimuli in a motive circuit composed of the nucleus accumbens, ventral pallidum, and ventral tegmental area dopamine projection system; and (3) creates an incentive motivational state that can be transmitted to the motor system. Individual differences in the functioning of this network arise from functional variation in the ventral tegmental area dopamine projections, which are directly involved in coding the intensity of incentive motivation. The animal evidence suggests that there are three neurodevelopmental sources of individual differences in dopamine: genetic, "experience-expectant," and "experience-dependent." Individual differences in dopamine promote variation in the heterosynaptic plasticity that enhances the connection between incentive context and incentive motivation and behavior. Our psychobiological threshold model explains the effects of individual differences in dopamine transmission on behavior, and their relation to personality traits is discussed.

/pdf/neurobiology-of-the-structure-of-personality-dopamine-tisykn89uu.pdf

Neurobiology of the structure of personality: Dopamine, facilitation of incentive motivation, and extraversion.

Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Geneticists have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits—describing the methods, limitations, and recent applications to biological problems.

Genetic Dissection of Complex Traits

Twin and adoption studies suggest that 30 to 60% of the variance in many personality traits is due to inherited factors. However, there is little knowledge of the number or identity of the responsible genes, how they differ between individuals, or how their gene products interact with the developing brain and with environmental and experiential factors to generate the complex blend of attitudes and actions that comprise human temperament1. In the accompanying paper, Ebstein et al.2 have found a population association between a long allele of polymorphic exon III repeat sequence of the D4 dopamine receptor gene (DADR) and the normal personality trait of Novelty Seeking. The possibility of a causal relationship between DADR and Novelty Seeking is further supported by studies showing that the number of exon III repeats can affect the binding of ligands to the receptor3,4; that DADR is expressed in lim-bic areas involved in cognition and emotion5,6; that dopamine mediates exploratory behaviour in experimental animals7–12; that the rewarding effects of amphetamines and cocaine are related to dopamine release13; and that Novelty Seeking is low in dopamine-deficient patients with Parkinson's disease14. We investigated the relationship between DADR exon III sequence variants and personality test scores in a population of 315 mostly male siblings, other family members and individuals from the United States. The association between long alleles of exon III and personality traits related to Novelty Seeking was confirmed. Moreover, family studies showed that this association is the result of genetic transmission rather than of population stratification.

Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking

We have extended our analysis of the role of the long arm of the X chromosome (Xq28) in sexual orientation by DNA linkage analyses of two newly ascertained series of families that contained either two gay brothers or two lesbian sisters as well as heterosexual siblings. Linkage between the Xq28 markers and sexual orientation was detected for the gay male families but not for the lesbian families or for families that failed to meet defined inclusion criteria for the study of sex-linked sexual orientation. Our results corroborate the previously reported linkage between Xq28 and male homosexuality in selected kinships and suggest that this region contains a locus that influences individual variations in sexual orientation in men but not in women.

https://zenodo.org/record/1233407/files/article.pdf

Linkage between sexual orientation and chromosome Xq28 in males but not in females

The ends of the long arms of the human X and Y chromosomes contain a homologous region that can undergo sequence exchange. We have developed new polymorphic markers to analyze the genetic behavior of this region in the three-generation CEPH reference families. These Xq/Yq markers undergo crossovers in approximately 2% of male meioses in a pattern consistent with reciprocal recombination rather than gene conversion. Although the rate of recombination in males is significantly higher than in females or in autosomal sequences, it is more than an order of magnitude lower than in the short arm pseudoautosomal region at Xp/Yp. The Xq/Yq markers exhibit allelic association with one another, but not with markers in the X-specific or Y-specific regions of the sex chromosomes. Hence the Xq/Yq homology region displays behavior that is intermediate between sex-linked and true pseudoautosomal, and is unlikely to be essential for proper chromosome segregation.

Lin Li

Papers

Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking

Linkage between sexual orientation and chromosome Xq28 in males but not in females

Recombination and allelic association in the Xq/Yq homology region