Stella Hu

A functional polymorphism in the monoamine oxidase A gene promoter

Abstract We describe a new polymorphism upstream of the gene for monoamine oxidase A (MAOA), an important enzyme in human physiology and behavior. The polymorphism, which is located 1.2 kb upstream of the MAOA coding sequences, consists of a 30-bp repeated sequence present in 3, 3.5, 4, or 5 copies. The polymorphism is in linkage disequilibrium with other MAOA and MAOB gene markers and displays significant variations in allele frequencies across ethnic groups. The polymorphism has been shown to affect the transcriptional activity of the MAOA gene promoter by gene fusion and transfection experiments involving three different cell types. Alleles with 3.5 or 4 copies of the repeat sequence are transcribed 2–10 times more efficiently than those with 3 or 5 copies of the repeat, suggesting an optimal length for the regulatory region. This promoter region polymorphism may be useful as both a functional and an anonymous genetic marker for MAOA.

A GENETIC ASSOCIATION FOR CIGARETTE SMOKING BEHAVIOR

Dopaminergic genes are likely candidates for heritable influences on cigarette smoking. In an accompanying article, Lerman et al. (1999) report associations between allele 9 of a dopamine transporter gene polymorphism (SLC6A3-9) and lack of smoking, late initiation of smoking, and length of quitting attempts. The present investigation extended their study by examining both smoking behavior and personality traits in a diverse population of nonsmokers, current smokers, and former smokers (N = 1,107). A significant association between SLC6A3-9 and smoking status was confirmed and was due to an effect on cessation rather than initiation. The SLC6A3-9 polymorphism was also associated with low scores for novelty seeking, which was the most significant personality correlate of smoking cessation. It is hypothesized that individuals carrying the SLC6A3-9 polymorphism have altered dopamine transmission, which reduces their need for novelty and reward by external stimuli, including cigarettes.

Copper activates metallothionein gene transcription by altering the conformation of a specific DNA binding protein

Copper homeostasis in yeast involves a copper binding protein, metallothionein, and a trans-acting regulatory protein that activates transcription of the metallothionein gene in response to copper ions. We show that the regulatory protein specifically binds to the metallothionein gene control sequences in the presence, but not in the absence, of copper. Both the DNA binding and metalloregulatory functions of the transacting factor are contained within its aminoterminal domain, and partial proteolysis experiments show that copper activates this domain by causing a major switch in its conformation. Silver also activates the DNA binding domain in vitro and induces metallothionein gene transcription in vivo. We propose a novel copper cluster model for the DNA binding domain based on its surprising structural similarities to metallothionein itself.

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

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.

Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior

Cigarette smoking behavior is influenced by both personality traits and inherited factors. Previous research showed that neuroticism—a broad personality domain that includes anxiety, depression, impulsiveness and vulnerability—increases the risk of being a smoker, primarily because of difficulty in quitting. Neuroticism has also been associated with the 5-HTTLPR, a functional polymorphism in the promoter for the serotonin transporter gene. We used population and family-based methods to analyze the joint effects of the 5-HTTLPR and neuroticism on smoking behavior in a population of 759 never, current, and former smokers, all members of sib-pairs. Our main finding is that smoking behavior is influenced by an interaction between neuroticism and 5-HTTLPR genotype. Specifically, neuroticism was positively correlated with current smoking and negatively associated with smoking cessation in individuals and siblings with poorly transcribed 5-HTTLPR-S genotypes, but not in those with the more highly expressed 5-HTTLPR-L genotype. Individuals with both a 5-HTTLPR-S genotype and a high level of neuroticism had the greatest difficulty in quitting smoking. These data, if replicated, suggest that smoking behavior is more strongly influenced by the combination of the serotonin transporter gene and neuroticism than by either factor alone, and that personality scores and 5-HTTLPR genotype may predict the clinical efficacy of certain smoking cessation drugs.

Molecular genetics of shyness and aggression in preschoolers

Abstract Associations between three candidate gene polymorphisms [dopamine D4 receptor (DRD4), serotonin transporter (5-HTT), and serotonin 2C receptor (5-HT2C)] with shy and aggression-related behaviors derived from maternal report and peer play at age four were examined. We noted a significant association of the DRD4 receptor gene with maternal report of problems with aggression at age four. Children with long versus short repeat alleles of the DRD4 gene were reported by their mothers to have significantly more problems with aggression at age four. There were no significant associations of the DRD4 gene with observed behavioral measures of aggression at age four. There were, in addition, no significant associations of either of the serotonin genes with any of the maternal report and observed behavioral measures. The present study extends earlier findings of adults to the preschool years and appears to be the first large scale investigation to examine the molecular genetics of preschoolers’ temperament using behavioral and maternal report measures in normal childhood development.

Association of DRD4 with attention problems in normal childhood development

Several previous studies found an association of clinically diagnosed attention deficit hyperactivity disorder with long alleles of a variation in the DRD4 dopamine receptor gene exon III coding sequence. We evaluated the DRD4 polymorphism in a non‐clinically selected sample of children for whom maternal reports of attention problems were available at 4 and 7 years of age. There was a significant elevation in attention problem scores in children carrying DRD4 long alleles that accounted for 3–4% of total variation at each age and for 5–7% of the temporally stable component of the phenotype. Our results show that the DRD4 gene influences normal as well as pathological attention processes, and the results highlight the utility of longitudinal measurements in psychiatric genetics.

Covariance Structure of Neuroticism and Agreeableness: A Twin and Molecular Genetic Analysis of the Role of the Serotonin Transporter Gene

The Revised NEO Personality Inventory domains of Neuroticism and Agreeableness are considered factorially distinct despite several intercorrelations between these domains. The genetic correlation, an index of the degree to which these intercorrelations are caused by genetic influences, was estimated using data from 913 monozygotic and 562 dizygotic volunteer twin pairs from Canada, Germany, and Japan. The serotonin transporter gene, 5-HTTLPR, was assayed in a sample of 388 nontwin sibling pairs from the United States to determine the contribution of the serotonin transporter locus to the covariation between the Neuroticism and Agreeableness scales. In all four samples, genetic influences contributed to the covariance of Neuroticism and Agreeableness, with the serotonin transporter gene accounting for 10% of the relationship between these domains.