Genomics in Psychology and Psychiatry

The review considers the most interesting data on the molecular genetic basis of mental disorders and personality traits, which were obtained within the framework of the Russian program Human Genome. Polymorphic markers Taq1A of the dopamine receptor gene and T102C of the serotonin receptor type 2A gene were associated with schizophrenia, in particular, chronic forms with poor prognosis. In mentally health people, the insertion/deletion polymorphism of the serotonin transporter gene was associated with schizoid traits.     

Serotonin 1B Receptor Gene (HTR1B) Methylation as a Risk Factor for Callous-Unemotional Traits in Antisocial Boys

The serotonin system is thought to play a role in the aetiology of callous-unemotional (CU) traits in children. Previous research identified a functional single nucleotide polymorphism (SNP) from the promoter region of the serotonin 1B receptor gene as being associated with CU traits in boys with antisocial behaviour problems. This research tested the hypothesis that CU traits are associated with reduced methylation of the promoter region of the serotonin 1B receptor gene due to the influence of methylation on gene expression. Participants (N = 117) were boys with antisocial behaviour problems aged 3-16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered a saliva sample from which the genotype of a SNP from the promoter region of the serotonin 1B receptor gene and the methylation levels of 30 CpG sites from 3 CpG regions surrounding the location of this polymorphism were assayed. Lower levels of serotonin 1B receptor gene methylation were associated with higher levels of CU traits. This relationship, however, was found to be moderated by genotype and carried exclusively by two CpG sites for which levels of methylation were negatively associated with overall methylation levels in this region of the gene. Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of CU traits. Furthermore, the results suggest that there may be two pathways to CU traits that involve methylation of the serotonin 1B receptor gene; one that is driven by a genotypic risk and another that is associated with risk for generally increased levels of methylation. Future research that aims to replicate and further investigate these results is required.     

Serotonin type 2a (5-HTR2A) receptor gene polymorphism and personality traits in patients with endogenous psychoses]

Genetic polymorphism of the serotonin receptor (5-HTR2A) gene has been reported to be associated with the expression of clinical signs characteristic of major psychoses, including schizophrenia and affective disorders. In this study, personality traits of patients with these diseases and the associations of these traits with 5-HTR2A allelic polymorphisms were studied. It was demonstrated that schizophrenic and affective patients with the 2/2 genotype of serotonin receptor had lower scores on the anxiety scale and on the anxiety-related hypochondriasis and neuroticism scales than subjects with the 1/1 and 1/2 genotypes.     

Polymorphism of the serotonin 2A receptor gene (5HTR2A) and personality traits

The interindividual variation of temperament features (such as anxiety, neuroticism, harm avoidance) is determined, in particular, by allele polymorphism of genes involved in serotonin metabolism and has earlier been associated with the insertion/deletion polymorphism of the serotonin transporter gene. Polymorphic alleles of the serotonin 2A receptor gene (5HTR2A) were tested for association with personality traits assessed with several tests. The T102C and A1438G polymorphisms were associated with a variation in emotionality, activity, and sociability, which are integral characteristics of temperament. With each polymorphism, differences were significant only between heterozygotes and homozygotes. Carriers of T102C genotype A1/A2 displayed a lower level of anxiety-related traits, a higher score on scale Hypomania, and a lower score on scale Social Introversion and were assumed to have higher activity and sociability. Carriers of A1428G genotype A/G differed from homozygotes G/G in having a lower level of social introversion and a lower score on scale No close friends, which testified to higher sociability of heterozygotes. Thus, the polymorphic alleles of SHTR2A proved to be associated with personality traits in mentally healthy people.     

Serotonin Type 2a (5-HTR2A) Receptor Gene Polymorphism and Personality Traits in Patients with Major Psychoses

Genetic polymorphism of the serotonin receptor (5-HTR2A) gene has been reported to be associated with the expression of clinical traits characteristic of major psychoses, including schizophrenia and affective disorders. In this study, personality traits of patients with these diseases and the associations of these traits with 5-HTR2A allelic polymorphisms were studied. It was demonstrated that schizophrenic and affective patients with the 2/2genotype of serotonin receptor had lower scores on the anxiety scale and on the anxiety-related hypochondriasis and neuroticism scales than subjects with the 1/1and 1/2genotypes.     

Polymorphism of the Serotonin 2A Receptor Gene (5HTR2A) and Personality Traits

The individual variation of temperament features (such as anxiety, neuroticism, harm avoidance) is determined, among other things, by allele polymorphism of genes involved in serotonin metabolism and has earlier been associated with the insertion/deletion polymorphism of the serotonin transporter gene. Polymorphic alleles of the serotonin 2A receptor gene (5HTR2A) were tested for association with personality traits assessed in several tests. The T102C and A1438G polymorphisms were associated with variation in emotionality, activity, and sociability, which are integral characteristics of temperament. With each polymorphism, differences were significant only between heterozygotes and homozygotes. Carriers of T102C genotype A1/A2 displayed a lower level of anxiety-related traits, a higher score on the Hypomania scale, and a lower score on the Social Introversion scale and were assumed to have higher activity and sociability. Carriers of A1438G genotype A/G differed from homozygotes G/G in having a lower level of social introversion and a lower score on the No Close Friends scale, which testified to higher sociability of heterozygotes. Thus, the polymorphic alleles of 5HTR2A proved to be associated with personality traits in mentally healthy people.     

An Exploration of the Serotonin System in Antisocial Boys with High Levels of Callous-Unemotional Traits

Background

The serotonin system is thought to play a role in the aetiology of antisocial and aggressive behaviour in both adults and children however previous findings have been inconsistent. Recently, research has suggested that the function of the serotonin system may be specifically altered in a sub-set of antisocial populations – those with psychopathic (callous-unemotional) personality traits. We explored the relationships between callous-unemotional traits and functional polymorphisms of selected serotonin-system genes, and tested the association between callous-unemotional traits and serum serotonin levels independently of antisocial and aggressive behaviour.

Method

Participants were boys with antisocial behaviour problems aged 3–16 years referred to University of New South Wales Child Behaviour Research Clinics. Participants volunteered either a blood or saliva sample from which levels of serum serotonin (N = 66) and/or serotonin-system single nucleotide polymorphisms (N = 157) were assayed.

Results

Functional single nucleotide polymorphisms from the serotonin 1b receptor gene (HTR1B) and 2a receptor gene (HTR2A) were found to be associated with callous-unemotional traits. Serum serotonin level was a significant predictor of callous-unemotional traits; levels were significantly lower in boys with high callous-unemotional traits than in boys with low callous-unemotional traits.

Conclusion

Results provide support to the emerging literature that argues for a genetically-driven system-wide alteration in serotonin function in the aetiology of callous-unemotional traits. The findings should be interpreted as preliminary and future research that aims to replicate and further investigate these results is required.     

Survey of neurotransmitter receptor gene expression into and out of parental care in the burying beetle Nicrophorus vespilloides

Understanding the genetic influences of traits of nonmodel organisms is crucial to understanding how novel traits arise. Do new traits require new genes or are old genes repurposed? How predictable is this process? Here, we examine this question for gene expression influencing parenting behavior in a beetle, Nicrophorus vespilloides. Parental care, produced from many individual behaviors, should be influenced by changes of expression of multiple genes, and one suggestion is that the genes can be predicted based on knowledge of behavior expected to be precursors to parental care, such as aggression, resource defense, and mating on a resource. Thus, testing gene expression during parental care allows us to test expectations of this “precursor hypothesis” for multiple genes and traits. We tested for changes of the expression of serotonin, octopamine/tyramine, and dopamine receptors, as well as one glutamate receptor, predicting that these gene families would be differentially expressed during social interactions with offspring and associated resource defense. We found that serotonin receptors were strongly associated with social and aggression behavioral transitions. Octopamine receptors produced a complex picture of gene expression over a reproductive cycle. Dopamine was not associated with the behavioral transitions sampled here, while the glutamate receptor was most consistent with a behavioral change of resource defense/aggression. Our results generate new hypotheses, refine candidate lists for further studies, and inform the genetic mechanisms that are co‐opted during the evolution of parent–offspring interactions, a likely evolutionary path for many lineages that become fully social. The precursor hypothesis, while not perfect, does provide a starting point for identifying candidate genes.     

Gene insertion and deletion polymorphism in the serotonin transporter gene and personality traits measured by MMPI

Polymorphisms of the serotonin transporter gene are known to be associated with some personality traits measured by means of various psychological inventories. In the present work we attempted to find an association between genetic variants of serotonin transporter (loci VNTR-17 and 5-HTTLPR) and psychological traits scored by the MMPI inventory in 125 mentally healthy donors. No statistically significant differences in personality traits were found between carriers of different VNTR-17 genotypes. At locus 5-HTTLPR, significant between-genotype differences were revealed on the Schizophrenia scale (F = 3.49; P = 0.034) and on the validity scale F (F = 3.24; P = 0.042). The ss genotype carriers had the lowest scores on these scales. The score on the Psychopathic Deviate scale was significantly lower in the carriers of the ss genotype than in the combined group of the carriers of genotypes ll and ls (t = 2.07; P = 0.041). The differences on the validity scale K between the carriers of the ll and ss genotypes were also statistically significant (t = 2.49; P = 0.015). These results suggest that polymorphism of the serotonin transporter gene may be associated with the expression of schizoid traits (namely, social introversion, internal tension, weird thoughts and actions) in mentally healthy individuals. In the context of social adaptation, the personality profile configuration and data of statistical analysis indicate that the carriers of the ss genotype are more inclined to observe social norms than the carriers of the ll and ls genotypes.     

Association between temperament related traits and single nucleotide polymorphisms in the serotonin and oxytocin systems in Merino sheep

Animal temperament is defined as the consistent behavioral and physiological differences that are seen between individuals in response to the same stressor. Neurotransmitter systems, like serotonin and oxytocin in the central nervous system, underlie variation in behavioral traits in humans and other animals. Variations like single nucleotide polymorphisms (SNPs) in the genes for tryptophan 5-hydroxylase (TPH2), the serotonin transporter (SLC6A4), the serotonin receptor (HTR2A), and the oxytocin receptor (OXTR) are associated with behavioral phenotype in humans. Thus, the objective of this study was to identify SNPs in those genes and to test if those variations are associated with the temperament in Merino sheep. Using ewes from the University of Western Australia temperament flock, which has been selected on emotional reactivity for more than 20 generations, eight SNPs (rs107856757, rs107856818, rs107856856 and rs107857156 in TPH2, rs20917091 in SLC6A4, rs17196799 and rs17193181 in HTR2A, and rs17664565 in OXTR) were found to be distributed differently between calm and nervous sheep. These eight SNPs were then genotyped in 260 sheep from a flock that has never been selected on emotional reactivity, followed by the estimation of the behavioral traits of those 260 sheep using an arena test and an isolation box test. We found that several SNPs in TPH2 (rs107856757, rs107856818, rs107856856 and rs107857156) were in strong linkage disequilibrium, and all were associated with behavioral phenotype in the nonselected sheep. Similarly, rs17196799 in HTR2A was also associated with the behavioral phenotype.     

Evidence for the effect of serotonin receptor 1A gene (HTR1A) polymorphism on tractability in Thoroughbred horses

Tractability, or how easily animals can be trained and controlled, is an important behavioural trait for the management and training of domestic animals, but its genetic basis remains unclear. Polymorphisms in the serotonin receptor 1A gene (HTR1A) have been associated with individual variability in anxiety‐related traits in several species. In this study, we examined the association between HTR1A polymorphisms and tractability in Thoroughbred horses. We assessed the tractability of 167 one‐year‐old horses reared at a training centre for racehorses using a questionnaire consisting of 17 items. A principal components analysis of answers contracted the data to five principal component (PC) scores. We genotyped two non‐synonymous single nucleotide polymorphisms (SNPs) in the horse HTR1A coding region. We found that one of the two SNPs, c.709G>A, which causes an amino acid change at the intracellular region of the receptor, was significantly associated with scores of four of five PCs in fillies (all Ps < 0.05) and one PC in colts (P < 0.01). Horses carrying an A allele at c.709G>A showed lower tractability. This result provides the first evidence that a polymorphism in a serotonin‐related gene may affect tractability in horses with the effect partially different depending on sex.     

Allele polymorphism of the serotonin transporter gene and clinical heterogeneity of depressive disorders

Depression disorders are a clinically heterogeneous disease group. Their development is to a substantial extent underlain by dysfunction of the serotonin system, in particular, disturbed serotonin transport. The heterogeneity of depressions is associated, among other factors, with the age at disease onset. Allele polymorphism of the serotonin transporter (5-HTT) gene was tested for association with age at disease onset, clinical signs, and anxiety-related traits of depression patients. A sample included 77 patients (mean age 61.2 +/- 8.8 years) with late-onset depression (LOD, mean age at onset 56.58 +/- 9.7 years) and 74 patients (mean age 31.0 +/- 11.8 years) with early-onset depression (EOD, mean age at onset 23.9 +/- 7.4 years). In genotype frequency distribution of two 5-HTT gene polymorphism, the LOD and EOD groups did not differ from each other (chi 2 = 0.33, P = 0.85 for VNTR-17; chi 2 = 3.33, P = 0.19 for HTTLPR) and from a control group (chi 2 = 0.34, P = 0.84 for VNTR-17; chi 2 = 2.1, P = 0.35 for HTTLPR). In either group, patients differing in VNTR-17 and HTTLPR genotypes did not differ in psychological traits and, in particular, in anxiety-related traits. In the case of the HTTLPR polymorphism, LOD patients with genotype ss tended to display less severe neuroticism (t = 2.03, P = 0.0507) and scored significantly less on the Hamilton depression scale (t = 2.19, P = 0.039). Thus, the 5-HTT gene polymorphisms do not affect the risk of depression but is possibly associated with specific clinical signs of the disease, at least in elderly patients.     

Serotonin receptors antagonistically modulate Caenorhabditis elegans longevity

The neurotransmitter serotonin has been implicated in affecting the variation of longevity in natural Drosophila populations and age-related diseases in mammals. Based on these observations, it has been predicted that serotonin signal, perhaps at levels of serotonin biosynthesis, may control lifespan. Here, we investigated a variety of mutations in serotonin-signal genes, including serotonin biosynthesis genes, a serotonin transporter gene, and serotonin receptor genes. Despite this prediction, mutations in the serotonin biosynthesis genes had little or modest effects on lifespan, while the mod-5 mutation with increased availability of serotonin caused a modest life-shortening effect. In contrast, a deletion mutation of the ser-1 serotonin receptor gene increased longevity by up to 46%, likely through the insulin/insulin-like growth factor 1 pathway. This result suggests an interaction between the serotonin pathway and the insulin/insulin-like growth factor 1 pathway. A deletion mutation of another serotonin receptor gene, ser-4 , shortened early to mid lifespan. The results suggest that serotonin signal antagonistically modulates longevity through different serotonin receptors. This study may indicate serotonin receptors as a potential target for antigeric interventions.     

Variation in ITGB3 has sex-specific associations with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample

A recent genome-scan identified the Leu33Pro polymorphism in the 3 integrin (ITGB3) gene as a quantitative trait locus for whole blood serotonin level in a large Hutterite pedigree. Because both the Leu33Pro polymorphism and the serotonin system have been implicated in cardiovascular disease (CVD) risk and treatment response, we studied additional variation in ITGB3 and its relationship to intermediate phenotypes associated with CVD in the same population. We examined associations between 15 single nucleotide polymorphisms (SNPs) across ITGB3 and five CVD-related traits in the Hutterites: plasma levels of high density lipoprotein-cholesterol (HDL-c), triglycerides (TG), low density lipoprotein-cholesterol (LDL-c), and lipoprotein(a) [Lp(a)] and blood pressure or hypertension. Seven of these SNPs in ITGB3 were associated with whole blood serotonin. Among the intermediate CVD-related phenotypes, only Lp(a) was associated with multiple ITGB3 SNPs, five of which were also associated with serotonin. A sex-stratified analysis revealed that the association between ITGB3 and Lp(a) is present only in females, whereas the association between ITGB3 and serotonin is concentrated in males. Our results suggest that variation in ITGB3 in addition to Leu33Pro could contribute to susceptibility to CVD and serotonin in a sex-specific manner.     

Associations of Polymorphisms in Four Candidate Genes with Carcass and/or Meat-Quality Traits in Two Meat-Type Chicken Lines

The associations between polymorphisms of five genes, calpain 1 ( CAPN1 ), follicle stimulating hormone beta (FSHB), follicle stimulating hormone receptor (FSHR), peroxisome proliferator-activated receptor gamma (PPARG), and retinol binding protein 7 (RBP7), and live weight, carcass composition, and meat-quality traits were estimated from two meat-type chickens lines (n = 311). Except for the variants of the FSHR gene, 11 SNPs of the other four genes and two diplotypes of PPARG were associated with one or more traits excluding shear factor (SF). SNP C31566680T of the CAPN1 gene was significantly associated with live weight (LW) carcass traits. The SNP A4580859C of FSHB gene was significantly associated with breast muscle weight (BrW) and LW. One of the PPARG SNPs, C5070948T, was associated with intramuscular fat content in breast (IMF _br ). Diplotype P1 of the PPARG gene was significantly associated with LW and all carcass traits. P3 were significantly associated with abdominal fat weight (AbFW). SNPs in RBP7 were only associated with BrW. These results indicate that the four genes were associated with these traits and have promise as genetic markers for future marker-assisted selection. Supplementary materials for this paper are available online.     

Insertion/Deletion Polymorphism of the Serotonin Transporter Gene and Neuroticism as a Temperament Trait in Affective Patients and Healthy Individuals

Some studies associate the insertion/deletion polymorphism of the serotonin transporter (5-HTT) gene with anxiety-related personality traits in mentally healthy people, the short (s) allele being associated with a higher neuroticism score. The 5-HTT genotype and neuroticism score were established for 114 affective patients, 87 healthy relatives of endogenous psychosis patients, and for 156 mentally healthy people without familial psychiatric history. The effects of sex and age on the association between the two parameters was studied. Neuroticism proved to be not associated with the 5-HTT genotype.     

Identification of estrogen receptor alpha gene polymorphisms by SSCP and its effect on reproductive traits in Japanese flounder (Paralichthys olivaceus)

Estrogen receptor (ERalpha) modifies the expression of genes involved in cell growth, proliferation and differentiation through binding to estrogen response elements (EREs) located in a number of gene promoters, so the ERalpha gene is considered as an important factor affecting reproductive endocrinology in Japanese flounder (Paralichthys olivaceus). In this study, twelve single nucleotide polymorphisms (SNPs) within eight CDS exons and 1 kb of 3'-UTR of the ERalpha gene were tested to association with four reproductive traits in a population of 119 Japanese flounder individuals with polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP). The association analysis of SNPs within Japanese flounder ERalpha gene with the reproductive traits was carried out using General Linear Model (GLM) estimation. Results indicated that two SNPs in the exon4 of ERalpha gene, P1 (A803G and C864T), were significantly associated with hepatosomatic index (HSI) (P<0.05) in female Japanese flounder. Other ten SNPs in 3'-UTR associated to serum 17beta-estradiol (E(2)) and HSI showed that P2 (A1982T) was significantly associated with E(2) (P<0.01) and P3 (A2149G, 2181TTACAAG2182 insertion or deletion, T2324G, A2359G and G2391A) was significantly associated with HSI (P<0.05) in female Japanese flounder. However, P2 (A1982T) and P4 (G2256T, T2294C, T2309G and A2333T) had significant effects on E(2) (P<0.05 and P<0.01, respectively) in male Japanese flounder. In addition, there were significant associations between diplotype D1 based on fourteen SNPs and reproductive traits. The genetic effects for HSI (female) or E(2) (male) of diplotype D1 were significantly higher than those of other eight diplotypes (P<0.05), respectively. Our findings implied that P1 of ERalpha gene affecting the reproductive traits could be a potential QTN (quantitative trait nucleotide) which would be useful genetic marker in the selection of some reproductive traits for its in Japanese flounder.     

Insertion-deletion polymorphism of the serotonin carrier gene and evaluation of neurotism as a temperament trait in patients with affective disorders and mentally healthy people]

Some studies associate the insertion/deletion polymorphism of the serotonin transporter (5-HTT) gene with anxiety-related personality traits in mentally healthy people, the short (s) allele being associated with a higher neuroticism score. The 5-HTT genotype and neuroticism score were established for 114 affective patients, 87 healthy relatives of endogenous psychosis patients, and for 156 mentally healthy people without familial psychiatric history. The effects of sex and age on the association between the two parameters was studied. Neuroticism proved to be not associated with the 5-HTT genotype.