[show abstract][hide abstract] ABSTRACT: The Allen Brain Atlas shows that the semaphorin 5A (SEMA5A) gene, which encodes an important protein for neurogenesis and neuronal apoptosis, is predominantly expressed in the human hippocampus. Structural and functional neuroimaging studies have further shown that the hippocampus plays an important role in the performance on Raven's Progressive Matrices (RPM), a measure of reasoning ability and general fluid intelligence. Thus far, however, no study has examined the relationships between the SEMA5A gene polymorphism, hippocampal volume, and RPM performance. The current study collected both structural MRI, genetic, and behavioral data in 329 healthy Chinese adults, and examined associations between SEMA5A variants, hippocampal volume, and performance on RAPM (the advanced form of RPM). After controlling for intracranial volume (ICV), sex, and age, SEMA5A genetic polymorphism at the SNP rs42352 had the strongest association with hippocampal volume (p=0.00000552 and 0.000103 for right and left hippocampal volumes, respectively), with TT homozygotes having higher hippocampal volume than the other genotypes. Furthermore, there was a high correlation between right hippocampal volume and RAPM performance (r=0.42, p=0.0000509) for SEMA5A rs42352 TT homozygotes. This study provides the first evidence for the involvement of the SEMA5A gene in hippocampal structure and their interaction on RAPM performance. Future studies of the hippocampus-RPM associations should consider genetic factors as potential moderators.
[show abstract][hide abstract] ABSTRACT: Previous research reported that serotonin receptor 2A gene (HTR2A) polymorphisms were associated with memory. However, it is unknown whether these genetic variants were associated with both true and false memories. The current study of 336 Han Chinese subjects tested 30 single nucleotide polymorphisms (SNPs) within the HTR2A gene for potential associations with true and false memories. False memories were assessed using the Deese-Roediger-McDermott (DRM) paradigm, in which people falsely remember semantically related (but unpresented) words. We found that 11 SNPs within the HTR2A gene were associated with true memory (p=0.000076-0.043). The associations between true memory and seven adjacent SNPs (i.e., rs1923888, rs1745837, rs9567739, rs3742279, rs655888, rs655854, and rs2296972) were still significant after multiple testing corrections. Haplotype-based association analysis revealed that, true memory was positively associated with haplotype A-C-C-G-C-T-A for these seven adjacent SNPs (p=0.000075), which was still significant after multiple testing correction. Only one SNP rs655854 was associated with false memory (p=0.023), and it was not significant after multiple testing correction. This study replicates, in an Asian population, that genetic variation in HTR2A is associated with episodic memory, and also suggests that this association is restricted to true memory.
Neurobiology of Learning and Memory 09/2013; · 3.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: The seven-factor biopsychosocial model of personality distinguished four biologically based temperaments and three psychosocially based characters. Previous studies have suggested that the four temperaments-Novelty Seeking (NS), Reward Dependence (RD), Harm Avoidance (HA), and Persistence (P)-have their respective neurobiological correlates, especially in the striatum-connected subcortical and cortical networks. However, few studies have investigated their neurobiological basis in the form of fiber connectivity between brain regions. This study correlated temperaments with fiber connectivity between the striatum and subcortical and cortical hub regions in a sample of 50 Chinese adult males. Generally consistent with our hypotheses, results showed that: (1) NS was positively correlated with fiber connectivity from the medial and lateral orbitofrontal cortex (mOFC, lOFC) and amygdala to the striatum; (2) RD was positively correlated with fiber connectivity from the mOFC, posterior cingulate cortex/retrosplenial cortex (PCC), hippocampus, and amygdala to the striatum; (3) HA was positively linked to fiber connectivity from the dorsolateral prefrontal cortex (dlPFC) and PCC to the striatum; and (4) P was positively linked to fiber connectivity from the mOFC to the striatum. These results extended the research on the neurobiological basis of temperaments by identifying their anatomical fiber connectivity correlates within the subcortical-cortical neural networks.
[show abstract][hide abstract] ABSTRACT: Longevity is influenced by genetic and environmental factors. The brain's dopamine system may be particularly relevant, since it modulates traits (e.g., sensitivity to reward, incentive motivation, sustained effort) that impact behavioral responses to the environment. In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health. We tested the hypothesis that the DRD4 gene influences longevity and that its impact is mediated through environmental effects. Surviving participants of a 30-year-old population-based health survey (N = 310; age range, 90-109 years; the 90+ Study) were genotyped/resequenced at the DRD4 gene and compared with a European ancestry-matched younger population (N = 2902; age range, 7-45 years). We found that the oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p = 3.5 × 10(-9)), and that this genotype was strongly correlated with increased levels of physical activity. Consistent with these results, DRD4 knock-out mice, when compared with wild-type and heterozygous mice, displayed a 7-9.7% decrease in lifespan, reduced spontaneous locomotor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contribute to longevity in humans and in mice, and suggest that this effect is mediated by shaping behavioral responses to the environment.
Journal of Neuroscience 01/2013; 33(1):286-291. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Obesity has become a worldwide health problem in the past decades. Human and animal studies have implicated serotonin in appetite regulation, and behavior genetic studies have shown that body mass index (BMI) has a strong genetic component. However, the roles of genes related to the serotoninergic (5-hydroxytryptamine,5-HT) system in obesity/BMI are not well understood, especially in Chinese subjects.
With a sample of 478 healthy Chinese volunteers, this study investigated the relation between BMI and genetic variations of the serotoninergic system as characterized by 136 representative polymorphisms. We used a system-level approach to identify SNPs associated with BMI, then estimated their overall contribution to BMI by multiple regression and verified it by permutation.
We identified 12 SNPs that made statistically significant contributions to BMI. After controlling for gender and age, four of these SNPs accounted for 7.7% additional variance of BMI. Permutation analysis showed that the probability of obtaining these findings by chance was low (p = 0.015, permuted for 1000 times).
These results showed that genetic variations in the serotoninergic system made a moderate contribution to individual differences in BMI among a healthy Chinese sample, suggesting that a similar approach can be used to study obesity.
PLoS ONE 01/2013; 8(3):e58717. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: DOPA decarboxylase (DDC) is involved in the synthesis of dopamine, norepinephrine and serotonin. It has been suggested that genes involved in the dopamine, norepinephrine, and cholinergic systems play an essential role in the efficiency of human attention networks. Attention refers to the cognitive process of obtaining and maintaining the alert state, orienting to sensory events, and regulating the conflicts of thoughts and behavior. The present study tested seven single nucleotide polymorphisms (SNPs) within the DDC gene for association with attention, which was assessed by the Attention Network Test to detect three networks of attention, including alerting, orienting, and executive attention, in a healthy Han Chinese sample (N = 451). Association analysis for individual SNPs indicated that four of the seven SNPs (rs3887825, rs7786398, rs10499695, and rs6969081) were significantly associated with alerting attention. Haplotype-based association analysis revealed that alerting was associated with the haplotype G-A-T for SNPs rs7786398- rs10499695-rs6969081. These associations remained significant after correcting for multiple testing by max(T) permutation. No association was found for orienting and executive attention. This study provides the first evidence for the involvement of the DDC gene in alerting attention. A better understanding of the genetic basis of distinct attention networks would allow us to develop more effective diagnosis, treatment, and prevention of deficient or underdeveloped alerting attention as well as its related prevalent neuropsychiatric disorders.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2012; · 3.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Previous research reported that a rare serotonin receptor 2B gene (HTR2B) stop codon mutation predisposes subjects to severe impulsivity and novelty seeking. In this study, we expanded this previous work by testing six single nucleotide polymorphisms (SNPs) within the HTR2B gene for potential associations with the behavioral inhibition system (BIS) and the three components of the behavioral approach systems (BAS: fun seeking, drive, and reward responsiveness) in a Han Chinese sample (N = 478). Association analysis for individual SNPs indicated that four of the six SNPs (i.e., rs6437000, rs10194776, rs16827801, and rs1549339) were significantly associated with BAS fun seeking (p = .0003–.0022). Haplotype-based association analysis revealed that fun seeking was positively associated with haplotype A–A–G–A for SNPs rs6437000–rs10194776–rs16827801–rs1549339 (p = .0002), which survived Bonferroni correction. Except for the association between BAS reward responsiveness and rs16827801 (p = .005), no other association was found for BAS drive, BAS reward responsiveness, or BIS. This study provides the first evidence for the involvement of the HTR2B gene in BAS fun seeking. A better understanding of the genetic basis of the BIS and BAS would allow us to develop more effective diagnosis, treatment, and prevention of impulsive behavioral problems.
Personality and Individual Differences 12/2012; 53(8):1029–1033. · 1.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: The genetic and neural basis of working memory (WM) has been extensively studied. Many dopamine (DA) related genes, including the NTSR1 gene (a DA modulator gene), have been reported to be associated with WM performance. The NTSR1 protein is predominantly expressed in the cerebral cortex and the hippocampus, the latter of which is closely involved in WM processing based on both lesion and fMRI studies. Thus far, however, no study has examined the joint effects of NTSR1 gene polymorphism and hippocampal morphology on WM performance. Participants of the current study were 330 healthy Chinese college students. WM performance was measured with a 2-back WM paradigm. Structural MRI data were acquired and then analyzed using an automated procedure with atlas-based FreeSurfer segmentation software (v 4.5.0) package. Linear regression analyses were conducted with a NTSR1 C/T polymorphism previously associated with WM (rs4334545) , hippocampal volume, and their interaction as predictors of WM performance, with gender and intracranial volume (ICV) as covariates. Results showed a significant interaction between NTSR1 genotype and hippocampal volume (p<.05 for both the left and right hippocampi). Further analysis showed that the correlation between hippocampal volume and WM scores was significant for carriers of the NTSR1 T-allele (p<.05 for both hippocampi), but not for CC homozygotes. These results indicate that the association between hippocampal structure and WM performance was modulated by variation in the NTSR1 gene, and suggest that further studies of brain-behavior associations should take genetic background information into account.
[show abstract][hide abstract] ABSTRACT: Previous case-control and family-based association studies have implicated the SLC6A4 gene in obsessive-compulsive disorder (OCD). Little research, however, has examined this gene's role in obsessive-compulsive symptoms (OCS) in community samples. The present study genotyped seven tag SNPs and two common functional tandem repeat polymorphisms (5-HTTLPR and STin2), which together cover the whole SLC6A4 gene, and investigated their associations with OCS in normal Chinese college students (N = 572). The results revealed a significant gender main effect and gender-specific genetic effects of the SLC6A4 gene on OCS. Males scored significantly higher on total OCS and its three dimensions than did females (ps < .01). The 5-HTTLPR in the promoter region showed a female-specific genetic effect, with the l/l and l/s genotypes linked to higher OCS scores than the s/s genotype (ps < .05). In contrast, a conserved haplotype polymorphism (rs1042173| rs4325622| rs3794808| rs140701| rs4583306| rs2020942) covering from intron 3 to the 3' UTR of the SLC6A4 gene showed male-specific genetic effects, with the CGAAGG/CGAAGG genotype associated with lower OCS scores than the other genotypes (ps < .05). These effects remained significant after controlling for OCS-related factors including participants' depressive and anxiety symptoms as well as stressful life events, and correction for multiple tests. These results are discussed in terms of their implications for our understanding of the sex-specific role of the different sections of the SLC6A4 gene in OCD.
Journal of psychiatric research 06/2012; 46(9):1153-60. · 3.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: Response inhibition refers to the suppression of inappropriate or irrelevant responses. It has a central role in executive functions, and has been linked to a wide spectrum of prevalent neuropsychiatric disorders. Increasing evidence from neuropharmacological studies has suggested that gene variants in the norepinephrine neurotransmission system make specific contributions to response inhibition. This study genotyped five tag single-nucleotide polymorphisms covering the whole alpha-2B-adrenergic receptor (ADRA2B) gene and investigated their associations with response inhibition in a relatively large healthy Chinese sample (N=421). The results revealed significant genetic effects of the ADRA2B conserved haplotype polymorphisms on response inhibition as measured by stop-signal reaction time (SSRT) (F(2, 418)=5.938, p=0.003). Individuals with the AAGG/AAGG genotype (n=89; mean SSRT=170.2 ms) had significantly shorter SSRTs than did those with either the CCAC/AAGG genotype (n=216; mean SSRT=182.4 ms; uncorrected p=0.03; corrected p=0.09) or the CCAC/CCAC genotype (n=116; mean SSRT=195.8 ms; corrected p<0.002, Cohen's d=0.51). This finding provides the first evidence from association research in support of a critical role of the norepinephrine neurotransmission system in response inhibition. A better understanding of the genetic basis of response inhibition would allow us to develop more effective diagnosis, treatment, and prevention of deficient or underdeveloped response inhibition as well as its related prevalent neuropsychiatric disorders.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2012; 37(5):1115-21. · 6.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study investigated the relation between genetic variations in the dopamine system and facial expression recognition.
A sample of Chinese college students (n = 478) was given a facial expression recognition task. Subjects were genotyped for 98 loci [96 single-nucleotide polymorphisms (SNPs) and 2 variable number tandem repeats] in 16 genes involved in the dopamine neurotransmitter system, including its 4 subsystems: synthesis (TH, DDC, and DBH), degradation/transport (COMT,MAOA,MAOB, and SLC6A3), receptors (DRD1,DRD2,DRD3,DRD4, and DRD5), and modulation (NTS,NTSR1,NTSR2, and NLN). To quantify the total contributions of the dopamine system to emotion recognition, we used a series of multiple regression models. Permutation analyses were performed to assess the posterior probabilities of obtaining such results.
Among the 78 loci that were included in the final analyses (after excluding 12 SNPs that were in high linkage disequilibrium and 8 that were not in Hardy-Weinberg equilibrium), 1 (for fear), 3 (for sadness), 5 (for anger), 13 (for surprise), and 15 (for disgust) loci exhibited main effects on the recognition of facial expressions. Genetic variations in the dopamine system accounted for 3% for fear, 6% for sadness, 7% for anger, 10% for surprise, and 18% for disgust, with the latter surviving a stringent permutation test.
Genetic variations in the dopamine system (especially the dopamine synthesis and modulation subsystems) made significant contributions to individual differences in the recognition of disgust faces.
[show abstract][hide abstract] ABSTRACT: Both genetic and environmental factors have been shown to influence decision making, but their relative contributions and interactions are not well understood. The present study aimed to reveal possible gene-environment interactions on decision making in a large healthy sample. Specifically, we examined how the frequently studied COMT Val(158)Met polymorphism interacted with an environmental risk factor (i.e., stressful life events) and a protective factor (i.e., parental warmth) to influence affective decision making as measured by the Iowa Gambling Task. We found that stressful life events acted as a risk factor for poor IGT performance (i.e., high reward sensitivity) among Met carriers, whereas parental warmth acted as a protective factor for good IGT performance (i.e., higher IGT score) among Val/Val homozygotes. These results shed some new light on gene-environment interactions in decision making, which could potentially help us understand the underlying etiology of several psychiatric disorders associated with decision making impairment.
[show abstract][hide abstract] ABSTRACT: To investigate the combined effect of an exon III variable number tandem repeat in the dopamine receptor gene (DRD4) and insecure attachment style on risk for tobacco, cannabis and alcohol use problems in young adulthood. It was hypothesized that (1) individuals with 5, 6, 7 or 8 repeats (labelled 7R+) would be at increased risk for problematic drug use, and (2) risk for drug use would be further increased in individuals with 7R+ repeats who also have a history of insecure parent–child attachment relations. Data were drawn from the Victorian Adolescent Health Cohort Study, an eight-wave longitudinal study of adolescent and young adult development. DRD4 genotypes were available for 839 participants. Risk attributable to the combined effects of 7R+ genotype and insecure attachments was evaluated within a sufficient causes framework under the assumptions of additive interaction using a two-by-four table format with a common reference group. 7R+ alleles were associated with higher tobacco, cannabis and alcohol use (binging). Insecure attachments were associated with higher tobacco and cannabis use but lower alcohol use. For tobacco, there was evidence of interaction for anxious but not avoidant attachments. For cannabis, there was evidence of interaction for both anxious and avoidant attachments, although the interaction for anxious attachments was more substantial. There is no evidence of interaction for binge drinking. Results are consistent with a generic reward deficit hypothesis of drug addiction for which the 7R+ disposition may play a role. Interaction between 7R+ alleles and attachment insecurity may intensify risk for problematic tobacco and cannabis use.
[show abstract][hide abstract] ABSTRACT: Alcohol use is highly heritable and has been associated with many gene variants, including those related to dopamine (DA). However, single gene association studies have shown inconsistent and small effects. Using a system-level approach, the current study aimed to estimate the overall effect of genetic variations in the DA system on alcohol use among male drinkers. One hundred seventy-six male college students who reported to have ever drunk alcohol were enrolled. Alcohol use was measured using the Alcohol Use Disorders Identification Test. Ninety-eight representative polymorphisms in all major DA neurotransmitter genes were genotyped. Using analysis of variance, we identified six single-nucleotide polymorphisms (SNP)s that made statistically significant contributions to alcohol use. Next, main effects and interactions of these SNPs were assessed using multiple regression. The final model accounted for approximately 20% of the variance for alcohol use. Finally, permutation analyses ascertained the probability of obtaining these findings by chance to be low, p ranging from 0.024 to 0.048. These results confirmed that DA-related gene variants made strong contributions to reported alcohol use and suggest that multiple regression can be a promising way to explore the genetic basis for multi-gene-determined human behaviors.
[show abstract][hide abstract] ABSTRACT: Previous research has shown inconsistent findings regarding the relations between the functional Val158Met polymorphisms of the catechol-O-methyltransferase (COMT) gene and individual differences in personality traits. This study attempts to overcome some of the weaknesses of previous research, namely, small sample sizes, clinical samples, ethnic stratification, wide age ranges, neglecting sex differences, and single measures of personality traits. A large sample (n = 556, 250 male, 306 female) of healthy Chinese college students (mean age = 20.5 ± 1 years) was given a battery of personality scales, including the temperament and character inventory-revised, the behavioral inhibition system and behavioral approach system scale, the Beck depression inventory, and the Beck anxiety inventory. Factor analysis of the affect-related personality traits revealed two factors that corresponded to positive (PEM) and negative emotionality (NEM). We found a consistent COMT-by-sex interaction effect on affect-related personality traits. Compared with males with Met/Met alleles, males with Val/Val alleles showed significantly higher scores on NEM, but lower scores on PEM. Females, however, showed an opposite but nonsignificant pattern. Our results supported the role of the COMT gene in personality traits for males and contributed to the growing literature on sex differences in gene-behavior connections.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2011; 36(8):1593-8. · 6.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent molecular genetics studies showed significant associations between dopamine-related genes (including genes for dopamine receptors, transporters, and degradation) and working memory, but little is known about the role of genes for dopamine modulation, such as those related to neurotensin (NT), in working memory. A recent animal study has suggested that NT antagonist administration impaired working memory in a learning task. The current study examined associations between NT genes and working memory among humans.
Four hundred and sixty healthy undergraduate students were assessed with a 2-back working memory paradigm. 5 SNPs in the NTSR1 gene were genotyped. 5 ANOVA tests were conducted to examine whether and how working memory differed by NTSR1 genotype, with each SNP variant as the independent variable and the average accuracy on the working memory task as the dependent variable.
ANOVA results suggested that two SNPs in the NTSR1 gene (rs4334545 and rs6090453) were significantly associated with working memory. These results survived corrections for multiple comparisons.
Our results demonstrated that NTSR1 SNP polymorphisms were significantly associated with variance in working memory performance among healthy adults. This result extended previous rodent studies showing that the NT deficiency impairs the working memory function. Future research should replicate our findings and extend to an examination of other dopamine modulators.
PLoS ONE 01/2011; 6(3):e17365. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Traditional behavioral genetic studies (e.g., twin, adoption studies) have shown that human personality has moderate to high heritability, but recent molecular behavioral genetic studies have failed to identify quantitative trait loci (QTL) with consistent effects. The current study adopted a multi-step approach (ANOVA followed by multiple regression and permutation) to assess the cumulative effects of multiple QTLs. Using a system-level (dopamine system) genetic approach, we investigated a personality trait deeply rooted in the nervous system (the Highly Sensitive Personality, HSP). 480 healthy Chinese college students were given the HSP scale and genotyped for 98 representative polymorphisms in all major dopamine neurotransmitter genes. In addition, two environment factors (stressful life events and parental warmth) that have been implicated for their contributions to personality development were included to investigate their relative contributions as compared to genetic factors. In Step 1, using ANOVA, we identified 10 polymorphisms that made statistically significant contributions to HSP. In Step 2, these polymorphism's main effects and interactions were assessed using multiple regression. This model accounted for 15% of the variance of HSP (p<0.001). Recent stressful life events accounted for an additional 2% of the variance. Finally, permutation analyses ascertained the probability of obtaining these findings by chance to be very low, p ranging from 0.001 to 0.006. Dividing these loci by the subsystems of dopamine synthesis, degradation/transport, receptor and modulation, we found that the modulation and receptor subsystems made the most significant contribution to HSP. The results of this study demonstrate the utility of a multi-step neuronal system-level approach in assessing genetic contributions to individual differences in human behavior. It can potentially bridge the gap between the high heritability estimates based on traditional behavioral genetics and the lack of reproducible genetic effects observed currently from molecular genetic studies.
PLoS ONE 01/2011; 6(7):e21636. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Risky decision making is a complex process that involves weighing the probabilities of alternative options that can be desirable, undesirable, or neutral. Individuals vary greatly in how they make decisions either under ambiguity and/or under risk. Such individual differences may have genetic bases. Based on previous studies on the genetic basis of decision making, two decision making tasks [i.e., the Iowa Gambling Task (IGT) and Loss Aversion Task (LAT)] were used to test the effect of 5-HTTLPR polymorphism on decision making under ambiguity and under risk in a large Han Chinese sample (572 college students, 312 females). Basic intelligence and memory tests were also included to control for the influence of basic cognitive abilities on decision making. We found that 5-HTTLPR polymorphism significantly influenced performance in both IGT and LAT. After controlling for intelligence and memory abilities, subjects homozygous for s allele had lower IGT scores than l carriers in the first 40 trials of the IGT task. They also exhibited higher loss aversion than l carriers in the LAT task. Moreover, the effects of 5-HTTLPR were stronger for males than for females. These results extend the literature on the important role of emotion in decision making under ambiguity and risk, and shed additional lights on how decision making is influenced by culture as well as sex differences. Combining our results with existing literature, we propose that these effects might be mediated by a neural circuitry that comprises the amygdala, ventromedial prefrontal cortex, and insular cortex. Understanding the genetic factors affecting decision making in healthy subjects may allow us to better identify at-risk individuals, and better target the development of new potential treatments for specific disorders such as schizophrenia, addiction, and depression.