Fuchang Zhang

Identifying potential risk haplotypes for schizophrenia at the DTNBP1 locus in Han Chinese and Scottish populations

The dystrobrevin-binding protein 1 (DTNBP1) gene on chromosome 6p has emerged as a potential susceptibility gene for schizophrenia. Although a number of attempts to replicate the original association finding have been successful, they have not identified any obvious pathogenic variants or a single at risk haplotype common to all populations studied. In the present study we attempted further replication in an independent sample of 638 nuclear families from the Han Chinese population of Sichuan Province, SW China. We also examined 580 Scottish schizophrenic cases and 620 controls. We genotyped 10 single-nucleotide polymorphisms (SNPs) in DTNBP1 that were used in the original report of association, plus rs2619538 (SNP ‘A’) in the putative promoter region, which has also been associated with schizophrenia. In the Chinese trios we found that two SNPs (P1635 and P1765) were significantly overtransmitted, but with alleles opposite to those reported in the original studies. SNPs P1757 and P1765 formed a common haplotype, which also showed significant overtransmission. In the Scottish cases and controls, no individual markers were significantly associated with schizophrenia. A single haplotype, which included rs2619538 and P1583, and one rare haplotype, composed of P1320 and P1757, were significantly associated with schizophrenia, but no previously reported haplotypes were associated. Based on the data from the Chinese population, our results provide statistical support for DTNBP1 as a susceptibility gene for schizophrenia, albeit with haplotypes different from those of the original study. However, our lack of replication in the Scottish samples also indicates that caution is warranted when evaluating the robustness of the evidence for DTNBP1 as genetic risk factor for schizophrenia.

Effect of BDNF Val66Met Polymorphism on Digital Working Memory and Spatial Localization in a Healthy Chinese Han Population

Cognitive abilities are complex human traits influenced by genetic factors. Brain-derived neurotrophic factor (BDNF), a unique polypeptide growth factor, has an influence on the differentiation and survival of neurons in the nervous system. A single-nucleotide polymorphism (rs6265) in the human gene, resulting in a valine to methionine substitution in the pro-BDNF protein, was thought to associate with psychiatric disorders and might play roles in the individual difference of cognitive abilities. However, the specific roles of the gene in cognition remain unclear. To investigate the relationships between the substitution and cognitive abilities, a healthy population-based study and the PCR-SSCP method were performed. The results showed the substitution was associated with digital working memory (p = 0.02) and spatial localization (p = 0.03), but not with inhibition, shifting, updating, visuo-spatial working memory, long-term memory, and others (p > 0.05) among the compared genotype groups analyzed by general linear model. On the other hand, the participants with BDNFGG had higher average performance in digital working memory and spatial localization than the ones with BDNFAA. The findings of the present work implied that the variation in BDNF might play positive roles in human digital working memory and spatial localization.

Common genetic variants on 1p13.2 associate with risk of autism

Autism is a highly heritable neurodevelopmental disorder, and known genetic variants, mostly rare, account only for a small proportion of cases. Here we report a genome-wide association study on autism using two Chinese cohorts as gene discovery (n=2150) and three data sets of European ancestry populations for replication analysis of top association signals. Meta-analysis identified three single-nucleotide polymorphisms, rs936938 (P=4.49 × 10−8), non-synonymous rs6537835 (P=3.26 × 10−8) and rs1877455 (P=8.70 × 10−8), and related haplotypes, AMPD1-NRAS-CSDE1, TRIM33 and TRIM33-BCAS2, associated with autism; all were mapped to a previously reported linkage region (1p13.2) with autism. These genetic associations were further supported by a cis-acting regulatory effect on the gene expressions of CSDE1, NRAS and TRIM33 and by differential expression of CSDE1 and TRIM33 in the human prefrontal cortex of post-mortem brains between subjects with and those without autism. Our study suggests TRIM33 and NRAS-CSDE1 as candidate genes for autism, and may provide a novel insight into the etiology of autism.

An Association Study of the Genetic Polymorphisms in 13 Neural Plasticity-Related Genes with Semantic and Episodic Memories

Semantic and episodic memories were two different attributes of long-term memory. In the past few years, plenty of physiological evidence has indicated that neural plasticity is involved in the formation of long-term memory. In the present study, we hypothesized that some functional variants of neural plasticity-related genes were related to episodic and semantic memories. To confirm this hypothesis, we examined the relationship of 13 plasticity-related genes with episodic and semantic memories. The results indicated that there was a statistically significant difference in semantic memory scores among the three genotype groups of T267C in 5-HT6 (χ2 = 16.638, p = 0.0002). However, the functional variations in BDNF, COMT, DBH, DRD2, DRD3, DRD4, MAOA, TPH2, 5-HT2A, GRM1, and GRIN2B had no observable effects on the memories. Our preliminary results confirm the hypothesis that a small number of functional variants of the neural plasticity-related genes, such as T267C in 5-HT6, play important roles in human specific memory.

Variations in 5-HT2A influence spatial cognitive abilities and working memory.

BACKGROUND 5-hydroxytryptamine receptor 2A (5-HT2A) participates in diverse psychiatric disorders by regulating the activity of serotonin. Some previous studies have also suggested that the receptor is involved in cognitive abilities of disease groups. We hypothesize that some functional genetic variants in 5-HT2A have certain specific influences on cognitive abilities in a normal population. METHOD To confirm this hypothesis, two polymorphisms (rs6313 and rs4941573) in 5-HT2A were selected, and a population-based study was performed in a young healthy Chinese Han cohort. RESULTS The results indicated that the rs6313 and rs4941573 were associated with touching blocks and mental rotation-3D error ratio in males, and the rs4941573 was associated with visuo-spatial working memory in the whole cohort. CONCLUSION All the findings suggest that 5-HT2A participates in human spatial cognitive abilities and spatial working memory.

A study on the correlation between IL1RAPL1 and human cognitive ability

This study aimed to investigate the effects of IL1RAPL1 on the human cognitive ability. Four genetic marker sites, i.e., DXS1218, DXS9896, rs6526806 and rs12847959 on IL1RAPL1 were genotyped in 332 Qinba Mountain Area children. Meanwhile, a cognition test with a C-WISC scale was performed to study the relationship of genotype with cognition test scores. Results indicated that genotypes of DXS1218, DXS9896 and rs12847959 were associated with memory/concentration factor intelligence quotient (IQ) (P=0.027, 0.042, 0.029, respectively). DXS1218 also associated with full IQ, verbal IQ, and performance IQ (P=0.006, 0.014, 0.006, respectively). rs12847959 were related to verbal comprehension factor and perceptual organization factor IQ (P=0.021, 0.043, respectively). Further study on rat brain revealed that Il1rapl was mainly expressed in memory/concentration-associated encephalic regions, such as hippocampus, dentate fascia, osmesis perithelium, and piriform cortex. mRNA expression levels of Il1rapl in brains of rats with different learning and memory abilities showed significant difference. Combined data suggested that IL1RAPL1 affected human cognitive ability to some extent, especially the memory and concentration capability.

The Effects of DBH, MAOA, and MAOB on Attentional Biases for Facial Expressions

Attentional bias is the interaction that occurs between emotion and attention. Monoamine oxidase and dopamine β-hydroxylase are involved in the balances of neurotransmitters in the cortex. Much evidence has shown that those enzymes play important roles in human emotion and attention. To investigate the potential influences of some functional polymorphisms in DBH, MAOA, and MAOB on attentional bias, we performed a population-based study in a young Chinese Han group. The results indicated that −1021C/T in DBH was associated with index effect of the neutral facial expressions in spatial cueing task (F = 4.940, P = 0.007), and there was a positive correlation between the dosage of C allele and the index effect (r = 0.068, P = 0.040). Furthermore, we found significant interactions between 19-bp Ins/Del in DBH and VNTR of MAOA on attentional biases for negative expressions in spatial cueing task (F = 3.397, P = 0.009) and dot-probe task (F = 2.827, P = 0.024). The present study suggests that DBH and MAOA can influence human attentional biases, and there is a gene–gene interaction between the DBH and MAOA on attentional bias for negative expressions.

Genetic variations in COMT and DRD2 modulate attentional bias for affective facial expressions.

Studies have revealed that catechol-O-methyltransferase (COMT) and dopaminegic receptor2 (DRD2) modulate human attention bias for palatable food or tobacco. However, the existing evidence about the modulations of COMT and DRD2 on attentional bias for facial expressions was still limited. In the study, 650 college students were genotyped with regard to COMT Val158Met and DRD2 TaqI A polymorphisms, and the attentional bias for facial expressions was assessed using the spatial cueing task. The results indicated that COMT Val158Met underpinned the individual difference in attentional bias for negative emotional expressions (P = 0.03) and the Met carriers showed more engagement bias for negative expressions than the Val/Val homozygote. On the contrary, DRD2 TaqIA underpinned the individual difference in attentional bias for positive expressions (P = 0.003) and individuals with TT genotype showed much more engagement bias for positive expressions than the individuals with CC genotype. Moreover, the two genes exerted significant interactions on the engagements for negative and positive expressions (P = 0.046, P = 0.005). These findings suggest that the individual differences in the attentional bias for emotional expressions are partially underpinned by the genetic polymorphisms in COMT and DRD2.

Association Analysis Between 12 Genetic Variants of Ten Genes and Personality Traits in a Young Chinese Han Population

Some genes involved in neurotransmission synthesis and transmission have been hypothesized to affect personality traits. To investigate the possible roles of these genes in personality traits of 16 Personality Factor Questionnaire, we performed a population-based study in a young Chinese Han cohort. In the study, we selected some functional variations in ten candidate genes (COMT, DBH, DRD2, DRD3, DAT, MAOA, GRM1, GRIN2B, 5-TH2A, and 5-TH6) encoding components in dopamine, glutamate, and 5-hydroxytryptamine pathways. The results showed the T102C in 5-TH2A was associated with X3 (emotional and quiet alertness) and B (reasoning) (F = 4.71 and 6.23; p = 0.009 and 0.002), Val158Met in COMT with E (dominance) (F = 7.01; p = 0.0009), while the variations in DBH, DRD2, DRD3, MAOA, GRM1, GRIN2B, and 5-TH6 were not associated with any of the personality traits. This finding suggests that T102C in 5-TH2A and Val158Met in COMT play roles in some human personality traits.

Genetic Variations in FTSJ1 Influence Cognitive Ability in Young Males in the Chinese Han Population

Human cognitive ability is a trait that is known to be significantly influenced by genetic factors. Previous linkage data provide evidence suggesting that gene FtsJ homolog 1 (Escherichia coli) is associated with mental retardation. The gene may have a relation to individual differences in cognitive ability because it is most critical for brain development. In the present research, three tag single-nucleotide polymorphism (SNPs) (rs2268954, rs2070991, and rs5905692) in FtsJ homolog 1 (E. coli) are selected and genotyped by the PCR-SSCP method. An analysis of variance is performed to determine the relationship between the SNPs and cognitive ability of the Chinese Han population of youth in Qinba mountain. There are significant correlations between the variance in FtsJ homolog 1 (E. coli) and general cognitive ability, verbal comprehension, and preceptual organization. These findings suggest that genetic variations in FtsJ homolog 1 (E. coli) possibly influence human cognitive ability.