Multiple phenotypes in genome-wide genetic mapping studies

For many psychiatric and other traits, diagnoses are based on a number of different criteria or phenotypes. Rather than carrying out genetic analyses on the final diagnosis, it has been suggested that relevant phenotypes should be analyzed directly. We provide an overview of statistical methods for the joint analysis of multiple phenotypes in case-control association studies

Synthetic biology: From the first synthetic cell to see its current situation and future development

Synthetic biology is an emerging field, which, since its birth, has shown great value and potential in many fields including medicine, energy, environment and agriculture. It is also important for the study of the origin and evolution of life. Since the publication of the first synthetic cell in May, 2010, synthetic biology again attracts high attention and leads to extensive discussions all over the world. There have been a number of researches and achievements on synthetic biology in the United States and European countries. While in China, so far there is no systematic research on synthetic biology. In order to promote the development of this new discipline in China, we organized this review to systematically introduce the concept and research content of synthetic biology, summarize the achievements, and investigate the current situation in both China and abroad. We also analyzed the opportunities and challenges in synthetic biology, and looked forward to the future development of synthetic biology, especially its future development in China

Does conflict control occur without awareness? Evidence from an ERP study

The relationship between conflict control and awareness has attracted extensive interest. Although researchers have investigated the relationship between response conflict and awareness, it still remains unclear whether stimulus conflict can occur outside of awareness. In addition, previous studies on the role of awareness in conflict control have ignored the fact that conflict control includes both conflict detection and resolution. A modified version of the flanker task was used to manipulate stimulus and response conflicts under both masked and unmasked conditions. The masked condition elicited a sequence of distinct event-related potential components that were also observed in the unmasked condition. N2 amplitudes presented the following pattern: incongruent-eligible>incongruent-ineligible>congruent, they did not show any difference under the masked and unmasked conditions, suggesting that detection of stimulus-related conflict revealed by the comparison between incongruent-ineligible and congruent trials, and response-related conflict revealed by the comparison between incongruent-eligible and incongruent-ineligible trials can occur in the absence of awareness, and unconscious conflict detection might involve the same neural network employed for conscious conflict detection. Late positive component (LPC) amplitudes also presented as incongruent-eligible>incongruent-ineligible>congruent at CPz and Pz, irrespective of conscious awareness. However, LPC amplitudes under the masked condition were markedly reduced compared to unmasked trials. These LPC findings suggest that stimulus- and response-related conflict resolution can occur in the absence of awareness; furthermore, unconscious conflict resolution might involve a weaker cognitive control network compared to conscious conflict resolution. These findings have important implications for the theories concerning the relationship between cognitive control and awareness. (c) 2012 Elsevier B.V. All rights reserved

Pathway-based analysis for genome-wide association studies of schizophrenia to provide new insight in schizophrenia study

Schizophrenia (SZ) is an inheritable complex mental disease. There have been several genome-wide association studies (GWASs) of SZ to identify novel genetic susceptibility factors. To further interpret SZ GWASs, pathway-based analysis (PBA), which considers the combined effect of variants and identifies pathways associated with traits, provides a feasible solution to discover the biological function and mechanism of SZ. Furthermore, to investigate the common pathways between SZ and bipolar disorder (BD) will help explore common mechanism between psychiatric phenotypes. We performed a PBA, called improved gene set enrichment analysis (i-GSEA), on 3 independent GWASs of SZ to identify pathways associated with SZ. The results were further compared to the BD-associated pathways identified by i-GSEA for 2 BD GWASs and from literature reports. Our analysis identified a highly statistically significant association between SZ and pathway 'substrate specific channel activity' in all 3 SZ GWASs (false discovery rate (FDR) < 0.05). This association has not been reported elsewhere before. This pathway was also identified by PBA for 2 independent BD GWASs. Our results suggest that pathway 'substrate specific channel activity' is statistically significantly associated with SZ, and SZ and BD share the common biological function and mechanism represented by this pathway

Prioritization of candidate genes for attention deficit hyperactivity disorder by computational analysis of multiple data sources

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder characterized by hyperactivity, inattention and increased im-pulsivity. In recent years, a large number of genetic studies for ADHD have been published and related genetic data has been accumulated dramatically. To provide researchers a comprehensive ADHD genetic resource, we previously developed the first genetic database for ADHD (ADHDgene). The abundant genetic data provides novel candidates for further study. Meanwhile, it also brings new challenge for selecting promising candidate genes for replication and verification research. In this study, we surveyed the computational tools for candidate gene prioritization and selected five tools, which integrate multiple data sources for gene prioritization, to prioritize ADHD candidate genes in ADHDgene. The prioritization analysis resulted in 16 prioritized candidate genes, which are mainly involved in several major neurotransmitter systems or in nervous system development pathways. Among these genes, nervous system development related genes, especially SNAP25, STX1A and the gene-gene interactions related with each of them deserve further investigations. Our results may provide new insight for further verification study and facilitate the exploration of pathogenesis mechanism of ADHD

ICSNPathway: identify candidate causal SNPs and pathways from genome-wide association study by one analytical framework

Genome-wide association study (GWAS) is widely utilized to identify genes involved in human complex disease or some other trait. One key challenge for GWAS data interpretation is to identify causal SNPs and provide profound evidence on how they affect the trait. Currently, researches are focusing on identification of candidate causal variants from the most significant SNPs of GWAS, while there is lack of support on biological mechanisms as represented by pathways. Although pathway-based analysis (PBA) has been designed to identify disease-related pathways by analyzing the full list of SNPs from GWAS, it does not emphasize on interpreting causal SNPs. To our knowledge, so far there is no web server available to solve the challenge for GWAS data interpretation within one analytical framework. ICSNPathway is developed to identify candidate causal SNPs and their corresponding candidate causal pathways from GWAS by integrating linkage disequilibrium (LD) analysis, functional SNP annotation and PBA. ICSNPathway provides a feasible solution to bridge the gap between GWAS and disease mechanism study by generating hypothesis of SNP gene pathway(s). The ICSNPathway server is freely available at http://icsnpathway.psych.ac.cn/

MK4MDD: A Multi-Level Knowledge Base and Analysis Platform for Major Depressive Disorder

Background: Major depressive disorder (MDD) is a complex neuropsychiatric syndrome with high heterogeneity. There are different levels of biological components that underlie MDD and interact with each other. To uncover the disease mechanism, large numbers of studies at different levels have been conducted. There is a growing need to integrate data from multiple levels of research into a database to provide a systematic review of current research results. The cross level integration will also help bridge gaps of different research levels for further understanding on MDD. So far, there has been no such effort for MDD

Differences in learning rates for item and associative memories between amnestic mild cognitive impairment and healthy controls

Background: It has been established that the overall performance of associative memory was disproportionately impaired in contrast to item memory in aMCI (Amnestic mild cognitive impairment) patients, but little is known about the specific aspects of the memory process that show differences between aMCI and healthy controls. By comparing an item-item associative learning test with an individual item learning test, the present study investigated whether the rate of learning was slower in associative memory than in item memory in aMCI. Furthermore, we examined whether deficits in intertrial acquisition and consolidation contributed to the potential disproportionate impairments in the learning rate of associative memory for aMCI patients. In addition, we further explored whether the aMCI-discriminative power of the associative memory test increases more than that of the item memory test when the number of learning-test trials increases. Methods: A group of 40 aMCI patients and 40 matched control participants were administered a standardized item memory test (Auditory Verbal Learning Test, AVLT) and a standardized associative memory test (Paired Associative Learning Test, PALT), as well as other neuropsychological tests and clinical assessments. Results: The results indicated that the learning rate deficits in aMCI patients were more obvious for associative memory than for item memory and that the deficits resulted from impairments in both intertrial acquisition and consolidation. In addition, the receiver operating characteristic curve and logistical regression analysis revealed that the discriminative power of the associative memory test for aMCI was larger than that of the item memory test, especially with more than one learning-test trials. Conclusions: Due to more deficits in learning rate of associative memory than that of item memory, the discriminative power for aMCI tended to be larger in associative memory than in item memory when the number of learning-test trials increased. It is suggested that associative memory tests with multiple trials may be particularly useful for early detection of aMCI.</p

The neural correlates of reward-related processing in major depressive disorder: A meta-analysis of functional magnetic resonance imaging studies

Background: A growing number of functional magnetic resonance imaging (fMRI) studies have been conducted in major depressive disorder (MDD) to elucidate reward-related brain functions. The aim of this meta-analysis was to examine the common reward network in the MDD brain and to further distinguish the brain activation patterns between positive stimuli and monetary rewards as well as reward anticipation and outcome. Methods: A series of activation likelihood estimation (ALE) meta-analyses were performed across 22 fMRI studies that examined reward-related processing, with a total of 341 MDD patients and 367 healthy controls. Results: We observed several frontostriatal regions that participated in reward processing in MDD. The common reward network in MDD was characterized by decreased subcortical and limbic areas activity and an increased cortical response. In addition, the cerebellum, lingual gyms, parahippocampal gyrus and fusiform gyrus preferentially responded to positive stimuli in MDD, while the insula, precuneus, cuneus, PFC and inferior parietal lobule selectively responded to monetary rewards. Our results indicated a reduced caudate response during both monetary anticipation and outcome stages as well as increased activation in the middle frontal gyrus and dorsal anterior cingulate during reward anticipation in MDD. Limitations: The reward-related tasks and mood states of patients included in our analysis were heterogeneous. Conclusions: Our current findings suggest that there exist emotional or motivational pathway dysfunctions in MDD during reward-related processing. Future studies may be strengthened by paying careful attention to the types of reward used as well as the different components of reward processing examined. (C) 2013 Elsevier B.V. All rights reserved

Systematic evaluation of genome-wide methylated DNA enrichment using a CpG island array

Background: Recent progress in high-throughput technologies has greatly contributed to the development of DNA methylation profiling. Although there are several reports that describe methylome detection of whole genome bisulfite sequencing, the high cost and heavy demand on bioinformatics analysis prevents its extensive application. Thus, current strategies for the study of mammalian DNA methylomes is still based primarily on genome-wide methylated DNA enrichment combined with DNA microarray detection or sequencing. Methylated DNA enrichment is a key step in a microarray based genome-wide methylation profiling study, and even for future high-throughput sequencing based methylome analysis