精神分裂症易感基因

精神分裂症是一类遗传倾向性较高的多基因疾病。近年来,随着遗传学和分子生物学为主的多学科研究技术的快速发展,不断有新的易感基因报道;一些重要易感基因的生物学功能及其在该疾病发病机制中的作用研究也取得了一定进展。     

精神分裂症易感基因的研究进展

精神分裂症迄今病因未明,家系研究、双生子与寄养子的研究显示了精神分裂症的遗传倾向,各国学者开展了许多寻找其致病基因的研究工作。已经有大量关于精神分裂症易感基因的报道,有些结果也在后续试验中取得了较好的重复性。本文主要就精神分裂症易感基因的研究近况做一综述。     

A Genomewide Screen for Schizophrenia Genes in an Isolated Finnish Subpopulation, Suggesting Multiple Susceptibility Loci

Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Here, we report the results from a three-stage genomewide screen performed in a study sample from an internal isolate of Finland. An effort was made to identify genes predisposing for schizophrenia that are potentially enriched in this isolate, which has an exceptionally high lifetime risk for this trait. Ancestors of the local families with schizophrenia were traced back to the foundation of the population in the 17th century. This genealogical information was used as the basis for the study strategy, which involved screening for alleles shared among affected individuals originating from common ancestors. We found four chromosomal regions with markers revealing pairwise LOD scores>1.0: 1q32.2-q41 (Z(max)=3.82, dominant affecteds-only model), 4q31 (Z(max)=2. 74, dominant 90%-penetrance model), 9q21 (Z(max)=1.95, dominant 90%-penetrance model), and Xp11.4-p11.3 (Z(max)=2.01, recessive 90%-penetrance model). This finding suggests that there are several putative loci predisposing to schizophrenia, even in this isolate.     

A Two-Stage Association Study Suggests BRAP as a Susceptibility Gene for Schizophrenia

Schizophrenia (SZ) is a neurodevelopmental disorder in which altered immune function typically plays an important role in mediating the effect of environmental insults and regulation of inflammation. The breast cancer suppressor protein associated protein (BRAP) is suggested to exert vital effects in neurodevelopment by modulating the mitogen-activated protein kinase cascade and inflammation signaling. To explore the possible role of BRAP in SZ, we conducted a two-stage study to examine the association of BRAP polymorphisms with SZ in the Han Chinese population. In stage one, we screened SNPs in BRAP from our GWAS data, which detected three associated SNPs, with rs3782886 being the most significant one (P  =  2.31E-6, OR  =  0.67). In stage two, we validated these three SNPs in an independently collected population including 1957 patients and 1509 controls, supporting the association of rs3782886 with SZ (P  =  1.43E-6, OR  =  0.73). Furthermore, cis-eQTL analysis indicates that rs3782886 genotypes are associated with mRNA levels of aldehyde dehydrogenase 2 family (ALDH2) (P  =  0.0039) and myosin regulatory light chain 2 (MYL2) (P < 1.0E-4). Our data suggest that the BRAP gene may confer vulnerability for SZ in Han Chinese population, adding further evidence for the involvement of developmental and/or neuroinflammatory cascades in the illness.     

No Evidence for Prolonged Visible Persistence in Patients with Schizophrenia

Background

Temporal visual processing is strongly deteriorated in patients with schizophrenia. For example, the interval required between a visual stimulus and a subsequent mask has to be much longer in schizophrenic patients than in healthy controls. We investigated whether this deficit in temporal resolution is accompanied by prolonged visual persistence and/or deficient temporal precision (temporal asynchrony perception).

Methodology/Principal Findings

We investigated visual persistence in three experiments. In the first, measuring temporal processing by so-called backward masking, prolonged visible persistence is supposed to decrease performance. In the second experiment, requiring temporal integration, prolonged persistence is supposed to improve performance. In the third experiment, we investigated asynchrony detection, as another measure of temporal resolution. Eighteen patients with schizophrenia and 15 healthy controls participated. Asynchrony detection was intact in the patients. However, patients'' performance was inferior compared to healthy controls in the first two experiments. Hence, temporal processing in schizophrenic patients is indeed significantly impaired but this impairment is not caused by prolonged temporal integration.

Conclusions/Significance

Our results argue against a generally prolonged visual persistence in patients with schizophrenia. Together with the preserved ability of patients, to detect temporal asynchronies in permanently presented stimuli, the results indicate a more specific deficit in temporal processing of schizophrenic patients.     

Candidate Genes Associated with Susceptibility for SARS-Coronavirus

Assuming that no human had any previously acquired immunoprotection against severe acute respiratory syndrome coronavirus (SARS-CoV) during the 2003 SARS outbreak, the biological bases for possible difference in individual susceptibility are intriguing. However, this issue has never been fully elucidated. Based on the premise that SARS patients belonging to a given genotype group having a significantly higher SARS infection rate than others would imply that genotype group being more susceptible, we make use of a compartmental model describing disease transmission dynamics and clinical and gene data of 100 laboratory confirmed SARS patients from Chinese Han population in Taiwan to estimate the infection rates of distinct candidate genotype groups among these SARS-infected individuals. The results show that CXCL10(−938AA) is always protective whenever it appears, but appears rarely and only jointly with either Fgl2(+158T/*) or HO-1(−497A/*), while (Fgl2)(+158T/*) is associated with higher susceptibility unless combined with CXCL10/IP-10(−938AA), when jointly is associated with lower susceptibility. The novel modeling approach proposed, which does not require sizable case and control gene datasets, could have important future public health implications in swiftly identifying potential high-risk groups associated with being highly susceptible to a particular infectious disease.     

Eleven Candidate Susceptibility Genes for Common Familial Colorectal Cancer

Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes.     

妊高征易感基因的研究进展

妊高征具有明显的遗传倾向,其发病机理尚不清楚。本文综述了妊高征易感基因的研究进展,讨论了与高血压、内皮细胞损害、免疫反应失调相关基因和妊高征的关联,并论述了这些基因突变或多态性对妊高征的影响。 Abstract:The etiology and pathogenesis of pregnancy induced hypertension (PIH) remain still unknown.In recent years an increasing amount of evidence supports the concept that PIH is a complex genetic susceptibility disease.The progress in susceptibility gene for PIH is reviewed.The associations between the genes for hypertension,endothelial?cell dysfunction.,immune maladaptation?interaction and PIH have been recently investigated.Meanwhile,the paper evaluates the influences of mutations and polymorphism at the genes on PIH.     

Identification of Novel Candidate Genes for Early-Onset Colorectal Cancer Susceptibility

Approximately 25–30% of colorectal cancer (CRC) cases are expected to result from a genetic predisposition, but in only 5–10% of these cases highly penetrant germline mutations are found. The remaining CRC heritability is still unexplained, and may be caused by a hitherto-undefined set of rare variants with a moderately penetrant risk. Here we aimed to identify novel risk factors for early-onset CRC using whole-exome sequencing, which was performed on a cohort of CRC individuals (n = 55) with a disease onset before 45 years of age. We searched for genes that were recurrently affected by rare variants (minor allele frequency ≤0.001) with potentially damaging effects and, subsequently, re-sequenced the candidate genes in a replication cohort of 174 early-onset or familial CRC individuals. Two functionally relevant genes with low frequency variants with potentially damaging effects, PTPN12 and LRP6, were found in at least three individuals. The protein tyrosine phosphatase PTP-PEST, encoded by PTPN12, is a regulator of cell motility and LRP6 is a component of the WNT-FZD-LRP5-LRP6 complex that triggers WNT signaling. All variants in LRP6 were identified in individuals with an extremely early-onset of the disease (≤30 years of age), and two of the three variants showed increased WNT signaling activity in vitro. In conclusion, we present PTPN12 and LRP6 as novel candidates contributing to the heterogeneous susceptibility to CRC.     

Variation in Constraint Versus Positive Selection as an Explanation for Evolutionary Rate Variation Among Anthocyanin Genes

It has been argued that downstream enzymes in metabolic pathways are expected to be subject to reduced selective constraint, while upstream enzymes, particularly those at pathway branch points, are expected to exhibit more frequent adaptive substitution than downstream enzymes. We examined whether these expectations are met for enzymes in the anthocyanin biosynthetic pathway in Ipomoea. Previous investigations have demonstrated that downstream enzymes in this pathway have substantially higher rates of nonsynonymous substitution than upstream enzymes. We demonstrate here that the difference in rates between the most upstream enzyme (CHS) and the two most downstream enzymes (ANS and UFGT) is explained almost entirely by differences in levels of selective constraint. Adaptive substitutions were not detected in any of these genes. Our results are consistent with suggestions that constraint is greater on enzymes with greater connectivity.     

Olfactory Receptor Multigene Family in Vertebrates: From the Viewpoint of Evolutionary Genomics

Olfaction is essential for the survival of animals. Diverse odor molecules in the environment are detected by the olfactory receptors (ORs) in the olfactory epithelium of the nasal cavity. There are ~400 and ~1,000 OR genes in the human and mouse genomes, respectively, forming the largest multigene family in mammals. The relationships between ORs and odorants are multiple-to-multiple, which allows for discriminating almost unlimited number of different odorants by a combination of ORs. However, the OR-ligand relationships are still largely unknown, and predicting the quality of odor from its molecular structure is unsuccessful.Extensive bioinformatic analyses using the whole genomes of various organisms revealed a great variation in number of OR genes among species, reflecting the diversity of their living environments. For example, higher primates equipped with a well-developed vision system and dolphins that are secondarily adapted to the aquatic life have considerably smaller numbers of OR genes than most of other mammals do. OR genes are characterized by extremely frequent gene duplications and losses. The OR gene repertories are also diverse among human individuals, explaining the diversity of odor perception such as the specific anosmia.OR genes are present in all vertebrates. The number of OR genes is smaller in teleost fishes than in mammals, while the diversity is higher in the former than the latter. Because the genome of amphioxus, the most basal chordate species, harbors vertebrate-like OR genes, the origin of OR genes can be traced back to the common ancestor of the phylum Chordata.     

Resequencing and Association Analysis of PTPRA,a Possible Susceptibility Gene for Schizophrenia and Autism Spectrum Disorders

Background

The PTPRA gene, which encodes the protein RPTP-α, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks.

Methods

We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3′UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls.

Results

Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3′UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element.

Major Conclusions

No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.     

Immunity Genes and Susceptibility to Otitis Media: A Comprehensive Review

Otitis media (OM) is a middle ear infection associated with inflammation and pain. This disease frequently afflicts humans and is the major cause of hearing loss worldwide. OM continues to be one of the most challenging diseases in the medical field due to its diverse host targets and wide range of clinical manifestations. Substantial morbidity associated with OM is further exacerbated by high frequency of recurrent infections leading to chronic suppurative otitis media (CSOM). Children have greater susceptibility to, and thus, suffer most frequently from OM, which can cause significant deterioration in quality of life. Genetic factors have been demonstrated, in large part by twin and family studies, to be key determinants of OM susceptibility. In this review, we summarize the current knowledge on immunity genes and selected variants that have been associated with predisposition to OM. In particular, polymorphisms in innate immunity and cytokine genes have been strongly linked with the risk of developing OM. Future studies employing state-of-the-art technologies, including next-generation sequencing (NGS), will aid in the identification of novel genes associated with susceptibility to OM. This, in turn, will open up avenues for identifying high-risk individuals and designing novel therapeutic strategies based on precise targeting of these genes.     

Multiple Sclerosis Susceptibility Genes: Associations with Relapse Severity and Recovery

Objective

Patients with early multiple sclerosis (MS) have stereotyped attack severity and recovery. We sought to determine if polymorphisms in MS susceptibility genes are associated with these attack features or with the risk of a second attack.

Methods

503 white subjects evaluated within a year of MS onset were included in the study. The severity of and recovery from the first two attacks were determined based on published definitions. Seventeen MS susceptibility genes were genotyped at the UCSF MS Genetics laboratory. Each polymorphism was evaluated in multivariate ordinal models, adjusted for the other polymorphisms, for its association with attack severity and recovery. We also assessed if these polymorphisms were associated with increased risk of a second attack.

Results

The MPHOSPH9 polymorphism was associated with greater attack severity (odds ratios [OR] = 1.47, 95% CI [1.11, 1.94], p = 0.008), while the RGS1 and TNFRSF1A polymorphisms tended to be associated with reduced attack severity. The CD6 polymorphism tended to be associated with increased odds of worse attack recovery (OR = 1.25, 95% CI [0.93, 1.68], p = 0.13). In those who were HLA-DRB1-negative, the EVI5 polymorphism was associated with attacks of less severity; in HLA-DRB1 positive patients, EVI5 was associated with attacks of greater severity and worse recovery. The IL7R, TNFRSF1A, and GPC5 polymorphisms tended to be associated with having a second event within a year.

Conclusions

Some MS susceptibility polymorphisms may be associated with attack severity, recovery, or frequency. Further characterization of these genes may lead to a better understanding of MS pathogenesis and to a more individualized treatment approach.