复杂性疾病遗传学研究进展

近十年,随着人类基因组计划的建立及不断完善、遗传学队列研究和基因分型技术的日趋成熟,复杂性疾病遗传背景的研究获得了突飞猛进的发展.迄今已发现数百个与复杂性疾病存在可靠关联的遗传变异,这为我们认识复杂性疾病发病机制提供了重要线索.该文将重点回顾近十年复杂性疾病遗传学研究的进展,主要包括:人类对基因组序列和结构认识的进步,复杂性疾病研究策略、队列的进步,基因分型技术的进展,最后简要概括这些进步对于复杂性疾病遗传学研究的新贡献.     

Investigation of brain dynamics in Parkinson's disease by methods derived from nonlinear dynamics

EEGs were recorded from patients in early stages of Parkinson's disease (17 patients, 9 females) and healthy controls (12 subjects, 8 females) during rest and during execution/imagining of a complex motor task. The prediction that Parkinson's disease patients compared to controls would show more complex brain dynamics during performance of a complex motor task and imagination of the movements was confirmed by methods derived from nonlinear dynamics. In the resting state, analysis of correlation dimension of EEG time series revealed only slight topographical differences between the groups. During performance of a complex motor task, however, data from Parkinson's disease patients showed higher dimensionality than data from controls, indicating more complex EEG time series. The same difference was found when subjects did not perform any motor movements but imagined the complex movements they had just performed. The data are consistent with the hypothesis that the disturbances in Parkinson's disease result in the recruitment of superfluous cortical networks due to failed inhibition of alternative motor programs in the striatum and thus increase the complexity of cortical representation in motor conditions.     

Community of protein complexes impacts disease association

One important challenge in the post-genomic era is uncovering the relationships among distinct pathophenotypes by using molecular signatures. Given the complex functional interdependencies between cellular components, a disease is seldom the consequence of a defect in a single gene product, instead reflecting the perturbations of a group of closely related gene products that carry out specific functions together. Therefore, it is meaningful to explore how the community of protein complexes impacts disease associations. Here, by integrating a large amount of information from protein complexes and the cellular basis of diseases, we built a human disease network in which two diseases are linked if they share common disease-related protein complex. A systemic analysis revealed that linked disease pairs exhibit higher comorbidity than those that have no links, and that the stronger association two diseases have based on protein complexes, the higher comorbidity they are prone to display. Moreover, more connected diseases tend to be malignant, which have high prevalence. We provide novel disease associations that cannot be identified through previous analysis. These findings will potentially provide biologists and clinicians new insights into the etiology, classification and treatment of diseases.     

Celiac disease: moving from genetic associations to causal variants

Genome-wide association studies are providing insight into the genetic basis of common complex diseases: more than 1150 genetic loci [2165 unique single nucleotide polymorphisms (SNPs)] have recently been associated to 159 complex diseases. The hunt for genes contributing to immune-related diseases has been particularly successful in celiac disease, for example, with 27 genome-wide significantly associated loci identified so far. One of the current challenges is how to move from a genetic association with a disease to finding disease-associated genes and causal variants, as a step towards understanding the underlying disease process. About 50% of disease-associated SNPs affect the expression of nearby genes (so-called expression quantitative traits loci or eQTLs) and these can provide clues for finding causal variants. Although eQTLs can be useful, fine mapping and sequencing are required to refine the association signal. Ultimately, sophisticated study designs will be needed to find the causal variants involved in complex diseases. In this review, we use celiac disease as an example to describe the different aspects that need to be considered on the path from genetic association to disease-causing variants.     

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

Dystonia associated with Huntington's disease, Parkinson's disease or other neurodegenerative diseases substantially affects patients’ quality of life and is a major health problem worldwide. The above‐mentioned diseases are characterized by neurodegeneration accompanied by motor and cognitive impairment and often have complex aetiology. A frequent feature of these conditions is the abnormal accumulation of protein aggregates within specific neuronal populations in the affected brain regions. Familial neurodegenerative diseases are associated with a number of genetic mutations. Identification of these mutations allowed creation of modern model systems for studying neurodegeneration, either in cultured cells or in model animals. Animal models, especially mouse models, have contributed considerably to improving our understanding of the pathophysiology of neurodegenerative diseases. These models have allowed study of the pathogenic mechanisms and development of new disease‐modifying strategies and therapeutic approaches. However, due to the complex nature of these pathologies and the irreversible damage that they cause to the neural tissue, effective therapies against neurodegeneration remain to be elaborated. In this review, we provide an overview of cellular and animal models developed for studying neurodegenerative diseases, including Huntington's disease and dystonia of different origins.     

自身免疫性甲状腺疾病红细胞膜上免疫复合物的检测及其意义

本文应用抗人IgG,抗人C_3及抗人甲状腺球蛋白单克隆抗体的免疫荧光技术,检测了48例甲状腺疾病患者外周血红细胞,发现9例Graves′病活动期、4例桥本氏甲状腺炎患者的红细胞膜上存在特异性荧光着色,从而证实在一些自身免疫性甲状腺疾病的红细胞膜存在人甲状腺球蛋白免疫复合物,并探讨了在免疫病理损伤方面的意义。     

The immunogenetics of neurological disease

Genes encoding antigen‐presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. Myriad genetic, immunological and environmental factors may contribute to an individual's susceptibility to neurological disease. Here, we review and discuss the decades long research on the influence of genetic variation at the MHC locus and the role of immunogenetic killer cell immunoglobulin‐like receptor (KIR) loci in neurological diseases, including multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. The findings of immunogenetic association studies are consistent with a polygenic model of inheritance in the heterogeneous and multifactorial nature of complex traits in various neurological diseases. Future investigation is highly recommended to evaluate both coding and non‐coding variation in immunogenetic loci using high‐throughput high‐resolution next‐generation sequencing technologies in diverse ethnic groups to fully appreciate their role in neurological diseases.     

Diagnosis and classification of Goodpasture's disease (anti-GBM)

Goodpasture's disease or anti-glomerular basement membrane disease (anti-GBM-disease) is included among immune complex small vessel vasculitides. The definition of anti-GBM disease is a vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-GBM autoantibodies. The disease is a prototype of autoimmune disease, where the patients develop autoantibodies that bind to the basement membranes and activate the classical pathway of the complement system, which start a neutrophil dependent inflammation. The diagnosis of anti-GBM disease relies on the detection of anti-GBM antibodies in conjunction with glomerulonephritis and/or alveolitis. Overt clinical symptoms are most prominent in the glomeruli where the inflammation usually results in a severe rapidly progressive glomerulonephritis. Despite modern treatment less than one third of the patients survive with a preserved kidney function after 6 months follow-up. Frequencies vary from 0.5 to 1 cases per million inhabitants per year and there is a strong genetic linkage to HLA-DRB1¹1501 and DRB1¹1502. Essentially, anti-GBM disease is now a preferred term for what was earlier called Goodpasture's syndrome or Goodpasture's disease; anti-GBM disease is now classified as small vessel vasculitis caused by in situ immune complex formation; the diagnosis relies on the detection of anti-GBM in tissues or circulation in conjunction with alveolar or glomerular disease; therapy is effective only when detected at an early stage, making a high degree of awareness necessary to find these rare cases; 20–35% have anti-GBM and MPO-ANCA simultaneously, which necessitates testing for anti-GBM whenever acute test for ANCA is ordered in patients with renal disease.     

What is new about the genetic background of Hirschsprung disease?

Hirschsprung disease (HSCR) is a rare congenital disorder caused by an incorrect enteric nervous system development due to a failure in migration, proliferation, differentiation and/or survival of enteric neural crest cells. HSCR is a complex genetic disease, where alterations at different molecular levels are required for the manifestation of the disease. In addition, a wide spectrum of mutations affecting many different genes cause HSCR, although the occurrence and severity of HSCR from many cases still remain unexplained. This review summarizes the current knowledge about molecular genetic basis of HSCR.     

肥大细胞与炎症性肠病

炎症性肠病（Inflammatoryboweldisease，IBD）包括溃疡性结肠炎（Ulcerativecolitis）和克罗恩病（Crohn’sdisease），是一种原因不明的慢性非特异性肠道炎症，其发病机制主要和免疫、遗传、感染、应激等多种因素有关。近年来发现其发病与肥大细胞也密切相关。     

同种异体带瓣管道在小儿复杂先天性心脏病中的应用

目的 探讨同种异体带瓣管(VHC)在复杂先天性心脏病（先心病）中的临床应用价值。方法 1993年－2000年共应用VHC重建右心室流了道治疗各种复杂先心病9年。VHC均采用同种异体带瓣主动脉；术后常规监测心肺功能，呼吸机辅助呼吸，应用正性肌力药物和血管扩张剂等辅助心功能。结果 8例成活，1例死亡，死亡率11．1％，死亡原因急性右心衰竭，合并纵隔感染2例，经清创引流治愈。随访3－6年，患儿生长发育良好，能正常上学；无远期死亡。结论 VHC对某些复杂先心病有广泛的应用前景。     

Use of support vector machines for disease risk prediction in genome‐wide association studies: Concerns and opportunities

The success of genome‐wide association studies (GWAS) in deciphering the genetic architecture of complex diseases has fueled the expectations whether the individual risk can also be quantified based on the genetic architecture. So far, disease risk prediction based on top‐validated single‐nucleotide polymorphisms (SNPs) showed little predictive value. Here, we applied a support vector machine (SVM) to Parkinson disease (PD) and type 1 diabetes (T1D), to show that apart from magnitude of effect size of risk variants, heritability of the disease also plays an important role in disease risk prediction. Furthermore, we performed a simulation study to show the role of uncommon (frequency 1–5%) as well as rare variants (frequency <1%) in disease etiology of complex diseases. Using a cross‐validation model, we were able to achieve predictions with an area under the receiver operating characteristic curve (AUC) of ～0.88 for T1D, highlighting the strong heritable component (～90%). This is in contrast to PD, where we were unable to achieve a satisfactory prediction (AUC ～0.56; heritability ～38%). Our simulations showed that simultaneous inclusion of uncommon and rare variants in GWAS would eventually lead to feasible disease risk prediction for complex diseases such as PD. The used software is available at http://www.ra.cs.uni‐tuebingen.de/software/MACLEAPS/ . Hum Mutat 33:1708–1718, 2012. © 2012 Wiley Periodicals, Inc.     

Behavioral Adjustment of Children with Surgically Palliated Complex Congenital Heart Disease

Examined the behavioral adjustment at school age of 26 childrenwith surgically treated complex congenital heart disease comparedto that of 26 children who had been diagnosed as having an innocentmurmur. The children with complex heart disease were rated bytheir parents as more withdrawn, having more social problems,and engaging in fewer activities, and by their teachers as morewithdrawn. The families of the children with complex heart diseasereported experiencing more stress. Two variables, family strainand exercise tolerance, were strong predictors of teacher-ratedschool adjustment in the children with complex heart disease,with family strain accounting for 33% of the variance, and exercisetolerance 24%. The impact of the child's chronic condition onthe family thus seems to be a critical factor in the schooladjustment of these children, more so even than the physicallimitations imposed on the child by the chronic condition.     

Chromosome 12 and late-onset Alzheimer's disease

Alzheimer's disease is a complex neurodegenerative disorder, characterized by cognitive decline and distinctive neuropathology. Using large extended families with multiple affected, we found that three markers on chromosome 12 were linked with late-onset Alzheimer's disease. These markers were downstream from the gene for alpha-2 macroglobulin. It is likely that multiple genes will be identified either as risk factors or as causative agents for late-onset Alzheimer's disease.     

Disparity between association and linkage analysis for HNF1A G319S in type 2 diabetes in Canadian Oji-Cree

In parallel experiments designed to find the genetic determinants of type 2 diabetes in Oji-Cree, we identified several linked chromosomal regions, using genomic scanning, in addition to a private diabetes-associated mutation, namely HNF1A G319S, using candidate gene sequencing. The genome scan did not identify the region harboring HNF1A as being linked with diabetes. Also, the HNF1A mutation, when used directly in sib-pair linkage analysis, was not linked with diabetes. However, HNF1A G319S was very strongly associated with diabetes, predicted the clinical severity of diabetes, and performed well as a diagnostic predictive test for diabetes in the Oji-Cree. Despite the failure of linkage analysis to identify HNF1A as a determinant of type 2 diabetes, we feel justified in interpreting that G319S has a very important pathogenic role in Oji-Cree diabetes, based upon the highly suggestive association studies. The probable etiologic heterogeneity of type 2 diabetes in the Oji-Cree created a situation in which association analysis was much more sensitive to detect a relationship between HNF1A S319 and diabetes than was linkage analysis. The effectiveness of linkage analysis will probably be limited in study samples that have an even greater complexity of genetic background and/or disease etiology. Thus, the absence of linkage does not always mean that a genomic variant is not an impor-tant determinant of a complex disease. Furthermore, our experience confirms the value of using several complementary strategies to identify susceptibility genes for a complex disease. Received: October 29, 1999 / Accepted: January 5, 2000     

Exome sequencing reveals an unexpected genetic cause of disease: NOTCH3 mutation in a Turkish family with Alzheimer's disease

Alzheimer's disease (AD) is a genetically complex disorder for which the definite diagnosis is only accomplished postmortem. Mutations in 3 genes (APP, PSEN1, and PSEN2) are known to cause AD, but a large number of familial cases do not harbor mutations in these genes and several unidentified genes that contain disease-causing mutations are thought to exist. We performed whole exome sequencing in a Turkish patient clinically diagnosed with Alzheimer's disease from a consanguineous family with a complex history of neurological and immunological disorders and identified a mutation in NOTCH3 (p.R1231C), previously described as causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Complete screening of NOTCH3 in a cohort of 95 early onset AD cases and 95 controls did not reveal any additional pathogenic mutations. Although the complex history of disease in this family precluded us to establish segregation of the mutation found with disease, our results show that exome sequencing is a rapid, cost-effective and comprehensive tool to detect genetic mutations, allowing for the identification of unexpected genetic causes of clinical phenotypes. As etiological based therapeutics become more common, this method will be key in diagnosing and treating disease.     

黄芩的化学成分及治疗阿尔兹海默病的研究进展

阿尔茨海默病是一种神经系统退行性疾病,中医称之为“痴呆”,其发病机制复杂,普遍认为主要有β-淀粉样蛋白（Aβ）过度沉积、神经炎症反应、Tau蛋白过度磷酸化等,目前临床还没有找到有效的治疗药物。黄芩的化学成分复杂,作用广泛,研究发现其主要有效成分黄酮类化合物黄芩苷、黄芩素等可改善神经退行性疾病,具有潜在的治疗阿尔兹海默病的发展前景。本文对黄芩的化学成分及治疗阿尔兹海默病的机制作一综述。     

Sporadic cases are the norm for complex disease

The results of genome-wide association studies have revealed that most human complex diseases (for example, cancer, diabetes and psychiatric disorders) are affected by a large number of variants, each of which explains a small increase in disease risk, suggesting a pattern of polygenic inheritance. At the same time, it has been argued that most complex diseases are genetically heterogeneous because many sporadic cases are observed, as well as cases with a family history. In this study, under the assumption of polygenic inheritance, we derive the expected proportion of sporadic cases using analytical methods and simulation. We show how the proportion of sporadic cases depends on disease prevalence (K) and heritability on the underlying liability scale (h_L²). We predict the underlying heritability and the proportion of sporadic cases for a range of human complex diseases, and show that this proportion is typically large. For a disease with h_L²=63% and K=0.4%, such as schizophrenia, >83% of proband cases are predicted to be sporadic (no affected first-, second- and third-degree relatives) in typical families (on an average, two children per couple). For the majority of these diseases, a large proportion of sporadic cases is expected under the polygenic model, implying that the observed large proportion of sporadic cases is not informative to the causal mechanism of a complex genetic disease.     

人工智能及机器学习在心血管疾病中的应用

人工智能(AI)及机器学习(ML)因其独特的优势逐渐在医学领域得到了较为广泛的应用。在心血管疾病中,该技术在处理电子病历记录中繁杂的数据,预测分析疾病发展及预后,自动分析和识别心血管影像学及心律失常,发现疾病新亚型等方面已经取得了一定进展。AI及ML在心血管疾病研究中潜力巨大,将会为心血管领域带来全新的突破。     

HLA in coeliac disease: unravelling the complex genetics of a complex disorder

Coeliac disease (gluten sensitive enteropathy) is a common, polygenic and multifactorial disorder that serves as a pioneering model for the study of inflammatory disease. A major environmental factor is known (ingested gluten from wheat), and there is unprecedented genetic and functional evidence pinpointing HLA-DQA1*05-DQB1*02 ( DQ2) and DQA1*03-DQB1*0302 ( DQ8) in disease predisposition. We discuss the current state of play in coeliac disease genetics, focussing particularly on the HLA complex. Emerging evidence suggests that additional HLA risk loci exert weak effects, independent of DQA1*05-DQB1*02, on the B8-DR3-DQ2 haplotype. There is also good evidence from linkage studies of disease gene(s) on chromosome 5q. We discuss the role and implications of linkage disequilibrium and haplotype blocks in complex disease gene mapping. We briefly address findings from studies of animal models for chronic inflammatory disease, and consider roles for both common genes associated with multiple inflammatory diseases, and genes unique to coeliac disease. The coeliac genetics research community has established a sound foundation for the identification of additional disease genes in the not-too-distant future. Functional studies will play a critical role, and coeliac disease has a promising future in this respect. Coeliac disease continues to function as a model disorder, facilitating the development and implementation of complex disease gene mapping strategies.