Diabetes mellitus and the β cell: the last ten years

Diabetes is a major global problem. During the past decade, the genetic basis of various monogenic forms of the disease, and their underlying molecular mechanisms, have been elucidated. Many genes that increase type 2 diabetes (T2DM) risk have also been identified, but how they do so remains enigmatic. Nevertheless, defective insulin secretion emerges as the main culprit in both monogenic and polygenic diabetes, with environmental and lifestyle factors, via obesity, accounting for the current dramatic increase in T2DM. There also have been significant advances in therapy, particularly for some monogenic disorders. We review here what ails the β cell and how its function may be restored.     

Science,medicine, and the future. Hypertension.

The abundance of drugs now available for treating hypertension, and evidence that small reductions in blood pressure reverse the associated risk of stroke have shifted clinical concerns away from hypertension. However, we do not understand the cause of hypertension in 95% of patients, fail to achieve a normal blood pressure in 50% of patients, and are unable fully to reverse the cardiac and vascular changes that predate the diagnosis and treatment of hypertension. Consequently, hypertension remains the commonest cause of strokes in Britain and of renal failure in the United States. Essential hypertension is a polygenic disease whose understanding can now be advanced through molecular genetic analyses. Several different syndromes are likely to be recognised; most will be due to interactions between genetic and environmental factors, but there are also likely to be further monogenic syndromes in families with multiple affected members. Recognition of these syndromes will permit accurate genetic prediction of prognosis and optimal treatment and perhaps lead to new and more powerful classes of antihypertensive treatment.     

Human molecular genetics: from monogenic to polygenic or complex disorders

Human molecular genetics has successfully identified the genes involved in several monogenic disorders. It now aims at pinpointing the genetic determinants of polygenic or complex traits with a strong genetic component. This constitutes a new challenge. We discuss the methodological and practical aspects of identifying such genes as well as the challenges facing physicians that will have to use efficiently these new diagnostic tools.     

The genetics of human obesity

Obesity is an important cause of morbidity and mortality in developed countries, and is also becoming increasingly prevalent in the developing world. Although environmental factors are important, there is considerable evidence that genes also have a significant role in its pathogenesis. The identification of genes that are involved in monogenic, syndromic and polygenic obesity has greatly increased our knowledge of the mechanisms that underlie this condition. In the future, dissection of the complex genetic architecture of obesity will provide new avenues for treatment and prevention, and will increase our understanding of the regulation of energy balance in humans.     

Genetics of Alzheimer's disease: new evidences for an old hypothesis?

Alzheimer's disease (AD) is the prime cause of dementia and presents a strong genetic predisposition (60-80% of the attributable risk). In addition to APOE, a major recognized genetic determinant of AD, systematic, high-throughput genomic approaches have recently allowed the characterization of four new genetic determinants: CLU, CR1, PICALM and BIN1. Even if the complete picture of AD genetics is still not fully understood, the characterization of these new AD genetic determinants is probably going to strongly modify our perception of the pathophysiological process involved in AD. The new AD genetic landscape suggests that the common and late-onset forms of the disease are associated with a defect in peripheral Aβ peptide clearance, implying that the amyloid cascade hypothesis could be relevant not only in the AD monogenic forms.     

Pathophysiology and genetics of obesity

Obesity, a global problem, is a multifactorial disorder. The factors are environmental, metabolic and genetic and their interaction with each other regulates the body weight. Imbalance in either of the factors may be responsible for weight gain. With advancement of research techniques in the last decade, genetic studies have been undertaken for several different causative mutations involving obesity loci on different chromosomes. Monogenic and polygenic obesity has been observed however, polygenic forms are more common. So far more than 200 genes in mouse and more than 100 genes in humans have been identified which result in phenotypes that affect body weight regulation. In spite of this knowledge, the field of obesity has still not been explored extensively. There remain a lot of lacuna regarding causes and treatment of obesity. Challenges are still there to identify the exact cause of weight gain and the use of current knowledge for development of anti-obesity drugs targeted for body weight regulation. In this review, we have explained neuropathophysiologic regulation of feeding behaviour and some aspects of obesity-genetics especially with single nucleotide polymorphism of selected candidate genes and their functional aspects mainly in monogenic obesity.     

Does cutting herbicide rates threaten the sustainability of weed management in cropping systems?

Evolution of herbicide resistance in weeds is a growing problem across the world, and it has been suggested that low herbicide rates may be contributing to this problem. An individual-based simulation model that represents weed population dynamics and the evolution of polygenic herbicide resistance was constructed and used to investigate whether using lower herbicide rates or standard rates at reduced efficacy could reduce the sustainability of cropping systems by causing faster increases in weed population density as herbicide resistance develops. A number of different possible genetic bases for resistance were considered, including monogenic resistance and polygenic resistance conferred by several genes. The results show that cutting herbicide rates does not affect the rate at which weed densities reach critical levels when resistance is conferred exclusively by a single dominant gene. In some polygenic situations, cutting herbicide rates substantially reduces sustainability, due to a combination of faster increase in resistance gene frequency and reduced kill rates in all genotypes, while in other polygenic situations the effect is small. Differences in sustainability depend on combined strength of the resistance genes, variability in phenotypic susceptibility and rate delivered, level of control due to alternative measures, and degree of genetic dominance and epistasis. In the situation where resistance can be conferred by both a single dominant major gene or a number of co-dominant minor genes in combination, the difference made by low rates depends on the relative initial frequency of the major and minor genes. These results show that careful consideration of herbicide rate and understanding the genetic basis of resistance are important aspects of weed management.     

Inheritance of guttural pouch tympany in the arabian horse

The objective of the present study was to analyze the mode of inheritance of guttural pouch tympany (GPT) using pedigrees of Arabian horses. Complex segregation analyses were employed to test for the significance of nongenetic transmission and for monogenic, polygenic, and mixed monogenic-polygenic modes of inheritance. Horses affected by GPT comprised 27 Arabian purebred foals. Of these 27 animals, 22 were patients at the Clinic for Horses, School of Veterinary Medicine Hannover, Hannover, Germany, between 1994 and 2001 and 5 Arabian foals were from stud farms. Information on the pedigrees of these patients allowed us to classify the affected foals into four families with a total of 276 animals. The regressive logistic model analysis took into account the nonrandomness of the pedigrees through multiple single ascertainment correction. The complex segregation analysis showed that, among all other models employed, a polygenic and a mixed monogenic-polygenic model best explained the segregation of Arabian foals with GPT. Models including only nongenetic distributions and monogenic inheritance could be significantly rejected. This is the first report in which a genetic component could be shown to be responsible for GPT in horses.     

The genetic, molecular and phenotypic consequences of selection for insecticide resistance

Studies of insecticide resistance allow theories of the adaptive process to be tested where the selective agent, the insecticide, is unambiguously defined. Thus, the consequences of selection of phenotypic variation can be investigated in genetic, biochemical, molecular, population biological and, most recently, developmental contexts. Are the options limited biochemically and molecularly? Is the genetic mechanism monogenic or polygenic, general or population/species specific? Are fitness and developmental patterns associated? These questions of general evolutionary significance can be considered with experimental approaches to determine how insecticide resistance evolves.     

Reaching new heights: insights into the genetics of human stature

Human height is a highly heritable, classic polygenic trait. Until recently, there had been limited success in identifying the specific genetic variants that explain normal variation of human height. The advent of large-scale genome-wide association studies, however, has led to dramatic progress. In the past 18 months, the first robust common variant associations were identified and there are now 44 loci known to influence normal variation of height. In this review, we summarize this exciting recent progress, discuss implicated biological pathways, the overlap with monogenic growth and skeletal dysplasia syndromes, links to disease and insights into the genetic architecture of this model polygenic trait. We also discuss the strong probability of finding several hundred more such loci in the near future.     

Unraveling monogenic channelopathies and their implications for complex polygenic disease

Ion channels are a large family of >400 related proteins representing >1% of our genetic endowment; however, ion-channel diseases reflect a relatively new category of inborn error. They were first recognized in 1989, with the discovery of cystic fibrosis transmembrane conductance regulator, and rapidly advanced as positional and functional studies converged in the dissection of components of the action potential of excitable tissues. Although it remains true that diseases of excitable tissue still most clearly illustrate this family of disease, ion-channel disorders now cover the gamut of medical disciplines, causing significant pathology in virtually every organ system, producing a surprising range of often unanticipated symptoms, and providing valuable targets for pharmacological intervention. Many of the features shared among the monogenic ion-channel diseases provide a general framework for formulating a foundation for considering their intrinsically promising role in polygenic disease. Since an increasingly important approach to the identification of genes underlying polygenic disease is to identify "functional candidates" within a critical region and to test their disease association, it becomes increasingly important to appreciate how these ion-channel mechanisms can be implicated in pathophysiology.     

Insights into the molecular correlates modulating functional compensation between monogenic and polygenic disease gene duplicates in human

Functional redundancy by gene duplication appears to be a common phenomenon in biological system and hence understanding its underlying mechanism deserves much attention. Here, we investigated the differences between functional compensation of monogenic and polygenic disease genes which are unexplored till date. We found that the competence of functional buffering varies in the order of non-disease genes>monogenic disease genes>polygenic disease genes. This fact has been explained by the sequence identity, expression profile similarity, shared interaction partners and cellular locations between duplicated pairs. Moreover, we observed an inverse relationship between backup capacity and the non-synonymous substitution rate of disease and non-disease genes while the opposite trend is found for their corresponding paralogs. Logistic regression analysis among sequence identity, sharing of expression profile, interaction partners and cellular locations with backup capacity between duplicated pairs demonstrated that the sharing of expression profile is the most dominant regulator of backup capacity.     

New insights from the last decade of research in psychiatric genetics: discoveries,challenges and clinical implications

Psychiatric genetics has made substantial progress in the last decade, providing new insights into the genetic etiology of psychiatric disorders, and paving the way for precision psychiatry, in which individual genetic profiles may be used to personalize risk assessment and inform clinical decision-making. Long recognized to be heritable, recent evidence shows that psychiatric disorders are influenced by thousands of genetic variants acting together. Most of these variants are commonly occurring, meaning that every individual has a genetic risk to each psychiatric disorder, from low to high. A series of large-scale genetic studies have discovered an increasing number of common and rare genetic variants robustly associated with major psychiatric disorders. The most convincing biological interpretation of the genetic findings implicates altered synaptic function in autism spectrum disorder and schizophrenia. However, the mechanistic understanding is still incomplete. In line with their extensive clinical and epidemiological overlap, psychiatric disorders appear to exist on genetic continua and share a large degree of genetic risk with one another. This provides further support to the notion that current psychiatric diagnoses do not represent distinct pathogenic entities, which may inform ongoing attempts to reconceptualize psychiatric nosology. Psychiatric disorders also share genetic influences with a range of behavioral and somatic traits and diseases, including brain structures, cognitive function, immunological phenotypes and cardiovascular disease, suggesting shared genetic etiology of potential clinical importance. Current polygenic risk score tools, which predict individual genetic susceptibility to illness, do not yet provide clinically actionable information. However, their precision is likely to improve in the coming years, and they may eventually become part of clinical practice, stressing the need to educate clinicians and patients about their potential use and misuse. This review discusses key recent insights from psychiatric genetics and their possible clinical applications, and suggests future directions.     

Molecular genetics of Parkinson's disease

The current views on the role of genetic factors in the pathogenesis of Parkinson's disease are considered. The review is focused on monogenic forms of the disease, for which 11 loci are mapped and seven genes whose mutations cause the disease are identified. In addition, a number of candidate genes for sporadic Parkinson's disease are described. The further development of studying genetic bases of Parkinson's disease will follow two main directions: in-depth analysis of genes related to the monogenic form of the disease and more large-scale associative investigation of candidate genes for the sporadic form of Parkinson's disease.     

Molecular genetics of Parkinson’s disease

The current views on the role of genetic factors in the pathogenesis of Parkinson’s disease are considered. The review is focused on monogenic forms of the disease, for which 11 loci are mapped and seven genes whose mutations cause the disease are identified. In addition, a number of candidate genes for sporadic Parkinson’s disease are described. The further development of studying genetic bases of Parkinson’s disease will follow two main directions: in-depth analysis of genes related to the monogenic form of the disease and more large-scale associative investigation of candidate genes for the sporadic form of Parkinson’s disease.     

Genetics of Obesity: What have we Learned?

Candidate gene and genome-wide association studies have led to the discovery of nine loci involved in Mendelian forms of obesity and 58 loci contributing to polygenic obesity. These loci explain a small fraction of the heritability for obesity and many genes remain to be discovered. However, efforts in obesity gene identification greatly modified our understanding of this disorder. In this review, we propose an overlook of major lessons learned from 15 years of research in the field of genetics and obesity. We comment on the existence of the genetic continuum between monogenic and polygenic forms of obesity that pinpoints the role of genes involved in the central regulation of food intake and genetic predisposition to obesity. We explain how the identification of novel obesity predisposing genes has clarified unsuspected biological pathways involved in the control of energy balance that have helped to understand past human history and to explore causality in epidemiology. We provide evidence that obesity predisposing genes interact with the environment and influence the response to treatment relevant to disease prediction.     

Commentary: the year in endocrine genetics for basic scientists

During the past several years, one of the most interesting and challenging issues in endocrine genetics is determining how to integrate the findings and approaches traditionally used to understand the powerful, single-gene mutations causing endocrine syndromes with those newer techniques used to dissect the complex genetic architecture of polygenic conditions. With this overriding consideration in mind, it makes sense to begin these considerations with recent novel findings derived from the study of a particularly prismatic monogenic disorder, isolated GnRH deficiency, in defining an area of neuroendocrinology and development. Careful study of this human disease model has been employed successfully by several groups to provide unique windows through which to gain an improved understanding of the challenging issues of the developmental biology of the GnRH neurons where previous nonhuman approaches have had significant technical limitations. For example, study of this disorder has provided the field of neuroendocrinology with several unique insights into the surprising origins and early development of the GnRH neuronal network. Its associated clinical phenotypes have helped to unearth a growing list of genes responsible for GnRH neuronal specification, migration, and neuroendocrine function. Finally, this human genetic model is beginning to provide increasing evidence of interactions between these single genes, clearly demonstrating that an oligogenic genetic architecture underlies this condition.     

The Role of Genetic Factors in the Development of Individual Predisposition to Ischemic Stroke

Intensive development of DNA analysis technologies and large-scale genome-wide association studies have led to accumulation of a large array of data on the relationship between genetic factors and various phenotypic manifestations, including monogenic and polygenic hereditary diseases. This has greatly extended the capabilities of clinical diagnostics and predictive medicine in the field of socially significant diseases. For example, the role of a genetic component of the risk for such multifactorial and polyetiologic disease as stroke is now actively explored. Large-scale studies have revealed both general and specific genetic markers associated only with a certain type and subtype of stroke. This review analyzes the current state of the problem of using genetic markers for diagnosis of predisposition to stroke, complex issues associated with multiplicity of risk factors for stroke, and potential development in this area.     

Rapid-throughput skeletal phenotyping of 100 knockout mice identifies 9 new genes that determine bone strength

Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary phenotype data with quantitative x-ray microradiography, micro-computed tomography, statistical approaches and biomechanical testing in 100 unselected knockout mouse strains identified nine new genetic determinants of bone mass and strength. These nine new genes include five whose deletion results in low bone mass and four whose deletion results in high bone mass. None of the nine genes have been implicated previously in skeletal disorders and detailed analysis of the biomechanical consequences of their deletion revealed a novel functional classification of bone structure and strength. The organ-specific and disease-focused strategy described in this study can be applied to any biological system or tractable polygenic disease, thus providing a general basis to define gene function in a system-specific manner. Application of the approach to diseases affecting other physiological systems will help to realize the full potential of the International Mouse Phenotyping Consortium.