Mouse models of type 1 and type 2 diabetes derived from the same closed colony: genetic susceptibility shared between two types of diabetes

Except for rare subtypes of diabetes, both type 1 and type 2 diabetes are multifactorial diseases in which genetic factors consisting of multiple susceptibility genes and environmental factors contribute to the disease development. Due to complex interaction among multiple susceptibility genes and between genetic and environmental factors, genetic analysis of multifactorial diseases is difficult in humans. Inbred animal models, in which the genetic background is homogeneous and environmental factors can be controlled, are therefore valuable in genetic dissection of multifactorial diseases. We are fortunate to have excellent animal models for both type 1 and type 2 diabetes--the nonobese diabetic (NOD) mouse and the Nagoya-Shibata-Yasuda (NSY) mouse, respectively. Congenic mapping of susceptibility genes for type 1 diabetes in the NOD mouse has revealed that susceptibility initially mapped as a single locus often consists of multiple components on the same chromosome, indicating the importance of congenic mapping in defining genes responsible for polygenic diseases. The NSY mouse is an inbred animal model of type 2 diabetes established from Jcl:ICR, from which the NOD mouse was also derived. We have recently mapped three major loci contributing to type 2 diabetes in the NSY mouse. Interestingly, support intervals where type 2 diabetes susceptibility genes were mapped in the NSY mouse overlapped the regions where type 1 diabetes susceptibility genes have been mapped in the NOD mouse. Although additional evidence is needed, it may be possible that some of the genes predisposing to diabetes are derived from a common ancestor contained in the original closed colony, contributing to type 1 diabetes in the NOD mouse and type 2 diabetes in the NSY mouse. Such genes, if they exist, will provide valuable information on etiological pathways common to both forms of diabetes, for the establishment of effective methods for prediction, prevention, and intervention in both type 1 and type 2 diabetes.     

Genetic susceptibility to ageing-associated diseases

The constant and rapid increase of life expectancy in western countries is associated with a major ageing of our populations. In these conditions, we can expect an epidemic progression of most chronic diseases, especially cardiovascular, neurodegenerative and metabolic disorders, the main causes of death in the world. The global burden of these diseases will have a dramatic impact on the health and on the socio-economical context of our societies. From a global point of view, the occurrence and progression of these multifactorial diseases rely upon the nature and intensity of the environmental determinants we are exposed to all life long, but also to our individual genetic susceptibility. Through the determination of this higher susceptibility to an environmental risk factor and the understanding of its mechanisms of action, prevention and management efforts will be better focused. In such multifactorial affections, the development and the transmission of the disease do not follow the simple laws of monogenic Mendelian models. The complexity of this transmission is associated with the influence, at various degrees, of several genes and of a close interaction between this particular genetic susceptibility and environmental risk factors. With the recent development of automated and high throughput molecular biology techniques and their use in epidemiological studies, gene expression regulation and post genomic studies, the determination of sub-groups facing a higher individual genetic susceptibility has begun. This determination will offer new clues for a better-targeted disease management.     

Ionizing radiation and genetic risks: VI. Chronic multifactorial diseases: a review of epidemiological and genetical aspects of coronary heart disease,essential hypertension and diabetes mellitus

This paper provides a broad overview of the epidemiological and genetical aspects of common multifactorial diseases in man with focus on three well-studied ones, namely, coronary heart disease (CHD), essential hypertension (EHYT) and diabetes mellitus (DM). In contrast to mendelian diseases, for which a mutant gene either in the heterozygous or homozygous condition is generally sufficient to cause disease, for most multifactorial diseases, the concepts of `genetic susceptibility' and `risk factors' are more appropriate. For these diseases, genetic susceptibility is heterogeneous. The well-studied diseases such as CHD permit one to conceptualize the complex relationships between genotype and phenotype for chronic multifactorial diseases in general, namely that allelic variations in genes, through their products interacting with environmental factors, contribute to the quantitative variability of biological risk factor traits and thus ultimately to disease outcome. Two types of such allelic variations can be distinguished, namely those in genes whose mutant alleles have (i) small to moderate effects on the risk factor trait, are common in the population (polymorphic alleles) and therefore contribute substantially to the variability of biological risk factor traits and (ii) profound effects, are rare in the population and therefore contribute far less to the variability of biological risk factor traits. For all the three diseases considered in this review, a positive family history is a strong risk factor. CHD is one of the major contributors to mortality in most industrialized countries. Evidence from epidemiological studies, clinical correlations, genetic hyperlipidaemias etc., indicate that lipids play a key role in the pathogenesis of CHD. The known lipid-related risk factors include: high levels of low density lipoprotein cholesterol, low levels of high density lipoprotein cholesterol, high apoB levels (the major protein fraction of the low density lipoprotein particles) and elevated levels of Lp(a) lipoprotein. Among the risk factors which are not related to lipids are: high levels of homocysteine, low activity of paraoxonase and possibly also elevated plasma fibrinogen levels. In addition to the above, hypertension, diabetes and obesity (which themselves have genetic determinants) are important risk factors for CHD. Among the environmental risk factors are: high dietary fat intake, smoking, stress, lack of exercise etc. About 60% of the variability of the plasma cholesterol is genetic in origin. While a few genes have been identified whose mutant alleles have large effects on this trait (e.g., LDLR, familial defective apoB-100), variability in cholesterol levels among individuals in most families is influenced by allelic variation in many genes (polymorphisms) as well as environmental exposures. A proportion of this variation can be accounted for by two alleles of the apoE locus that increase (ϵ4) and decrease (ϵ2) cholesterol levels, respectively. A polymorphism at the apoB gene (XbaI) also has similar effects, but is probably not mediated through lipids. High density lipoprotein cholesterol levels are genetically influenced and are related to apoA1 and hepatic lipase (LIPC) gene functions. Mutations in the apoA1 gene are rare and there are data which suggest a role of allelic variation at or linked LIPC gene in high density lipoprotein cholesterol levels. Polymorphism at the apoA1–C3 loci is often associated with hypertriglyceridemia. The apo(a) gene which codes for Lp(a) is highly polymorphic, each allele determining a specific number of multiple tandem repeats of a unique coding sequence known as Kringle 4. The size of the gene correlates with the size of the Lp(a) protein. The smaller the size of the Lp(a) protein, the higher are the Lp(a) levels. Hyperhomocyst(e)inemia is a risk factor for myocardial infarction, stroke and peripheral vascular disease, but the precise nature and intensity of this association, the biochemical mechanisms involved and the role of environmental factors remain to be fully elucidated. Recently, it has been suggested that polymorphisms in genes that code for paraoxonase may need to be added to the list of genetic risk factors for CHD. There are suggestions that high plasma fibrinogen levels (which is exacerbated by smoking which also lowers high density lipoprotein cholesterol levels) may constitute yet another risk factor for CHD. Essential hypertension (EHYT) affects some 10–25% of the people of the industrial world. Its clinical relevance stems from the fact that it is one of the major risk factors for cardiovascular and renal diseases, especially, stroke, coronary heart disease and end-stage renal disease. The role of genetic factors in EHYT is clearly indicated by family studies in which correlations in blood pressure levels have been studied. The variations in the range and magnitude of these correlations however suggest that other, environmental factors must play an important role and which vary from individual to individual and population to population. No major genes controlling blood pressure have been identified. However during the past five years or so, linkage and association studies have shown that there are at least three gene loci, polymorphism at which may contribute to EHYT: these include the AGT, AT1 and ACE genes. Additionally, the molecular basis of three rare mendelian disorders associated with hypertension, namely those involved in glucocorticosteroid-remediable aldosteronism (GRA), Liddle syndrome and apparent mineralocorticosteroid excess (AME) have been delineated. On the basis of clinical phenotypes, four types of diabetes mellitus are distinguished, of which insulin-dependent diabetes melltius (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) have been the subject of extensive studies. IDDM is a group of heterogeneous diseases probably resulting from exposure to some environmental agent(s) in those individuals with a genetically-determined susceptibility. IDDM is the result of the destruction of insulin-producing β-cells of the pancreas, principally by immunologically-mediated (autoimmune) mechanisms. The major defined risk factor is genetic susceptibility: apart from IDDM1 (linked to the HLA complex) and IDDM2 (in the insulin gene region) at least 10 other genes are involved, mutations at which cause susceptibility to IDDM. There is recent evidence for the possible involvement of an endogenous retrovirus in the aetiology of acute onset IDDM. NIDDM is a very common disease and its prevalence varies in different populations. As in the case of IDDM, its major determinant is genetic susceptibility. Compared to IDDM, the concordance rates in monozygotic twins and risks to first-degree relatives are higher. With the exception of MODY subtype with earlier onset, most cases have onset in middle or late life. The known geographical variations in the prevalence and studies of migrant populations suggest that environmental factors might also be important. The number of genes mutations at which cause susceptibility to NIDDM is not yet known and so far, one putative major gene locus has recently been identified in a Mexican–American population. Several candidate genes are currently being investigated. The available data indicate that some of the genes act through inherited susceptibility to insulin resistance and to decreased capacity for insulin secretion. Rare forms are due to dominant mutations i.e., the MODY diabetes and rarer still are forms due to the production of abnormal insulin due to mutations in the insulin gene itself. Finally, a small proportion of diabetes may be due to mutations in the mitochondrial genome. The attributes, risk factors and interrelationships between the three diseases considered in this review clearly show that the task of using this information for reliably predicting the risk of any of these diseases is formidable, even for a scenario of no radiation exposures, not to mention radiation scenarios. Nonetheless, these data provide a useful framework for developing models aimed at quantifying the response of these diseases to an increase in mutation rate due to radiation. One such model is discussed in a later paper of this series.     

Many little things: one geneticist's view of complex diseases

Gene targeting is commonly used to knock out genes in order to understand their function. It has also been used successfully to model the relatively rare human genetic diseases that are caused by homozygous loss of gene function. Modelling the much more common multifactorial diseases that have strong genetic and environmental causes is less easy. Here, I describe my personal voyage into this challenging field, using gene targeting to alter the expression of genes that impact on hypertension and diabetes.     

Multifactorial inheritance in type 1 diabetes

To date, twelve separate chromosome regions have been implicated in the development of human type 1 (insulin-dependent) diabetes mellitus. The major disease locus, IDDM1 in the major histocompatibility complex (MHC) on chromosome 6p21, accounts for about 35% of the observed familial clustering and its contribution to disease susceptibility is likely to involve polymorphic residues of class II molecules in T-cell-mediated autoimmunity. IDDM2 is encoded by a minisatellite locus embedded in the 5 regulatory region of the insulin gene. Familial clustering of disease can be explained by the sharing of alleles of at least 10 loci. IDDM1 and IDDM2 interact epistatically. For a multifactorial disease, such as type 1 diabetes, important information concerning the pathways and mechanisms involved can be gained from examining such interactions between loci, using methods that simultaneously take account of the joint effects of the various underlying genetic components.     

A second-generation genetic linkage map of the baboon (Papio hamadryas) genome

Construction of genetic linkage maps for nonhuman primate species provides information and tools that are useful for comparative analysis of chromosome structure and evolution and facilitates comparative analysis of meiotic recombination mechanisms. Most importantly, nonhuman primate genome linkage maps provide the means to conduct whole genome linkage screens for localization and identification of quantitative trait loci that influence phenotypic variation in primate models of common complex human diseases such as atherosclerosis, hypertension, and diabetes. In this study we improved a previously published baboon whole genome linkage map by adding more loci. New loci were added in chromosomal regions that did not have sufficient marker density in the initial map. Relatively low heterozygosity loci from the original map were replaced with higher heterozygosity loci. We report in detail on baboon chromosomes 5, 12, and 18 for which the linkage maps are now substantially improved due to addition of new informative markers.     

Personalisierte Medizin – Vision oder Fiktion? Beispiel: Altersdiabetes

Typical civilization diseases, such as type II diabetes, are common, complex in the underlying pathogenic mechanisms, heterogenous in the phenotype and multifactorial due to a wide variety of possible combinations of disease susceptibility or protective genes in different relevant tissues and negative or positive environmental factors. This is in sharp contrast to classical inherited diseases, such as Chorea Huntington, which are often caused by complete loss‐ or gain‐of‐function mutations in a single gene. The causative polymorphisms of susceptibility genes, however, are characterized by relative subtle alterations in the function of the corresponding gene product, which per se do not support the pathogenesis, by high frequency, high expenditure for their identification and rather low predictive value. Consequently, the reliable and early diagnosis of civilization diseases depends on the individual determination of all (or as many as possible) polymorphisms of each susceptibility gene together with the corresponding gene products and the metabolites emerging thereof.     

Chromosome 17 and the inducible nitric oxide synthase gene in human essential hypertension

Essential hypertension is a common multifactorial trait that results in a significantly increased risk for heart attack and stroke. The condition has a genetic basis, although at present the number of genes is unknown. In order to identify such genes, we are utilising a linkage scanning approach using microsatellite markers and affected sibships. Here we provide evidence for the location of at least one hypertension susceptibility locus on chromosome 17. Analysis of 177 affected sibpairs gave evidence for significant excess allele sharing to D17S949 (SPLINK: P=0.0029; MAPMAKER SIBS: P=0.0033; ASPEX: P=0.0061; GENEHUNTER: P=0.0096; ANALYZE (SIBPAIR): P=0.0025) on 17q22-24, with significant allele sharing also indicated for an additional marker, D17S799 (SPLINK: P=0.025; MAPMAKER SIBS: P=0.025) located close to the centromere. Since these two genomic regions are well separated, our results indicate that there may be more than one chromosome 17 locus affecting human blood pressure. Moreover, further investigation of this chromosome, utilizing a polymorphism within the promoter of the iNOS candidate gene, NOS2A, revealed both increased allele sharing among sibpairs (SPLINK: P=0.02; ASPEX: P=0.00004) and positive association (P=0.034) of NOS2A to essential hypertension. Hence these results indicate that chromosome 17 and, more specifically, the NOS2A gene may play a role in human essential hypertension.     

Multiple DNA Variant Association Analysis: Application to the Insulin Gene Region in Type 1 Diabetes

Association and linkage studies have shown that at least one of the genetic factors involved in susceptibility to insulin-dependent diabetes mellitus (IDDM) is contained within a 4.1-kb region of the insulin gene. Sequence analysis has led to the identification of 10 DNA variants in this region that are associated with increased risk for IDDM. These variants are in strong linkage disequilibrium with each other, and previous studies have failed to distinguish between the variant(s) that cause increased susceptibility to IDDM and others that are associated with the disease because of linkage disequilibrium. To address this problem, we have undertaken a large population study of French diabetics and controls and have analyzed genotype patterns for several of the variant sites simultaneously. This has led to the identification of a subset consisting of four variants (−2733AC, −23HphI, −365VNTR, and +1140AC), at least one of which appears to be directly implicated in disease susceptibility. The multiple-DNA-variant association-analysis approach that is applied here to the problem of identifying potential susceptibility variants in IDDM is likely to be important in studies of many other multifactorial diseases.     

Detailed comparative gene map of rat chromosome 1 with mouse and human genomes and physical mapping of an evolutionary chromosomal breakpoint

We report the localization of 92 new gene-based markers assigned to rat chromosome 1 by linkage or radiation hybrid mapping. The markers were chosen to enrich gene mapping data in a region of the rat chromosome known to contain several of the principal quantitative trait loci in rodent models of human multifactorial disease. The composite map reported here provides map information on a total of 139 known genes, including 80 that have been localized in mouse and 109 that have been localized in human, and integrates the gene-based markers with anonymous microsatellites. The evolutionary breakpoints identifying 16 segments that are homologous regions in the human genome are defined. These data will facilitate genetic and comparative mapping studies and identification of novel candidate genes for the quantitative trait loci that have been localized to the region.     

Linkage analysis of systemic lupus erythematosus induced in diabetes-prone nonobese diabetic mice by Mycobacterium bovis

Systemic lupus erythematosus induced by Mycobacterium bovis in diabetes-prone nonobese diabetic mice was mapped in a backcross to the BALB/c strain. The subphenotypes-hemolytic anemia, antinuclear autoantibodies, and glomerular immune complex deposition-did not cosegregate, and linkage analysis for each trait was performed independently. Hemolytic anemia mapped to two loci: Bah1 at the MHC on chromosome 17 and Bah2 on distal chromosome 16. Antinuclear autoantibodies mapped to three loci: Bana1 at the MHC on chromosome 17, Bana2 on chromosome 10, and Bana3 on distal chromosome 1. Glomerular immune complex deposition did not show significant linkage to any genomic region. Mapping of autoantibodies (Coombs' or antinuclear autoantibodies) identified two loci: Babs1 at the MHC and Babs2 on distal chromosome 1. It has previously been reported that genes conferring susceptibility to different autoimmune diseases map nonrandomly to defined regions of the genome. One possible explanation for this clustering is that some alleles at loci within these regions confer susceptibility to multiple autoimmune diseases-the "common gene" hypothesis. With the exception of the H2, this study failed to provide direct support for the common gene hypothesis, because the loci identified as conferring susceptibility to systemic lupus erythematosus did not colocalize with those previously implicated in diabetes. However, three of the four regions identified had been previously implicated in other autoimmune diseases.     

International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16

Numerous familial, non-Mendelian (i.e., complex) diseases have been screened by linkage analysis for regions harboring susceptibility genes. Except for rare, high-penetrance syndromes showing Mendelian inheritance, such as BRCA1 and BRCA2, most attempts have failed to produce replicable linkage findings. For example, in multiple sclerosis and other complex diseases, there have been many reports of significant linkage, followed by numerous failures to replicate. In inflammatory bowel disease (IBD), linkage to two regions has elsewhere been reported at genomewide significance levels: the pericentromeric region on chromosome 16 (IBD1) and chromosome 12q (IBD2). As with other complex diseases, the subsequent support for these localizations has been variable. In this article, we report the results of an international collaborative effort to investigate these putative localization by pooling of data sets that do not individually provide convincing evidence for linkage to these regions. Our results, generated by the genotyping and analysis of 12 microsatellite markers in 613 families, provide unequivocal replication of linkage for a common human disease: a Crohn disease susceptibility locus on chromosome 16 (maximum LOD score 5.79). Despite failure to replicate the previous evidence for linkage on chromosome 12, the results described herein indicate the need to further investigate the potential role of this locus in susceptibility to ulcerative colitis. This report provides a convincing example of the collaborative approach necessary to obtain the sample numbers required to achieve statistical power in studies of complex human traits.     

Costs and Epidemiological Changes of Chronic Diseases: Implications and Challenges for Health Systems

Background

The need to integrate economic and epidemiological aspects in the clinical perspective leads to a proposal for the analysis of health disparities and to an evaluation of the health services and of the new challenges which are now being faced by health system reforms in middle income countries.

Objective

To identify the epidemiological changes, the demand for health services and economic burden from chronic diseases (diabetes and hypertension) in a middle income county.

Methods

We conducted longitudinal analyses of costs and epidemiological changes for diabetes and hypertension in the Mexican health system. The study population included both the insured and uninsured populations. The cost-evaluation method was used, based on the instrumentation and consensus techniques. To estimate the epidemiological changes and financial consequences for 2014–2016, six models were constructed according to the Box-Jenkins technique, using confidence intervals of 95%, and the Box-Pierce test.

Results

Regarding epidemiological changes expected in both diseases for 2014 vs. 2016, an increase is expected, although results predict a greater increase for diabetes, 8–12% in all three studied institutions, (p < .05). Indeed, in the case of diabetes, the increase was 41469 cases for uninsured population (SSA) and 65737 for the insured population (IMSS and ISSSTE). On hypertension cases the increase was 38109 for uninsured vs 62895 for insured. Costs in US$ ranged from $699 to $748 for annual case management per patient in the case of diabetes, and from $485 to $622 in patients with hypertension. Comparing financial consequences of health services required by insured and uninsured populations, the greater increase (23%) will be for the insured population (p < .05). The financial requirements of both diseases will amount to 19.5% of the total budget for the uninsured and 12.5% for the insured population.

Conclusions

If the risk factors and the different health care models remain as they currently are, the economic impact of expected epidemiological changes on the social security system will be particularly strong. Another relevant challenge is the appearance of internal competition in the use and allocation of financial resources with programs for other chronic and infectious diseases.     

Metagenomics and personalized medicine

The microbiome is a complex community of Bacteria, Archaea, Eukarya, and viruses that infect humans and live in our tissues. It contributes the majority of genetic information to our metagenome and, consequently, influences our resistance and susceptibility to diseases, especially common inflammatory diseases, such as type 1 diabetes, ulcerative colitis, and Crohn's disease. Here we discuss how host-gene-microbial interactions are major determinants for the development of these multifactorial chronic disorders and, thus, for the relationship between genotype and phenotype. We also explore how genome-wide association studies (GWAS) on autoimmune and inflammatory diseases are uncovering mechanism-based subtypes for these disorders. Applying these emerging concepts will permit a more complete understanding of the etiologies of complex diseases and underpin the development of both next-generation animal models and new therapeutic strategies for targeting personalized disease phenotypes.     

Association of a CAG/CAA repeat sequence in the TBP gene with type I diabetes

Type I diabetes is a complex disease in which multiple susceptibility loci have been implicated by whole genome scans. IDDM8, a susceptibility locus, is located on chromosome 6q27, however the specific susceptibility gene has yet to be identified. We have examined five potential candidate genes using 36 genetic markers, spanning 360kb located near the chromosome 6q27 terminus in 478 families for diabetes association. No associations with type I diabetes susceptibility were detected with the strength previously observed for IDDM1 or IDDM2. However, a novel CAG/CAA polymorphism was detected in exon 3 of the TATA box-binding protein gene, which shows preliminary evidence of association with diabetes susceptibility (p<0.05).     

Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?

Hypertension is a multifactorial disease in which the interplay of genetic and environmental factors that maintain blood pressure stable throughout life is altered. Cytochrome P450 (CYP)-derived metabolites of arachidonic acid such as epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), active on vascular tone, endothelial function and renal sodium reapportion, have been identified as candidate mediators in the development of hypertension in several animal models, with remarkable sex-specific effect. Several SNPs, some recognized as functional, in human genes implicated in EETs/20-HETE biosynthesis and metabolism, such as CYP2J2 and CYP4A11, have been tested for association with blood pressure, hypertension and its long-term cardiovascular consequences in different populations, with conflicting results. A sex-specific effect, related to CYP4F2 polymorphisms and expression, has been observed in association studies. This finding indicates that altered 20-HETE bioactivity underlay the excess of hypertension and associated vascular events observed in men with respect to women and is consistent with the results from experimental models. Further epidemiological and mechanistic studies are required to confirm the effect of lipid mediators on blood pressure in humans and define the mechanisms of a putative sex-specific effect.     

遗传风险评分在复杂疾病遗传学研究中的应用

心血管疾病、2型糖尿病、原发性高血压、哮喘、肥胖、肿瘤等复杂疾病在全球范围内流行,并成为人类死亡的主要原因。越来越多的人开始关注遗传易感性在复杂疾病发病机制中的作用。至今,与复杂疾病相关的易感基因和基因序列变异仍未完全清楚。人们希望通过遗传关联研究来阐明复杂疾病的遗传基础。近年来,全基因组关联研究和候选基因研究发现了大量与复杂疾病有关的基因序列变异。这些与复杂疾病有因果和(或)关联关系的基因序列变异的发现促进了复杂疾病预测和防治方法的产生和发展。遗传风险评分(Genetic risk score,GRS)作为探索单核苷酸多态(Single nucleotide polymorphisms,SNPs)与复杂疾病临床表型之间关系的新兴方法,综合了若干SNPs的微弱效应,使基因多态对疾病的预测性大幅度提升。该方法在许多复杂疾病遗传学研究中得到成功应用。本文重点介绍了GRS的计算方法和评价标准,简要列举了运用GRS取得的系列成果,并对运用过程中所存在的局限性进行了探讨,最后对遗传风险评分的未来发展方向进行了展望。     

High-resolution linkage mapping for susceptibility genes in human polygenic disease: Insulin-dependent diabetes mellitus and chromosome 11q

Insulin-dependent diabetes mellitus (IDDM) has a complex pattern of genetic inheritance. In addition to genes mapping to the major histocompatibility complex (MHC), several lines of evidence point to the existence of other genetic susceptibility factors. Recent studies of the nonobese diabetic mouse (NOD) model of IDDM have suggested the presence, on mouse chromosome 9, of a susceptibility gene linked to the locus encoding the T-cell antigen, Thy-1. A region on human chromosome 11q is syntenic to this region on mouse chromosome 9. We have used a set of polymorphic DNA markers from chromosome 11q to investigate this region for linkage to a susceptibility gene in 81 multiplex diabetic pedigrees. The data were investigated by maximization of lod scores over genetic models and by multiple-locus affected-sib-pair analysis. We were able to exclude the presence of a susceptibility gene (location scores less than -2) throughout greater than 90% of the chromosome 11q homology region, under the assumption that the susceptibility factor would cause greater than 50% of affected sib pairs to share two alleles identical by descent. Theoretical estimates of the power to map susceptibility genes with a high-resolution map of linked markers in a candidate region were made, using HLA as a model locus. This result illustrates the feasibility that IDDM linkage studies using mapped sets of polymorphic DNA markers have, both for other areas of the genome in IDDM and for other polygenic diseases. The analytic approaches introduced here will be useful for affected-sib-pair studies of other complex phenotypes.     

Whole-Exome Sequencing of 2,000 Danish Individuals and the Role of Rare Coding Variants in Type 2 Diabetes

It has been hypothesized that, in aggregate, rare variants in coding regions of genes explain a substantial fraction of the heritability of common diseases. We sequenced the exomes of 1,000 Danish cases with common forms of type 2 diabetes (including body mass index > 27.5 kg/m² and hypertension) and 1,000 healthy controls to an average depth of 56×. Our simulations suggest that our study had the statistical power to detect at least one causal gene (a gene containing causal mutations) if the heritability of these common diseases was explained by rare variants in the coding regions of a limited number of genes. We applied a series of gene-based tests to detect such susceptibility genes. However, no gene showed a significant association with disease risk after we corrected for the number of genes analyzed. Thus, we could reject a model for the genetic architecture of type 2 diabetes where rare nonsynonymous variants clustered in a modest number of genes (fewer than 20) are responsible for the majority of disease risk.