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Impulsivity describes the tendency to act prematurely without appropriate foresight and is symptomatic of a number of neuropsychiatric disorders. Although a number of genes for impulsivity have been identified, no study to date has carried out an unbiased, genome-wide approach to identify genetic markers associated with impulsivity in experimental animals. Herein we report a linkage study of a six-generational pedigree of adult rats phenotyped for one dimension of impulsivity, namely premature responding on the five-choice serial reaction time task, combined with genome wide sequencing and transcriptome analysis to identify candidate genes associated with the expression of the impulsivity trait. Premature responding was found to be heritable (h2 = 13–16%), with significant linkage (LOD 5.2) identified on chromosome 1. Fine mapping of this locus identified a number of polymorphic candidate genes, however only one, beta haemoglobin, was differentially expressed in both the founder strain and F6 generation. These findings provide novel insights into the genetic substrates and putative neurobiological mechanisms of impulsivity with broader translational relevance for impulsivity-related disorders in humans.

Model organisms have played a huge part in the history of studies of human genetic disease, both in identifying disease genes and characterizing their normal and abnormal functions. But is the importance of model organisms diminishing? The direct discovery of disease genes and variants in humans has been revolutionized, first by genome-wide association studies and now by whole-genome sequencing. Not only is it now much easier to directly identify potential disease genes in humans, but the genetic architecture that is being revealed in many cases is hard to replicate in model organisms. Furthermore, disease modelling can be done with increasing effectiveness using human cells. Where does this leave non-human models of disease?

Crescentic glomerulonephritis (CRGN) is a major cause of rapidly progressive renal failure for which the underlying genetic basis is unknown. Wistar-Kyoto (WKY) rats show marked susceptibility to CRGN, whereas Lewis rats are resistant. Glomerular injury and crescent formation are macrophage dependent and mainly explained by seven quantitative trait loci (Crgn1-7). Here, we used microarray analysis in basal and lipopolysaccharide (LPS)-stimulated macrophages to identify genes that reside on pathways predisposing WKY rats to CRGN. We detected 97 novel positional candidates for the uncharacterized Crgn3-7. We identified 10 additional secondary effector genes with profound differences in expression between the two strains (>5-fold change

The Fcgamma-receptor locus on chromosome 1q23 shows copy-number variation (CNV), and it has previously been shown that individuals with reduced numbers of copies of the Fcgamma-receptor-IIIB gene (FCGR3B) have an increased risk of developing systemic lupus erythematosus (SLE). It is not understood whether the association arises from FCGR3B (CD16b) itself, is observed because of linkage disequilibrium with actual causal alleles and/or is an effect of CNV on flanking FCGR genes. Thus, we extended this previous work by genotyping the FCGR3B alleles NA1/NA2 and re-assaying CNV using a paralogue ratio test assay in a family study (365 families). We have developed a novel case/pseudo-control approach to analyse family data, as the phase of copy number (CN) is not known in parents and cannot always be inferred in offspring. The results, obtained by fitting logistic regression models, confirm the association of low CN of FCGR3B with SLE (P=0.04). The risk conferred by low copies (2) was contingent on FCGR3B allotype, being greater for deletion of NA1 than the for lower-affinity NA2. The simpler model with just CN was rejected in favour of the biallelic-CN model (P=0.03). We observed a correlation (R(2)=0.75, P0.0001) between FCGR3B CNV and neutrophil expression in both healthy controls and patients with SLE. Our results suggest that one mechanism by which CNV at this locus confers disease risk is directly as a result of reduced FcgammaRIIIb function, either because of reduced expression (related to CNV) or because of reduced affinity for its ligand (NA1/NA2 allotype).

Glomerulonephritis is a kidney inflammation that occurs alone or as part of other conditions, including the autoimmune disorder lupus. A novel mutation has now been identified as the cause of the disease in a rat model. The mutation affects the Fcgr3 immunoglobulin receptor, but it does not produce a defective receptor. Rather, too many copies of an otherwise normal gene are produced. A similar gene-number defect was then detected in a subset of human systemic lupus erythematosus patients with a kidney inflammation. In these patients an equivalent receptor gene, FCGR3B, is present at a low copy number. Disease seems to result when copy number is altered in either direction, so receptor levels must need to be very finely tuned. Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics1,2,3. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation3,4,5. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.

Patients with insulin resistance syndromes are at an increased risk of developing cardiovascular disease. This review discusses the relationship between insulin resistance and heart disease, and describes how aggressive risk factor management and multifactoral treatment approaches are being used to improve the clinical outcomes of these patients. Insulin-resistance syndromes are of pandemic proportions; 150 million people worldwide and an estimated 43 million people in the US are currently affected by type 2 diabetes mellitus or metabolic syndrome respectively. Treatment of heart disease in the context of type 2 diabetes requires multifactorial risk-factor management, including lifestyle modification and drug treatment for comorbidities. Management of coronary risk extends beyond simple cholesterol lowering. Early use of cardiac imaging and, where appropriate, revascularization should be considered in high-risk or symptomatic patients. Traditionally, patients with type 2 diabetes and coronary arterial disease have been treated surgically, but percutaneous revascularization of these patients is increasingly common. Indeed, revascularization by use of drug-eluting coronary stents combined with administration of novel antiplatelet agents has revolutionized percutaneous coronary intervention in patients with type 2 diabetes. Despite these advances, there is no consensus of opinion regarding revascularization strategies or risk-factor management in insulin-resistant patients with symptomatic or prognostically important coronary arterial disease. Furthermore, specific therapies and preventative strategies for diabetic cardiomyopathy and heart failure in patients with type 2 diabetes remain elusive. The identification of optimized approaches for the prevention and treatment of the metabolic syndrome and heart disease in insulin-resistant, nondiabetic patients remains a major global challenge.

The spontaneously hypertensive rat (SHR) is a model of human essential hypertension. Increased blood pressure in SHR is associated with other risk factors associated with cardiovascular disease, including insulin resistance and dyslipidemia. DNA microarray studies identified over 200 differentially expressed genes and ESTs between SHR and normotensive control rats. These clones represent candidate genes that may underlie previously detected QTLs in SHR. This study made use of the publication of two whole-genome maps to identify positional QTL candidates. Radiation hybrid (RH) mapping was used to determine the chromosomal locations of 70 rat genes and ESTs from this dataset. Most of the locations are novel, but in five cases we identified a definitive map location for genes previously mapped by somatic cell hybrids and/or linkage analysis. Genes for which the mouse genome map location was already determined mapped to syntenic segments in the rat genome map, except for two rat genes whose map locations confirmed previous findings. Where synteny comparisons could be made only with the human, 74% of the genes mapped in this study lay in a conserved syntenic segment. Chromosomal localisation of these mouse and human orthologs to syntenic segments produces a high level of confidence in the data presented in this study. The data provide new map locations for rat genes and will aid efforts to advance the rat genome map. The data may also be used to prioritize candidate QTL genes in SHR and other rat strains on the basis of their map location.

To investigate the relationship between polymorphisms in the OB-R and OB genes and metabolic markers for obesity and glucose intolerance in a population of Nauruan men. In addition, we examined the effect of the simultaneous presence of the three polymorphisms on the phenotype of individuals in this population.This study was conducted in a population from the Pacific Island of Nauru. Populations in this region have some of the highest recorded rates of obesity and type 2 diabetes and are therefore of great interest in the genetic analysis of these diseases. Two hundred and thirty-two male subjects were examined in this cross-sectional study. All subjects were non-diabetic and the group had a mean age of 31 y and a mean body weight of 104 kg.Several phenotypic measures of body fatness and fat distribution (anthropometry), fasting plasma insulin, glucose and leptin concentrations, blood pressure and 2 h plasma glucose concentration, genotypes of subjects for the Gln223Arg, PRO1019pro (OB-R gene) and OB gene polymorphisms.Individually, the OB gene and Gln223Arg OB-R polymorphisms were not associated with the obese or glucose-intolerant phenotype in this population. Individuals with the PRO1019pro polymorphism were found to have elevated insulin concentrations and diastolic blood pressure (Pc = 0.04). In addition, individuals found to simultaneously exhibit homozygosity of the common allele of all three polymorphisms (genotypes: Arg/Arg, pro/pro and II/II) exhibited significantly elevated fasting insulin levels (Pc = 0.03).Pacific Island populations exhibit a remarkably high prevalence rate of obesity and type 2 diabetes and represent a unique population for genetic studies of obesity. In the present study we have revealed that a specific combination of alleles in OB and OB-R, two candidate genes for obesity, may confer an increased risk for the development of insulin resistance in Nauruan males.

An inflection point in genetics has been reached and was witnessed at the Genomics of Common Diseases meeting ( http://www.nature.com/ng/meetings/genomics ) co-sponsored by the Wellcome Trust, held at the Wellcome Trust Hinxton Conference Centre July 7–10, 2007 and co-organized by Tim Aitman, David Altshuler and Eddy Rubin.

Spontaneously hypertensive rats (SHR) display several features of the human insulin-resistance syndromes. Cd36 deficiency is genetically linked to insulin resistance in SHR. We show that transgenic expression of Cd36 in SHR ameliorates insulin resistance and lowers serum fatty acids. Our results provide direct evidence that Cd36 deficiency can promote defective insulin action and disordered fatty-acid metabolism in spontaneous hypertension.

The rat genome sequence, the third mammalian genome sequence to be generated, was recently reported in Nature. The sequence provides new insights into mammalian genome evolution and the opportunity to translate decades of descriptive phenotyping to an understanding of the molecular mechanisms that underlie these phenotypes.

The metabolic overlap syndromes hyperlipidaemia, diabetes mellitus, insulin resistance, obesity and hypertension together constitute the major risk factors for coronary heart disease. The genetic predisposition to these conditions is strong but complex, and many of the genes involved have not been identified. The identification of the genes or metabolic pathways involved in these disorders would lead to new diagnostic and therapeutic targets with wide applicability. The spontaneously hypertensive rat (SHR) is a model of essential hypertension which also displays abnormalities of lipid metabolism and insulin resistance similar to those found in the human metabolic syndromes. These include raised blood triglycerides and fatty acids, defective catecholamine-mediated lipolysis and excessive growth of intra-abdominal adipocytes. Similar abnormalities have been identified in combined hyperlipidaemia, maturity-onset diabetes mellitus and obesity in humans. We are using the SHR as a model to identify genes and pathways that are likely to be in common with those causing the human diseases. Quantitative trait loci (QTL) for glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a locus on rat chromosome 4. We used cDNA microarrays, congenic strains and radiation hybrid mapping to identify a defective gene, Cd36 (encoding fatty acid translocase), at the peak of linkage. Cd36 cDNA contains multiple sequence variants and the encoded protein product is undetectable in SHR adipocyte plasma membrane. Transgenic mice overexpressing Cd36 have reduced blood lipids. We conclude Cd36 deficiency underlies insulin resistance, defective fatty acid metabolism and hypertriglyceridaemia in SHR 1. Human CD36 is being examined for mutation in subjects with insulin resistance from different ethnic backgrounds. The role of other genes showing primary or secondary alteration in expression and their role in metabolic pathway tracking ('pathwayomics') and QTL identification will be discussed.