Hypertriglyceridemia ( hTG ) is a lipid disorder, resulting from an elevation in triglyceride levels, with a strong genetic component. It constitutes a significant risk factor for coronary artery disease ( CAD ), a leading cause of death worldwide. In this study, we performed a common variant association study for hTG in ethnic Saudi Arabs. We genotyped 5501 individuals in a two‐phase experiment using Affymetrix Axiom ® Genome‐Wide CEU 1 Array (Affymetrix, Santa Cruz, CA) that contains a total of 587,352 single nucleotide polymorphisms ( SNPs ). The lead variant was the rs1558861 [1.99 (1.73–2.30); p = 7.37 × 10 −22 ], residing on chromosome (chr) 11 at the apolipoprotein A‐I/A‐5 ( APOA1 / APOA5 ) locus. The rs780094 [1.34 (1.21–1.49); p = 8.57 × 10 −8 ] on chr 2 at the glucokinase regulatory protein ( GCKR ) locus was similarly significantly associated, while the rs10911205 [1.29 (1.16–1.44); p = 3.52 × 10 −6 ] on chr1 at the laminin subunit gamma‐1 ( LAMC1 ) locus showed suggestive association with disease. Furthermore, the rs17145738 [0.68 (0.60–0.77); p = 6.69 × 10 −9 ] on chr7 at the carbohydrate‐responsive element‐binding protein‐encoding ( MLXIPL ) gene locus displayed significant protective characteristics, while another variant rs6982502 [0.76 (0.68–0.84); p = 5.31 × 10 −7 ] on chr8 showed similar but weaker properties. These findings were replicated in 317 cases vs 1415 controls from the same ethnic Arab population. Our study identified several variants across the human genome that are associated with hTG in ethnic Arabs.

Allergic contact dermatitis (ACD) is a T cell-mediated delayed hypersensitivity reaction with a median prevalence of 20% across North America and Europe. Susceptibility to the development of ACD is clearly variable amongst individuals and has been attributed to polymorphisms in genes associated with the immune response. Previous studies sought to determine the genetic factors underlying hapten sensitization, yet few have examined the subsequent stages of ACD resulting in dermatitis. In this study our aim was to determine the underlying genetic factors that contribute to the development of contact hypersensitivity, the murine model of ACD. 38 different strains of mice (n=5 per strain) from the Collaborative Cross (CC), a murine resource developed for investigation of complex genetic traits, were exposed in a reproducible manner to a strong sensitizer, oxazolone, and later challenged by a single application of the same allergen to determine intensity of the dermatitis at various timepoints and the recovery from the inflammation. The contact hypersensitivity response for 38 CC mouse strains showed remarkable differences in both the initial inflammatory phase and in their subsequent recovery. In genome wide association studies we identified major effect quantitative trait loci associated with these phenotypes and identified Bach2 and Gilz (Lod score of 10.1 and 15.4 respectively, p<0.001) as candidate genes modulating the induced contact hypersensitivity. Among other genes, these candidates point to an essential role of the MAPK/ERK pathway in the intensity and the recovery of the dermatitis associated with contact hypersensitivity and open new possibilities for targeted therapeutic intervention.

The genetic susceptibility to acquiring low high density lipoprotein‐cholesterol ( LHDLC ) levels is not completely elucidated yet. In this study, we performed a common variant association study for harboring this trait in ethnic Arabs. We employed the Affymetrix high‐density Axiom Genome‐Wide ASI Array (Asian population) providing a coverage of 598,000 single nucleotide variations ( SNPs ) to genotype 5495 individuals in a two‐phase study involving discovery and validation sets of experiments. The rs1800775 [1.31 (1.22–1.42); p = 3. 41E ‐12] in the CETP gene and rs359027 [1.26 (1.16–1.36); p = 2. 55E ‐08] in the LMCD1 gene were significantly associated with LHDLC levels. Furthermore, rs3104435 [1.26 (1.15–1.38); p = 1. 19E ‐06] at the MATN1 locus, rs9835344 [1.16 (1.08–1.26); p = 8. 75E ‐06] in the CNTN6 gene, rs1559997 [1.3 (1.14–1.47); p = 9. 48E ‐06] in the SDS gene and rs1670273 [1.2 (1.1–1.31); p = 4. 81E ‐06] in the DMN / SYNM gene exhibited suggestive association with the disorder. Seven other variants including rs1147169 in the PLCL1 gene, rs10248618 in the DNAH11 , rs476155 in the GLIS3 , rs7024300 in the ABCA1 , intergenic rs10836699, rs11603691 in P2RX3 and rs750134 in CORO1C gene exhibited borderline protective properties. Validation and joint meta‐analysis resulted in rs1800775, rs3104435 and rs359027 retaining their predisposing properties, while rs10836699 and rs11603691 showed protective properties. Our data show several predisposing variants across the genome for LHDLC levels in ethnic Arabs.

Patients with the same genetic mutation who differ in disease severity may possess genetic modifying factors. Such genetic modifiers have been identified for neuromuscular disorders; many of these have been found from mouse studies. The Collaborative Cross (CC) is a resource with the potential to effectively map genetic modifiers more effectively than previously available methods. Derived from eight genetically diverse founder mouse strains, the genome of each CC offspring strain is a mosaic of chromosomal segments inherited randomly from the founders. As a proxy measure of skeletal muscle function, we analysed voluntary running wheel activity of over 50 CC mouse strains at two different ages (6 weeks and 6 months). Marked phenotypic variation was seen across strains for all related traits measured (distance run per day, maximum speed, average speed, and time spent running per day). A select number of strains were chosen to breed with dystrophin-deficient muscular dystrophy (mdx) mice, and we evaluated voluntary running wheel activity of the resulting progeny. Progeny of some strains performed equal to, or worse than, mdx mice on the standard C57BL/10 background. However, the dystrophin-deficient progeny of one of the highest performing CC strains had significantly improved voluntary exercise performance. Comparison of the CC strains' genomes allowed mapping of a key modifier gene to a small chromosome region that is currently being scrutinised. Microarray analysis of skeletal muscles from “rescued” and “standard” mdx mice indicates a relatively small number of differentially expressed genes between the two cohorts. Pathway analysis of differentially expressed genes highlights the Parkinson's pathway. The genetic modifier/s for improved voluntary exercise ability by mdx mice could be targeted for modulation as a potential therapeutic avenue for muscular dystrophy.

Analysis of voluntary running wheel activity in mice is a useful phenotypic measure of skeletal muscle function. We have collected voluntary running wheel activity and total body weight data from >50 strains of mice belonging to the ‘Collaborative Cross’ (aka The Gene Mine), and compared these to known models of neuromuscular disease. The Gene Mine is a mouse reference population derived from eight genetically diverse founder strains, with the genome of each offspring strain being a mosaic of chromosomal segments inherited randomly from the founders. The Gene Mine is designed specifically for complex trait analysis and the identification of quantitative trait loci (QTL). Our analyses of voluntary running wheel activity has involved measuring distance, maximum speed, average speed and time spent on the wheel over a six day consecutive period in male and female Gene Mine mice at two different ages (6 weeks and 6–9 months). We also recorded real-time activity levels and are imaging selected mouse strains by magnetic resonance imaging and computed tomography. Our results indicate marked phenotypic variation across all traits measured, including comparisons of young and older Gene Mine mice. We are now mapping QTL for the various phenotypes and comparing these with skeletal muscle gene expression. We previously crossed skeletal muscle actin knockout mice with Gene Mine strains to identify strains capable of extending the usual early lethal phenotype of this model. The phenotype resource we and others are building can now be used to search for strains, and from there QTL, that modify voluntary running wheel activity, weight and muscle bulk in various models of neuromuscular diseases. Analysis of voluntary running wheel activity in mice is a useful phenotypic measure of skeletal muscle function. We have collected voluntary running wheel activity and total body weight data from >50 strains of mice belonging to the ‘Collaborative Cross’ (aka The Gene Mine), and compared these to known models of neuromuscular disease. The Gene Mine is a mouse reference population derived from eight genetically diverse founder strains, with the genome of each offspring strain being a mosaic of chromosomal segments inherited randomly from the founders. The Gene Mine is designed specifically for complex trait analysis and the identification of quantitative trait loci (QTL). Our analyses of voluntary running wheel activity has involved measuring distance, maximum speed, average speed and time spent on the wheel over a six day consecutive period in male and female Gene Mine mice at two different ages (6 weeks and 6–9 months). We also recorded real-time activity levels and are imaging selected mouse strains by magnetic resonance imaging and computed tomography. Our results indicate marked phenotypic variation across all traits measured, including comparisons of young and older Gene Mine mice. We are now mapping QTL for the various phenotypes and comparing these with skeletal muscle gene expression. We previously crossed skeletal muscle actin knockout mice with Gene Mine strains to identify strains capable of extending the usual early lethal phenotype of this model. The phenotype resource we and others are building can now be used to search for strains, and from there QTL, that modify voluntary running wheel activity, weight and muscle bulk in various models of neuromuscular diseases.

Susceptibility to most common cancers is likely to involve interaction between multiple low risk genetic variants. Although there has been great progress in identifying such variants, their effect on phenotype and the mechanisms by which they contribute to disease remain largely unknown. We have developed a mouse melanoma model harboring two mutant oncogenes implicated in human melanoma, CDK4(R24C) and NRAS(Q61K). In these mice, tumors arise from benign precursor lesions that are a recognized strong risk factor for this neoplasm in humans. To define molecular events involved in the pathway to melanoma, we have for the first time applied the Collaborative Cross (CC) to cancer research. The CC is a powerful resource designed to expedite discovery of genes for complex traits. We characterized melanoma genesis in more than 50 CC strains and observed tremendous variation in all traits, including nevus and melanoma age of onset and multiplicity, anatomical site predilection, time for conversion of nevi to melanoma and metastases. Intriguingly, neonatal ultraviolet radiation exposure exacerbated nevus and melanoma formation in most, but not all CC strain backgrounds, suggesting that genetic variation within the CC will help explain individual sensitivity to sun exposure, the major environmental skin carcinogen. As genetic variation brings about dramatic phenotypic diversity in a single mouse model, melanoma-related endophenotype comparisons provide us with information about mechanisms of carcinogenesis, such as whether melanoma incidence is dependent upon the density of pre-existing nevus cells. Mouse models have been used to examine the functional role of gene mutations in tumorigenesis. This work represents their next phase of development to study how biological variation greatly influences lesion onset and aggressiveness even in the setting of known somatic driver mutations.

Cardiac actin (ACTC) is the fetal homologue of skeletal muscle actin (ACTA1), and is switched off at birth in skeletal muscle but remains highly expressed in adult heart and in regenerating muscle. ACTC is 99% identical to ACTA1 protein, differing at only 4 amino acids. We previously showed an ACTC transgene could functionally replace ACTA1 in postnatal skeletal muscle of Acta1 knockout mice that normally die within a few days of birth, indicating that ACTC could have a therapeutic role in skeletal muscle actin diseases. We harnessed the power of two different recombinant inbred (RI) mouse models including BXD and the more recently developed Collaborative Cross (CC), to identify genetic elements controlling Actc expression. RI mice are genetic reference populations consisting of large numbers of inbred mouse strains descended from either 2 (BXD) or 8 (CC) founder strains. Characterization of these strains for a trait of interest allows for the mapping of gene(s) mediating that trait to genomic intervals called quantitative trait loci (QTL). We have identified in both RI sets a highly significant QTL regulating Actc expression in skeletal muscle. This QTL also regulates Actc expression in particular non-skeletal muscle tissues (eye and lung). Identification of the regulatory genetic element may provide a target for modifying expression of cardiac actin by therapeutic intervention. Cardiac actin (ACTC) is the fetal homologue of skeletal muscle actin (ACTA1), and is switched off at birth in skeletal muscle but remains highly expressed in adult heart and in regenerating muscle. ACTC is 99% identical to ACTA1 protein, differing at only 4 amino acids. We previously showed an ACTC transgene could functionally replace ACTA1 in postnatal skeletal muscle of Acta1 knockout mice that normally die within a few days of birth, indicating that ACTC could have a therapeutic role in skeletal muscle actin diseases. We harnessed the power of two different recombinant inbred (RI) mouse models including BXD and the more recently developed Collaborative Cross (CC), to identify genetic elements controlling Actc expression. RI mice are genetic reference populations consisting of large numbers of inbred mouse strains descended from either 2 (BXD) or 8 (CC) founder strains. Characterization of these strains for a trait of interest allows for the mapping of gene(s) mediating that trait to genomic intervals called quantitative trait loci (QTL). We have identified in both RI sets a highly significant QTL regulating Actc expression in skeletal muscle. This QTL also regulates Actc expression in particular non-skeletal muscle tissues (eye and lung). Identification of the regulatory genetic element may provide a target for modifying expression of cardiac actin by therapeutic intervention.

Determining modifier genes is extremely important for understanding differences in both normal and disease phenotypes, and for designing potential therapeutic avenues for disease. Finding modifier genes in humans is difficult, especially controlling for environmental factors. Therefore researchers have harnessed animal models for such studies, with proven success. The Collaborative Cross (CC) is a revolutionary genetic resource comprised of a reference population of hundreds of mouse lines descended from eight genetically and phenotypically diverse founder strains. This resource facilitates high resolution mapping of genes for traits of interest. We aim to identify quantitative trait loci (QTL) containing genes that in the future might be exploited as disease modifiers for neuromuscular disorders. We studied CC strains generated in Western Australia, measuring a range of traits, including gene expression levels from skeletal muscle, and in vivo phenotypes such as voluntary running wheel performance. These studies revealed great variation across strains. As we have previously shown that cardiac actin expression can modulate skeletal muscle actin disease, we also produced progeny from multiple CC strains that were deficient in skeletal muscle actin. Some of these strains survived significantly longer than the usual maximum lifespan of 9 days. From all these studies, measurements from a relatively low number of strains have allowed mapping of QTL, confirming the power of The CC, and setting a foundation for identification of important modifier genes for skeletal muscle disease. Determining modifier genes is extremely important for understanding differences in both normal and disease phenotypes, and for designing potential therapeutic avenues for disease. Finding modifier genes in humans is difficult, especially controlling for environmental factors. Therefore researchers have harnessed animal models for such studies, with proven success. The Collaborative Cross (CC) is a revolutionary genetic resource comprised of a reference population of hundreds of mouse lines descended from eight genetically and phenotypically diverse founder strains. This resource facilitates high resolution mapping of genes for traits of interest. We aim to identify quantitative trait loci (QTL) containing genes that in the future might be exploited as disease modifiers for neuromuscular disorders. We studied CC strains generated in Western Australia, measuring a range of traits, including gene expression levels from skeletal muscle, and in vivo phenotypes such as voluntary running wheel performance. These studies revealed great variation across strains. As we have previously shown that cardiac actin expression can modulate skeletal muscle actin disease, we also produced progeny from multiple CC strains that were deficient in skeletal muscle actin. Some of these strains survived significantly longer than the usual maximum lifespan of 9 days. From all these studies, measurements from a relatively low number of strains have allowed mapping of QTL, confirming the power of The CC, and setting a foundation for identification of important modifier genes for skeletal muscle disease.