Concordance of Murine Quantitative Trait Loci for Salt-Induced Hypertension with Rat and Human Loci

Sugiyama, Fumihiro; Churchill, Gary A.; Higgins, David; Johns, Conrado; Makaritsis, Konstatinos P.; Gavras, Haralambos; Paigen, Beverly

doi:10.1006/geno.2000.6401

Cited by 184 publications

(158 citation statements)

References 34 publications

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“…For the 1D_path, the averaged genome-wide thresholds were 4.28 and 5.08 (corresponding to a nominal P-value of 3.2 Â 10 À4 and 5.1 Â 10 À4 ) for the overall and interaction tests, respectively. In both cases, the threshold applied for the interaction tests were dramatically more stringent than the recommended nominal P-values of 0.01 (Sugiyama et al, 2001).…”

Section: Thresholdsmentioning

confidence: 97%

“…The key property of this framework is that the interaction test is nested in the overall test; only pairs that passed the overall test would proceed to the interaction test and the two loci in Model 2 must be the same as those in Model 1. It was suggested to use permutation (Churchill and Doerge, 1994) to derive a genome-wide threshold for the overall test, but a nominal, tabulated, threshold for the interaction test (Sen and Churchill, 2001;Sugiyama et al, 2001).…”

Section: Modified Nested Test Frameworkmentioning

confidence: 99%

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Controlling false positives in the mapping of epistatic QTL

et al. 2009

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This study addresses the poorly explored issue of the control of false positive rate (FPR) in the mapping of pair-wise epistatic quantitative trait loci (QTL). A nested test framework was developed to (1) allow pre-identified QTL to be used directly to detect epistasis in one-dimensional genome scans, (2) to detect novel epistatic QTL pairs in twodimensional genome scans and (3) to derive genome-wide thresholds through permutation and handle multiple testing. We used large-scale simulations to evaluate the performance of both the one-and two-dimensional approaches in mapping different forms and levels of epistasis and to generate profiles of FPR, power and accuracy to inform epistasis mapping studies. We showed that the nested test framework and genome-wide thresholds were essential to control FPR at the 5% level. The one-dimensional approach was generally more powerful than the two-dimensional approach in detecting QTL-associated epistasis and identified nearly all epistatic pairs detected from the two-dimensional approach. However, only the two-dimensional approach could detect epistatic QTL with weak main effects. Combining the two approaches allowed effective mapping of different forms of epistasis, whereas using the nested test framework kept the FPR under control. This approach provides a good search engine for high-throughput epistasis analyses.

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Section: Thresholdsmentioning

confidence: 97%

Section: Modified Nested Test Frameworkmentioning

confidence: 99%

Controlling false positives in the mapping of epistatic QTL

et al. 2009

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“…Through three rounds of backcrossing, the transgene was transferred into predominantly sodium-sensitive B6 and sodium-resistant AJ backgrounds, as can be inferred from the recessive nature of the sodium sensitivity of B6 relative to AJ (Sugiyama et al 2001;Woo and Kurtz 2003). Maintenance of transgene copy number of the transgene was investigated.…”

Section: Generation Of Transgenic Micementioning

confidence: 99%

“…Evidently, some genetic diversity that may affect the phenotypes under investigation may still segregate and induce greater variance than would be achieved in a quasi-homogeneous line, decreasing our statistical power. Regarding sodium sensitivity, however, it should be acknowledged that, in the two independent studies mentioned above (Sugiyama et al 2001;Woo and Kurtz 2003), the analysis of blood pressure in segregating F1 and F2 between B6 and AJ clearly demonstrated that the major genetic determinants of sodium sensitivity, identified so far only as quantitative trait loci (QTL), behave as recessive traits in the B6 background. Consequently, limited rounds of backcrossing were sufficient to induce the expression of these recessive components of sodium sensitivity in most B6 animals and to negate their expression in all of the AJ animals investigated.…”

Section: Limitationsmentioning

confidence: 99%

Response to genetic manipulations of liver angiotensinogen in the physiological range

et al. 2008

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Genetic variation in the human angiotensinogen gene (AGT) influences plasma AGT concentration and susceptibility to essential hypertension by a mechanism that remains to be clarified. When one or two additional copies of the gene were inserted by gene titration (by homologous recombination with gap-repair at the AGT locus), both plasma AGT and arterial pressure were elevated in the physiological range in the mouse. The causal dependency between plasma AGT and blood pressure and the relative contribution of the various tissues that express AGT to these two phenotypic parameters remained to be determined. To address these issues, we generated a transgenic mouse with overexpression of the mouse AGT gene restricted to the liver. The transgene was examined in two contrasted genetic backgrounds, the sodium-sensitive C57BL/6J and the sodium-resistant A/J. Transgenic and control male animals underwent continuous cardiovascular monitoring by telemetry for 14 days while under a standard sodium diet (0.2%). Moderate but significant increases in plasma AGT (40%, p = 0.01) and systolic blood pressure (4-6 mmHg, p ranging from 0.01 to \0.001) were observed in the sodium-sensitive background, but not in the sodium-resistant animals. Statistical analysis of a large number of consecutive, repeated measurements of blood pressure afforded power to detect small effects in the physiological range by use of advanced mixed models of analysis of variances and covariances. Although plasma renin activity was increased in the sodium-sensitive background, it did not reach statistical significance. These observations underline a potential contribution of systemic AGT to the mechanism of AGT-mediated hypertension, but the significance of sodium sensitivity in the genetic background suggests participation of the kidney in expression of the elevated blood pressure phenotype, a matter that will warrant further studies. They also highlight the challenge of identifying the contribution of individual genes in complex inheritance, as their effects are modulated by other genetic and environmental determinants.

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“…Linkage analysis and permutation analysis were performed using the software Map Manager QTXb15 (http://mapmgr.roswellpark.org/ mmQTX.html) (31,32). Loci with evidence of linkage were mapped with additional adjacent markers.…”

Section: Genetic Mapping and Linkage Analysismentioning

confidence: 99%

New Loci Regulating Rat Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

Bečanović

Wallström

Kornek

et al. 2003

The Journal of Immunology

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Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in rats that closely mimics many clinical and histopathological aspects of multiple sclerosis. Non-MHC quantitative trait loci regulating myelin oligodendrocyte glycoprotein-induced EAE have previously been identified in the EAE-permissive strain, DA, on rat chromosomes 4, 10, 15, and 18. To find any additional gene loci in another well-known EAE-permissive strain and thereby to assess any genetic heterogeneity in the regulation of the disease, we have performed a genome-wide linkage analysis in a reciprocal (LEW.1AV1 × PVG.1AV1) male/female F2 population (n = 185). We examined reciprocal crosses, but no parent-of-origin effect was detected. The parental rat strains share the RT1av1 MHC haplotype; thus, non-MHC genes control differences in EAE susceptibility. We identified Eae16 on chromosome 8 and Eae17 on chromosome 13, significantly linked to EAE phenotypes. Two loci, on chromosomes 1 and 17, respectively showed suggestive linkage to clinical and histopathological EAE phenotypes. Eae16 and Eae17 differ from those found in previously studied strain combinations, thus demonstrating genetic heterogeneity of EAE. Furthermore, we detected a locus-specific parent-of-origin effect with suggestive linkage in Eae17. Further genetic and functional dissection of these loci may disclose critical disease-regulating molecular mechanisms.

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Concordance of Murine Quantitative Trait Loci for Salt-Induced Hypertension with Rat and Human Loci

Cited by 184 publications

References 34 publications

Controlling false positives in the mapping of epistatic QTL

Controlling false positives in the mapping of epistatic QTL

Response to genetic manipulations of liver angiotensinogen in the physiological range

New Loci Regulating Rat Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

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