A Chromosome 13 locus is associated with male-specific mortality in mice.

BACKGROUND AND AIM: Mortality is a highly complex trait influenced by a wide array of genetic factors. METHODS: We examined a population of 1200 mice that were F2 generation offspring of a 4-way reciprocal cross between C57BL6/J and DBA2/J strains. Animals were sacrificed at age 200, 500, or 800 days and genotyped at 96 markers. The 800 days old cohort, which were the survivors of a much larger breeding group, were examined for enriched frequency of alleles that benefit survival and depletion of alleles that reduce survival. RESULTS: Loci on Chr 13 in males and on Chr X in females were significantly distorted from Mendelian expectations, even after conservative correction for multiple testing. DBA2/J alleles between 35 and 80 Mb on Chr 13 were underrepresented in the age 800 male animals. D2 genotypes in this region were also associated with premature death during behavioral testing. Furthermore, confirmatory analysis showed BXD recombinant inbred strains carrying the D2 alleles in this region had shorter median survival. Exploration of available pathology data indicated that a syndrome involving dental malocclusions, pancreatic islet hypertrophy, and kidney lipidosis may have mediated the effects of DBA alleles on mortality specifically in male mice. The heterozygote advantage locus on the X Chr was not found to be associated with any pathology. CONCLUSIONS: These results suggest a novel locus influencing survival in the B6/D2 genetic background, perhaps via a metabolic disorder that emerges by 200 days of age in male animals.

CHD7 gene polymorphisms and familial idiopathic scoliosis.

STUDY DESIGN: Model-independent linkage analysis and tests of association were performed for 22 single nucleotide polymorphisms in the CHD7 gene in 244 families of European descent with familial idiopathic scoliosis (FIS). OBJECTIVE: To replicate an association between FIS and the CHD7 gene on 8q12.2 in an independent sample of families of European descent. SUMMARY OF BACKGROUND DATA: The CHD7 gene on chromosome 8, responsible for the CHARGE syndrome, was previously associated with FIS in an independent study that included 52 families of European descent. METHODS: Model-independent linkage analysis and intrafamilial tests of association were performed on the degree of lateral curvature considered as a qualitative trait (with thresholds of ≥10°, ≥15°, ≥20°, and ≥30°) and as a quantitative trait (degree of lateral curvature). Results from the tests of associations from this study and the previous study were combined in a weighted meta-analysis. RESULTS: No significant results (P < 0.01) were found for linkage analysis or tests of association between genetic variants of the CHD7 and FIS in this study, failing to replicate the findings from the previous study. Furthermore, no significant results (P < 0.01) were found from meta-analysis of the results from the tests of association from this sample and from the previous sample. CONCLUSION: No association between the 22 genotyped single nucleotide polymorphisms in the CHD7 gene and FIS within this study sample was found, failing to replicate the earlier findings. Further investigation of the CHD7 gene and its potential association to FIS may be required. LEVEL OF EVIDENCE: N/A.