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SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis

Year: 2008
Type: article
Abstract: BACKGROUND: We report our experience of selecting tag SNPs in 35 genes involved in iron metabolism in a cohort study seeking to discover genetic modifiers of hereditary hemochromatosis. METHODS: We combined our own and publicly available resequencing data with HapMap to maximise our coverage to select 384 SNPs in candidate genes suitable for typing on the Illumina platform. RESULTS: Validation/design scores above 0.6 were not strongly correlated with SNP performance as estimated by Gentrain score. We contrasted results from two tag SNP selection algorithms, LDselect and Tagger. Varying r2 from 0.5 to 1.0 produced a near linear correlation with the number of tag SNPs required. We examined the pattern of linkage disequilibrium of three levels of resequencing coverage for the transferrin gene and found HapMap phase 1 tag SNPs capture 45% of the > or = 3% MAF SNPs found in SeattleSNPs where there is nearly complete resequencing. Resequencing can reveal adjacent SNPs (within 60 bp) which may affect assay performance. We report the number of SNPs present within the region of six of our larger candidate genes, for different versions of stock genotyping assays. CONCLUSION: A candidate gene approach should seek to maximise coverage, and this can be improved by adding to HapMap data any available sequencing data. Tag SNP software must be fast and flexible to data changes, since tag SNP selection involves iteration as investigators seek to satisfy the competing demands of coverage within and between populations, and typability on the technology platform chosen.
DOI: 10.1186/1471-2350-9-18
Authors: the HealthIron Investigators, Clare C Constantine, Lyle C Gurrin, Christine E McLaren, Melanie Bahlo, Gregory J Anderson, Chris D Vulpe, Susan M Forrest, Katrina J Allen, Dorota M Gertig
Institutions: The University of Melbourne, University of California, Irvine, Walter and Eliza Hall Institute of Medical Research, QIMR Berghofer Medical Research Institute, University of California, Berkeley, AGRF Ltd, Murdoch Children's Research Institute
Language: English
Subfield: Genetics
Open Access status: gold
Estimated APC paid: $2,380
Funders: National Institutes of Health, University of California, San Francisco, National Health and Medical Research Council, Cancer Council Victoria, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center on Minority Health and Health Disparities, National Institute on Minority Health and Health Disparities
Awards: Genetic modifiers of hemochromatosis phenotype, G3667269547, IRON OVERLOAD AND HEREDITARY HEMOCHROMATOSIS STUDY, G7208884935, G7678386373, G7994449332, Iron Status: A Pathway Analysis in Multiple Ethnicities, NCMHD Center of Excellence in Nutritional Genomics, Cancer Center Support Grant
OpenAlex ID: W1981642490
FWCI: 1.521
Cites: 13
Cited by: 24
Related to: 10