Newton Morton | PubMed Health

PubMed2006

Genome scanning by composite likelihood.

Ambitious programs have recently been advocated or launched to create genomewide databases for meta-analysis of association between DNA markers and phenotypes of medical and/or social concern. A necessary but not sufficient condition for success in association mapping is that the data give accurate estimates of both genomic location and its standard error, which are provided for multifactorial phenotypes by composite likelihood. That class includes the Malecot model, which we here apply with an illustrative example. This preliminary analysis leads to five inferences: permutation of cases and controls provides a test of association free of autocorrelation; two hypotheses give similar estimates, but one is consistently more accurate; estimation of the false-discovery rate is extended to causal genes in a small proportion of regions; the minimal data for successful meta-analysis are inferred; and power is robust for all genomic factors except minor-allele frequency. An extension to meta-analysis is proposed. Other approaches to genome scanning and meta-analysis should, if possible, be similarly extended so that their operating characteristics can be compared.

Chromosome Mapping↗

PubMed2005

Cosmopolitan linkage disequilibrium maps.

Linkage maps have been invaluable for the positional cloning of many genes involved in severe human diseases. Standard genetic linkage maps have been constructed for this purpose from the Centre d'Etude du Polymorphisme Humain and other panels, and have been widely used. Now that attention has shifted towards identifying genes predisposing to common disorders using linkage disequilibrium (LD) and maps of single nucleotide polymorphisms (SNPs), it is of interest to consider a standard LD map which is somewhat analogous to the corresponding map for linkage. We have constructed and evaluated a cosmopolitan LD map by combining samples from a small number of populations using published data from a 10-megabase region on chromosome 20. In support of a pilot study, which examined a number of small genomic regions with a lower density of markers, we have found that a cosmopolitan map, which serves all populations when appropriately scaled, recovers 91 to 95 per cent of the information within population-specific maps. Recombination hot spots appear to have a dominant role in shaping patterns of LD. The success of the cosmopolitan map might be attributed to the co-localisation of hot spots in all populations. Although there must be finer scale differences between populations due to other processes (mutation, drift, selection), the results suggest that a whole-genome standard LD map would indeed be a useful resource for disease gene mapping.

Chromosome Mapping↗