The first linkage disequilibrium (LD) maps: Delineation of hot and cold blocks by diplotype analysis

Abstract

Linkage disequilibrium (LD) provides information about positional cloning, linkage, and evolution that cannot be inferred from other evidence, even when a correct sequence and a linkage map based on more than a handful of families become available. We present theory to construct an LD map for which distances are additive and population-specific maps are expected to be approximately proportional. For this purpose, there is only a modest difference in relative efficiency of haplotypes and diplotypes: resolving the latter into 2-locus haplotypes has significant cost or error and increases information by about 50%. LD maps for a cold spot in 19p13.3 and a more typical region in 3q21 are optimized by interval estimates. For a random sample and trustworthy map the value of LD at large distance can be predicted reliably from information over a small distance and does not depend on the evolutionary variance unless the sample size approaches the population size. Values of the association probability that can be distinguished from the value at large distance are determined not by population size but by time since a critical bottleneck. In these examples, omission of markers with significant HardyWeinberg disequilibrium does not improve the map, and widely discrepant draft sequences have similar estimates of the genetic parameters. The LD cold spot in 19p13.3 gives an unusually high estimate of time, supporting an argument that this relationship is general. As predicted for a region with ancient haplotypes or uniformly high recombination, there is no clear evidence of LD clustering. On the contrary, the 3q21 region is resolved into alternating blocks of stable and decreasing LD, as expected from crossover clustering. Construction of a genomewide LD map requires data not yet available, which may be complemented but not replaced by a catalog of haplotypes. P ositional cloning of genes for disease susceptibility depends on linkage and ''allelic association'' (also called ''linkage disequilibrium'' or LD). A cold spot for LD is an interval in which LD declines rapidly with distance: neither linkage nor LD is proportional to the sequence-based map. To the extent that LD mirrors recombination it can extend the low resolution of linkage: a cold spot for LD is a hot spot for recombination and vice versa. However, this correspondence is disturbed by other factors that cannot be reliably predicted. To the extent that these phenomena are important, both the physical and linkage maps are unreliable guides to LD. We need an LD map to facilitate positional cloning, extend the resolution of the linkage map, compare populations, infer their paleodemography, and detect selective sweeps and other events of evolutionary interest. LD mapping is at the stage of linkage maps nearly a century ago, with the same promise.The definitive property of a chromosome map, whether physical or genetic, is that its distances are additive. With this constraint, we require a standard LD map to which populationspecific maps are approximately proportional. Here...

High-Resolution Genetic Maps Identify Multiple Type 2 Diabetes Loci at Regulatory Hotspots in African Americans and Europeans

“…Blocks of LD (SNPs with the same LDU location) represent areas of conserved LD and low haplotype diversity, and steps (increasing LDU distances) define LD breakdown, primarily caused by recombination, since crossover profiles agree precisely with the corresponding LDU steps. 16 The maps show numerous short blocks across the entire region with total LDU length being greater for AA (greater LD breakdown) than the EUR population. The functional location estimates A and E (13 kb apart) indicated by the vertical solid line arrows are associated with T2D in AA and EUR samples, respectively.…”

“…15 We constructed two highresolution genetic maps based upon HapMap data with genetic distances expressed in linkage disequilibrium units (LDU). 16 The EUR LDU map was used for analyses of the two EUR T2D datasets and the AA LDU map was used for the analysis of the AA T2D dataset. The autosomal genome (sex chromosomes were not included in the analyses) was divided into 4,800 non-overlapping analytical windows, each with a minimum distance of 10 LDU.…”

Extreme population differences across Neuregulin 1 gene, with implications for association studies

“…A number of recent studies of LD have shown that its distribution is not homogeneous across the genome. [33][34][35][36][37][38][39] The general pattern found in the regions examined so far is a series of discrete tracts of low recombination, high LD and therefore with a reduced number of haplotypes, the so-called 'haplotype blocks' bounded by recombination hotspots. Haplotype block structure has been found to vary according to genomic region (due to genomic factors affecting its pattern) and also between different global populations (due to demographic factors), 33,36,[38][39][40][41][42][43][44] see Bertranpetit et al 45 for a review.…”

Linkage disequilibrium analysis of case–control data: an application to generalized aggressive periodontitis

“…9,10 Furthermore, there can be remarkable differences in the extent of association from one genomic region to another, 11 reflecting the location of recombination hot spots which generates a pattern of blocks of conserved LD and steps where LD breaks down. 12,13 Ohashi et al 14 showed that one of the major difficulties in testing association in case-control association studies is attributable to the large number of SNPs that must be used. In fact, a marked reduction in the statistical power of LD studies arises from multiple testing and the extremely low P-values required after Bonferroni adjustment, which are unlikely to be achievable with realistic sample sizes.…”