The Structure of Linkage Disequilibrium at the DBH Locus Strongly Influences the Magnitude of Association between Diallelic Markers and Plasma Dopamine β-Hydroxylase Activity

Abstract

There is currently a great deal of interest in using linkage disequilibrium (LD) mapping to locate both disease and quantitative-trait loci on a genomewide scale. Recent findings suggest that much of the human genome is organized in discrete "blocks" of low haplotype diversity, but the utility of such blocks in identifying genes influencing complex traits is not yet known and must ultimately be tested empirically through use of real data. We recently identified a putative functional polymorphism (-1021C-->T) in the 5' upstream region of the DBH gene that accounted for 35%-52% of the total phenotypic variance in plasma dopamine beta-hydroxylase (DBH) activity in samples from three distinct populations. In the present study, we genotyped 11 diallelic markers at the DBH locus surrounding -1021C-->T in 386 unrelated individuals of European origin. We identified a single 10-kb block containing -1021C-->T, in which four haplotypes comprised 93% of the observed chromosomes. Only markers within the block were highly associated with phenotype (P< or =2.2 x 10(-10)), with one exception. In general, association with phenotype was strongly correlated with the degree of LD between each marker and -1021C-->T. Of four LD measures assessed, d(2) was the best predictor of this relationship. Had one attempted to map quantitative-trait loci for plasma DBH activity on a genomewide basis without prior knowledge of candidate regions and not included (by chance) markers within this haplotype block, the DBH locus might have been missed entirely. These results provide a direct example of the potential value of constructing a haplotype map of the human genome prior to embarking on large-scale association studies.

Linkage disequilibrium and association with methamphetamine dependence/psychosis of μ-opioid receptor gene polymorphisms

“…39,40 The identification of at least four LD blocks in the OPRM1 gene in the present study may be useful in future association studies of polymorphisms in the OPRM1 gene with other clinical traits. The incidence of recombination may be high in the OPRM1 gene relative to other genes owing to its telomeric position on chromosome 6 (6q24-q25).…”

Genotypic and haplotypic associations of the DBH gene with plasma dopamine β-hydroxylase activity in African Americans

“…Rs1611115 accounted for a greater proportion of the variance in pDbH than any of 10 other common diallelic variants at DBH examined in that study. 12 Linkage disequilibrium (LD) between each of those variants and rs1611115 appears to be responsible for the association of those variants to pDbH. 12 Another SNP, rs6271, is located in exon 11 and encodes a nonconservative change in predicted primary amino-acid sequence (arg535cys).…”

“…12 Linkage disequilibrium (LD) between each of those variants and rs1611115 appears to be responsible for the association of those variants to pDbH. 12 Another SNP, rs6271, is located in exon 11 and encodes a nonconservative change in predicted primary amino-acid sequence (arg535cys). Rs6271 is not in LD with rs1611115, and appears to be the only one of four common nonsynonymous SNPs at DBH that independently accounts for additional variance in pDbH after accounting for the effect of rs1611115.…”

Haplotypic relationship between SNP and microsatellite markers at the NOS2A locus in two populations

“…Increasingly, regions of low haplotype diversity and high LD ('haplotype blocks') have been described in the human genome 9 and the influence of local patterns of LD in determining the likely success of association mapping has been highlighted. 10,11 Single nucleotide polymorphisms (SNPs) are generally considered the ideal genetic marker, as they are common, stable and increasingly amenable to automated highthroughput genotyping methods. Estimates of the density of the SNP map required for mapping disease loci have varied with corresponding estimates of the extent of LD across the human genome.…”