The structure of linkage disequilibrium at the DBH locus strongly influences the magnitude of association between diallelic markers and plasma dopamine β-hydroxylase activity

被引:81
作者
Zabetian, CP
Buxbaum, SG
Elston, RC
Köhnke, MD
Anderson, GM
Gelernter, J
Cubells, JF
机构
[1] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA
[2] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA
[3] VA Connecticut Healthcare Syst, Dept Psychiat, West Haven, CT USA
[4] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA
[5] Univ Tubingen Hosp, Univ Hosp Psychiat & Psychotherapy, Tubingen, Germany
关键词
D O I
10.1086/375499
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 (-1021 C-->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 less than or equal to 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.
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页码:1389 / 1400
页数:12
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