Department of Human Genetics, Emory University School of Medicine, Atlanta 30322, GA, USA.
Hum Genet. 2011 Nov;130(5):635-43. doi: 10.1007/s00439-011-0989-6. Epub 2011 Apr 21.
Dopamine β-hydroxylase (DβH) catalyzes the conversion of dopamine to norepinephrine. DβH enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma DβH activity (pDβH) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pDβH to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which maps adjacent to ABO, as the locus regulating a large proportion of the heritable variation in pDβH. Prior studies have suggested that variation in pDβH, or genetic variants at DβH, associate with differences in expression of psychotic symptoms in patients with schizophrenia and other idiopathic or drug-induced brain disorders, suggesting that DBH might be a genetic modifier of psychotic symptoms. As a first step toward investigating that hypothesis, we performed linkage analysis on pDβH in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pDβH under several models (maximum multipoint LOD score, 6.33), but find no evidence to support linkage anywhere on chromosome 19. Accounting for the contributions to the linkage signal of three SNPs at DBH, rs1611115, rs1611122, and rs6271 reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Analysis of markers genome-wide uncovered positive evidence for linkage between markers at chromosome 20p12 (multi-point LOD = 3.1 at 27.2 cM). The present results provide the first direct evidence for linkage between DBH and pDβH, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pDβH, and suggest that a locus near 20p12 also influences pDβH.
多巴胺 β-羟化酶 (DβH) 催化多巴胺转化为去甲肾上腺素。DβH 从交感神经元和肾上腺髓质的小泡释放后进入血浆。个体间的血浆 DβH 活性 (pDβH) 差异很大,遗传继承调节这种变化。连锁研究表明,pDβH 与 9q34 上的 ABO 紧密连锁,并且在 19p13.2-13.3 上的补体固定部位有阳性证据。随后的关联研究强烈支持 DBH,它紧邻 ABO 定位,是调节 pDβH 大部分可遗传变异的基因座。先前的研究表明,pDβH 的变异或 DβH 的遗传变异与精神分裂症患者和其他特发性或药物引起的脑疾病患者的精神症状表达的差异相关,这表明 DBH 可能是精神症状的遗传修饰因子。作为研究该假说的第一步,我们对精神分裂症患者及其亲属的 pDβH 进行了连锁分析。结果强烈证实了在几种模型下 DBH 标记物与 pDβH 的连锁(最大多点 LOD 评分 6.33),但没有发现任何证据支持在 19 号染色体上的任何部位连锁。考虑到 DBH 上三个 SNP(rs1611115、rs1611122 和 rs6271)对连锁信号的贡献,rs1611115、rs1611122 和 rs6271 降低但没有消除连锁峰,而考虑到 DBH 附近的所有 SNP 则完全消除了信号。全基因组标记物分析提供了在 20p12 染色体上的标记物之间存在连锁的直接证据(多点 LOD = 3.1,在 27.2 cM)。本研究结果首次直接证明了 DBH 与 pDβH 之间的连锁关系,表明 rs1611115、rs1611122、rs6271 以及 DBH 或其附近的其他未知变异体有助于 pDβH 的遗传调节,并表明 20p12 附近的一个基因座也影响 pDβH。