Haplotype-Based Analyses for Alcoholism and Anxie

最近，对基因组相邻区域高密度单核苷酸多态(SNPs)之间的连锁不平衡(等位基因关联)的研究揭示了一种简单的不同长度的区块模式，在这些区块上只观察到少数常见的单倍型(一般有3-5种单倍型，频率大于或等于5%)，由重组位点分隔。这些单倍型反映了单个古老祖先染色体的后代。单倍型方法的主要优点是，常见的单倍型捕获了大范围内大部分的遗传变异，并且只能通过少量的SNP(通常是3到8个)来识别。因此，基于单倍型的病例对照研究可以检测与疾病或行为的关联，而不必发现和测试该区域的每一个变异。 我们使用了基于单倍型的分析，以检测与酒精中毒和焦虑的关联，主要是在GABAA受体基因的第4染色体簇。我们发现，在芬兰高加索人和美洲平原印第安人这两个不同种族的人群中，具有高维度焦虑(伤害回避(HA))的酗酒者具有最丰富的GABAAa2单倍型的频率最高，非酗酒者居中，低HA酗酒者该单倍型的频率最低。在相反的关系中，低HA酒精组的单倍型频率较高，非酒精组居中，高HA酒精组的单倍型频率较低。按性别进行的分析表明，这一发现仅限于男性。相比之下，高透明质酸和低透明质酸的非酒精者的单倍型频率在两个样本中都没有差异。4号染色体复合体的GABAAa4和GABAAb1以及5号染色体复合体的GABAAa6的SNPs的基因分型已经完成，单倍型块已经确定，基于单倍型的关联分析正在进行中。其他酒精中毒/焦虑候选基因，特别是甘丙素和伤害素的SNPs基因分型工作正在进行中。

Recently, studies of linkage disequilibrium (allelic association) between high densities of single nucleotide polymorphisms (SNPs) across contiguous regions of the genome have revealed a simple pattern of blocks of varying length over which only a few common haplotypes (in general, 3-5 haplotypes with greater than, or equal to, 5% frequency) are observed, separated by recombination sites. These haplotypes reflect descent from a single, ancient ancestral chromosome. The main advantage of haplotype methods is that common haplotypes capture most of the genetic variation across large regions and can be identified by only a small number of SNPs, usually 3 to 8. Thus haplotype-based case-control studies can detect associations with disease or behavior without having to find and test every single variant in the region. We have used haplotype-based analyses in order to detect associations with alcoholism and anxiety, primarily in the chromosome 4 cluster of GABAA receptor genes. We have found that in two ethnically diverse populations, Finnish Caucasians and Plains American Indians, alcoholics with high dimensional anxiety (harm avoidance (HA)) had the highest frequency of the most abundant GABAAa2 haplotype, non-alcoholics were intermediate, and low HA alcoholics had the lowest frequency of this haplotype. In an inverse relationship, low HA alcoholics had higher frequencies of the less abundant haplotypes, non-alcoholics were intermediate and high HA alcoholics had lower frequencies. Analysis by sex showed that this finding was confined to men. In contrast, haplotype frequencies in non-alcoholics with high and low HA did not differ in either sample. Genotyping of SNPs in GABAAa4 and GABAAb1 in the chromosome 4 complex, and GABAAa6 in the chromosome 5 complex has been completed, haplotype blocks have been identified and haplotype-based association analyses are underway. Genotyping of SNPs in other alcoholism/anxiety candidate genes, in particular galanin and nociceptin, is being undertaken.