GABRG1 and GABRA2 as independent predictors for alcoholism in two populations.
GABRG1 and GABRA2 as independent predictors for alcoholism in two populations.
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DOI：
10.1038/npp.2008.171
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发表时间：
2009-04
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影响因子：
--
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中科院分区：
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GABAA受体基因的4号染色体簇主要在大脑奖赏回路中表达，该染色体区域与酒精中毒的连锁扫描有关。一个4号染色体基因GABRA 2的变异与酒精使用障碍（AUD）密切相关，尽管尚未确定功能位点。由于HapMap数据显示GABRA 2和相邻基因GABRG 1之间存在中度长距离连锁不平衡，因此功能位点可能位于GABRG 1中。我们在两个人群中对GABRG 1和GABRA 2的24个SNP进行了基因分型：547名芬兰白人男性（266名酗酒者）和311名社区来源的平原印第安男性和女性（181名酗酒者）。在平原印第安人和高加索人中：（a）GABRG 1单倍型块没有延伸到GABRA 2;（B）GABRG 1单倍型和SNP与AUD显著相关;（c）GABRA 2单倍型与AUD之间没有关联;（d）有几种常见的（≥ 0.05）个跨越GABRG 1和GABRA 2（341 kb）的单倍型，其中3个在两个群体中都存在，其中一个与AUD相关，另外两个在非酒精成瘾者中更常见;这种关联由GABRG 1确定;（e）在芬兰人中，三种较不常见（< 0.05）的扩展单倍型显示出与AUD的关联，其由GABRA 2确定。我们的研究结果表明，有可能是独立的，复杂的贡献，从GABRG 1和GABRA 2酒精中毒的脆弱性。
The chromosome 4 cluster of GABAA receptor genes is predominantly expressed in the brain reward circuitry and this chromosomal region has been implicated in linkage scans for alcoholism. Variation in one chromosome 4 gene, GABRA2, has been robustly associated with alcohol use disorders (AUD) although no functional locus has been identified. Since HapMap data reveals moderate long-distance linkage disequilibrium across GABRA2 and the adjacent gene, GABRG1, it is possible that the functional locus is in GABRG1. We genotyped 24 SNPs across GABRG1 and GABRA2 in two population isolates: 547 Finnish Caucasian men (266 alcoholics) and 311 community-derived Plains Indian men and women (181 alcoholics). In both the Plains Indians and the Caucasians: (a) the GABRG1 haplotype block(s) did not extend to GABRA2; (b) GABRG1 haplotypes and SNPs were significantly associated with AUD; (c) there was no association between GABRA2 haplotypes and AUD; (d) there were several common (≥ 0.05) haplotypes that spanned GABRG1 and GABRA2 (341 kb), three of which were present in both populations: one of these ancestral haplotypes was associated with AUD, the other two were more common in non-alcoholics; this association was determined by GABRG1; (e) in the Finns, three less common (< 0.05) extended haplotypes showed an association with AUD that was determined by GABRA2. Our results suggest that there are likely to be independent, complex contributions from both GABRG1 and GABRA2 to alcoholism vulnerability.
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作者：
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发表时间：
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