遗传学期刊(英文)最新文献

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Family-based association analysis of alcohol dependence implicates KIAA0040 on Chromosome 1q in multiplex alcohol dependence families. 基于家族的酒精依赖关联分析表明，多重酒精依赖家族的1q染色体上存在KIAA0040。

遗传学期刊(英文)

Pub Date : 2013-12-01 DOI: 10.4236/ojgen.2013.34027

Shirley Y Hill, Bobby L Jones, Nicholas Zezza, Scott Stiffler

Background: A previous genome-wide linkage study of alcohol dependence in multiplex families found a suggestive linkage result for a region on Chromosome 1 near microsatellite markers D1S196 and D1S2878. The KIAA0040 gene has been mapped to this region (1q24 - q25). A recent genome-wide association study using SAGE (the Study of Addiction: Genetics and Environment) and COGA (Collaborative Study on the Genetics of Alcoholism) found five SNPs within the KIAA0040 gene significantly associated with alcohol dependence. A meta-analysis using data from these sources also found the KIAA0040 gene significantly associated with alcohol dependence.

Methods: Using family data consisting of 1000 individuals with phenotypic data (762 with both phenotype and DNA), finer mapping of a 0.3 cM region that included the KIAA0040 gene and a flanking gene was undertaken using SNPs with minor allele frequency (MAF) ≥ 0.15 and pair-wise linkage disequilibrium (LD) of r² < 0.8 using the HapMap CEU population.

Results: Significant FBAT p-values were observed for six SNPs, four within the KIAA0040 gene (rs2269650, rs2861158, rs1008459, rs2272785) and two adjacent to KIAA0040 (rs10912899 and rs3753555). Five haplotype blocks of varying size were identified using HAPLOVIEW. Analysis using the haplotype-based test function of FBAT revealed one two-SNP block (rs1008459-rs2272785) associated with alcohol dependence. This block showed a pattern of transmission in which one haplotype, CT, with a frequency of 0.577 was found to be over-transmitted to affected offspring (p = 0.017) while another haplotype, AG, with a frequency of 0.238 was found to be under-transmitted to affected offspring (p = 0.006). A three-SNP block (rs1008459-rs2272785-rs375355) showed an overall significant association (p = 0.011) with alcohol dependence with the haplotype ACT over-transmitted to affected offspring (p = 0.016) and the haplotype GAG under-transmitted (p = 0.002).

Conclusions: Family-based association analysis shows the KIAA0040 gene significantly associated with alcohol dependence. The potential importance of the KIAA0040 gene for AD risk is currently unknown. However, the present results support earlier findings from a genome-wide association study.

背景:先前的一项多家族酒精依赖的全基因组连锁研究发现，1号染色体上靠近微卫星标记D1S196和D1S2878的区域存在提示连锁结果。KIAA0040基因已定位于该区域(1q24 - q25)。最近一项使用SAGE(成瘾研究:遗传与环境)和COGA(酒精中毒遗传学合作研究)的全基因组关联研究发现，KIAA0040基因中的5个snp与酒精依赖显著相关。利用这些来源的数据进行的荟萃分析还发现，KIAA0040基因与酒精依赖显著相关。方法:利用由1000个具有表型数据的个体(762个具有表型和DNA数据)组成的家族数据，利用HapMap CEU群体，使用次要等位基因频率(MAF)≥0.15和成对连锁不平衡(LD) r2 < 0.8的SNPs，对包括KIAA0040基因和一个侧翼基因的0.3 cM区域进行更精细的定位。结果:6个snp的FBAT值显著，其中4个位于KIAA0040基因内(rs2269650、rs2861158、rs1008459、rs2272785)， 2个邻近KIAA0040基因(rs10912899和rs3753555)。利用HAPLOVIEW鉴定了5个大小不同的单倍型块。利用基于单倍型的FBAT测试功能进行分析，发现一个与酒精依赖相关的双snp块(rs1008459-rs2272785)。该块显示了一种传播模式，其中一种单倍型CT，频率为0.577，被发现过度传播给受影响的后代(p = 0.017)，而另一种单倍型AG，频率为0.238，被发现传播给受影响的后代(p = 0.006)。三个snp块(rs1008459-rs2272785-rs375355)与酒精依赖总体显著相关(p = 0.011)，单倍型ACT过度传递给受影响后代(p = 0.016)，单倍型GAG欠传递(p = 0.002)。结论:基于家族的关联分析显示KIAA0040基因与酒精依赖显著相关。KIAA0040基因对AD风险的潜在重要性目前尚不清楚。然而，目前的结果支持早期全基因组关联研究的发现。

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