Yin Xianyong, Bizon Chris, Tilson Jeffrey, Lin Yuan, Gizer Ian R, Ehlers Cindy L, Wilhelmsen Kirk C
Department of Genetics and Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Department of Psychological Sciences, University of Missouri, Columbia, Missouri.
Am J Med Genet B Neuropsychiatr Genet. 2017 Jul;174(5):557-567. doi: 10.1002/ajmg.b.32540. Epub 2017 Apr 25.
Nicotine dependence (ND) has a reported heritability of 40-70%. Low-coverage whole-genome sequencing was conducted in 1,889 samples from the UCSF Family study. Linear mixed models were used to conduct genome-wide association (GWA) tests of ND in this and five cohorts obtained from the database of Genotypes and Phenotypes. Fixed-effect meta-analysis was carried out separately for European (n = 14,713) and African (n = 3,369) participants, and then in a combined analysis of both ancestral groups. The meta-analysis of African participants identified a significant and novel susceptibility signal (rs56247223; p = 4.11 × 10 ). Data from the Genotype-Tissue Expression (GTEx) study suggested the protective allele is associated with reduced mRNA expression of CACNA2D3 in three human brain tissues (p < 4.94 × 10 ). Sequence data from the UCSF Family study suggested that a rare nonsynonymous variant in this gene conferred increased risk for ND (p = 0.01) providing further support for CACNA2D3 involvement in ND. Suggestive associations were observed in six additional regions in both European and merged populations (p < 5.00 × 10 ). The top variants were found to regulate mRNA expression levels of genes in human brains using GTEx data (p < 0.05): HAX1 and CHRNB2 (rs1760803), ADAMTSL1 (rs17198023), PEX2 (rs12680810), GLIS3 (rs12348139), non-coding RNA for LINC00476 (rs10759883), and GABBR1 (rs56020557 and rs62392942). A gene-based association test further supported the relation between GABBR1 and ND (p = 6.36 × 10 ). These findings will inform the biological mechanisms and development of therapeutic targets for ND.
据报道，尼古丁依赖（ND）的遗传度为40%-70%。对来自加州大学旧金山分校家族研究的1889个样本进行了低覆盖全基因组测序。使用线性混合模型对该研究以及从基因型和表型数据库获得的另外五个队列中的ND进行全基因组关联（GWA）测试。对欧洲参与者（n = 14713）和非洲参与者（n = 3369）分别进行固定效应荟萃分析，然后对两个祖先群体进行联合分析。对非洲参与者的荟萃分析确定了一个显著的新的易感信号（rs56247223；p = 4.11×10）。基因型-组织表达（GTEx）研究的数据表明，该保护性等位基因与三种人类脑组织中CACNA2D3的mRNA表达降低有关（p < 4.94×10）。加州大学旧金山分校家族研究的序列数据表明，该基因中的一个罕见非同义变体增加了ND的风险（p = 0.01），为CACNA2D3参与ND提供了进一步支持。在欧洲和合并人群的另外六个区域观察到了提示性关联（p < 5.00×10）。使用GTEx数据发现顶级变体调节人类大脑中基因的mRNA表达水平（p < 0.05）：HAX1和CHRNB2（rs1760803）、ADAMTSL1（rs17198023）、PEX2（rs12680810）、GLIS3（rs12348139）、LINC00476的非编码RNA（rs10759883）以及GABBR1（rs56020557和rs62392942）。基于基因的关联测试进一步支持了GABBR1与ND之间的关系（p = 6.36×10）。这些发现将为ND的生物学机制和治疗靶点的开发提供信息。
