Lu Shan, Zhao Lan-Juan, Chen Xiang-Ding, Papasian Christopher J, Wu Ke-Hao, Tan Li-Jun, Wang Zhuo-Er, Pei Yu-Fang, Tian Qing, Deng Hong-Wen
Key Lab of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, China.
Center for Bioinformatics and Genomics, Department of Biostatistics, School of Public Health and Tropical Medicine, Tulane University, 1440 Canal St.Suite 2001, New Orleans, LA, 70112, USA.
J Bone Miner Metab. 2017 Nov;35(6):649-658. doi: 10.1007/s00774-016-0802-7. Epub 2016 Dec 23.
Several studies indicated bone mineral density (BMD) and alcohol intake might share common genetic factors. The study aimed to explore potential SNPs/genes related to both phenotypes in US Caucasians at the genome-wide level. A bivariate genome-wide association study (GWAS) was performed in 2069 unrelated participants. Regular drinking was graded as 1, 2, 3, 4, 5, or 6, representing drinking alcohol never, less than once, once or twice, three to six times, seven to ten times, or more than ten times per week respectively. Hip, spine, and whole body BMDs were measured. The bivariate GWAS was conducted on the basis of a bivariate linear regression model. Sex-stratified association analyses were performed in the male and female subgroups. In males, the most significant association signal was detected in SNP rs685395 in DYNC2H1 with bivariate spine BMD and alcohol drinking (P = 1.94 × 10). SNP rs685395 and five other SNPs, rs657752, rs614902, rs682851, rs626330, and rs689295, located in the same haplotype block in DYNC2H1 were the top ten most significant SNPs in the bivariate GWAS in males. Additionally, two SNPs in GRIK4 in males and three SNPs in OPRM1 in females were suggestively associated with BMDs (of the hip, spine, and whole body) and alcohol drinking. Nine SNPs in IL1RN were only suggestively associated with female whole body BMD and alcohol drinking. Our study indicated that DYNC2H1 may contribute to the genetic mechanisms of both spine BMD and alcohol drinking in male Caucasians. Moreover, our study suggested potential pleiotropic roles of OPRM1 and IL1RN in females and GRIK4 in males underlying variation of both BMD and alcohol drinking.
多项研究表明，骨矿物质密度（BMD）与酒精摄入量可能共享共同的遗传因素。该研究旨在在全基因组水平上探索美国白种人中与这两种表型相关的潜在单核苷酸多态性（SNPs）/基因。对2069名无亲属关系的参与者进行了双变量全基因组关联研究（GWAS）。经常饮酒被分为1、2、3、4、5或6级，分别代表从不饮酒、每周少于一次、每周一至两次、每周三至六次、每周七至十次或每周超过十次。测量了髋部、脊柱和全身的骨密度。双变量GWAS基于双变量线性回归模型进行。在男性和女性亚组中进行了性别分层关联分析。在男性中，在动力蛋白2重链1（DYNC2H1）基因的单核苷酸多态性rs685395中检测到与双变量脊柱骨密度和饮酒最显著的关联信号（P = 1.94×10）。位于DYNC2H1同一单倍型块中的单核苷酸多态性rs685395和其他五个单核苷酸多态性，即rs657752、rs614902、rs682851、rs626330和rs689295，是男性双变量GWAS中最显著的前十名单核苷酸多态性。此外，男性中谷氨酸离子型受体钾离子通道4（GRIK4）基因中的两个单核苷酸多态性和女性中阿片受体μ1（OPRM1）基因中的三个单核苷酸多态性与（髋部、脊柱和全身的）骨密度和饮酒存在提示性关联。白细胞介素1受体拮抗剂（IL1RN）基因中的九个单核苷酸多态性仅与女性全身骨密度和饮酒存在提示性关联。我们的研究表明，DYNC2H1可能在男性白种人中参与了脊柱骨密度和饮酒的遗传机制。此外，我们的研究提示了OPRM1和IL1RN在女性中以及GRIK4在男性中对骨密度和饮酒变化潜在的多效性作用。
