Dumitrescu Logan, Brown-Gentry Kristin, Goodloe Robert, Glenn Kimberly, Yang Wenjian, Kornegay Nancy, Pui Ching-Hon, Relling Mary V, Crawford Dana C
Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37232, USA.
Ann Hum Genet. 2011 Sep;75(5):589-97. doi: 10.1111/j.1469-1809.2011.00664.x. Epub 2011 Jul 21.
In order to identify novel genetic variants that influence plasma lipid concentrations, we performed a genome-wide association study (GWAS) comprised of 411 children under 18 years of age, ascertained at St. Jude Children's Research Hospital, all of whom were of European, African, or Mexican descent. Promising associations (p < 10(-5)) were subsequently examined in 1040 additional youths and 3508 adults from the Third National Health and Nutrition Examination Survey (NHANES III), a diverse population-based study. Three genotype-phenotype associations replicated in NHANES III youths and three associated in NHANES III adults at p < 0.05; however, no single association was significant in both youths and adults. The most significant association (p= 0.009) in NHANES III youths was between low-density lipoprotein cholesterol (LDL-C) and intronic rs2429917 among participants of African descent. Given the known age dependency of lipid levels, we also tested for gene-age interactions in NHANES III participants across all ages. We identified a significant (p= 0.024) age-dependent association between SGSM2 rs2429917 and LDL-C. This finding illustrates the utility of using children to discover novel variants associated with complex phenotypes and the importance of considering age-dependent genetic effects in association studies of lipid levels.
为了识别影响血浆脂质浓度的新型基因变异，我们进行了一项全基因组关联研究（GWAS），该研究纳入了411名18岁以下的儿童，这些儿童来自圣裘德儿童研究医院，他们均为欧洲、非洲或墨西哥裔。随后，在基于人群的多样化研究——第三次全国健康与营养检查调查（NHANES III）中的另外1040名青少年和3508名成年人中，对有前景的关联（p < 10(-5)）进行了检测。在NHANES III的青少年中有3种基因型-表型关联得到重复验证，在NHANES III的成年人中有3种关联在p < 0.05水平上具有统计学意义；然而，没有一种关联在青少年和成年人中均具有显著性。在NHANES III的青少年中，最显著的关联（p = 0.009）存在于非洲裔参与者的低密度脂蛋白胆固醇（LDL-C）与内含子rs2429917之间。鉴于已知脂质水平存在年龄依赖性，我们还在NHANES III所有年龄段的参与者中测试了基因-年龄相互作用。我们发现SGSM2 rs2429917与LDL-C之间存在显著的（p = 0.024）年龄依赖性关联。这一发现说明了利用儿童来发现与复杂表型相关的新型变异的实用性，以及在脂质水平关联研究中考虑年龄依赖性遗传效应的重要性。
