EMR-linked GWAS study: investigation of variation landscape of loci for body mass index in children.
EMR-linked GWAS study: investigation of variation landscape of loci for body mass index in children.
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DOI：
10.3389/fgene.2013.00268
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发表时间：
2013
影响因子：
3.7
通讯作者：
Harley JB
中科院分区：
文献类型：
--
作者：
Namjou B;Keddache M;Marsolo K;Wagner M;Lingren T;Cobb B;Perry C;Kennebeck S;Holm IA;Li R;Crimmins NA;Martin L;Solti I;Kohane IS;Harley JB
据报道，含有脂肪量和肥胖基因 (FTO)、MC4R 和 TMEM18 的基因座的常见变异与肥胖和体重指数 (BMI) 有关，尤其是在成年人群中。为了证实这种对儿科人群的影响，对来自儿科 eMERGE-II 网络 (CCHMC-BCH) 的五个欧洲血统队列进行了评估。方法：从两个大型学术中心的电子病历 (EMR) 中获得了 5049 个欧洲血统样本的数据，分为五个不同的基因型队列。对于所有可用样本，收集性别、年龄、身高和体重并计算体重指数。为了考虑 BMI 的年龄和性别差异，BMI z 分数是使用 2000 年疾病控制和预防中心 (CDC) 生长图表生成的。使用 BMI z 评分进行全基因组关联研究 (GWAS)。根据主成分 (PC) 分析去除缺失数据和异常值后，2860 个样本用于 GWAS 研究。使用按队列调整年龄、性别和 PC 的线性回归测试每个单核苷酸多态性 (SNP) 与 BMI 之间的关联。 SNP 的效应是通过假设次要等位基因的加性、隐性和显性效应来建模的。使用加权 z 分数方法进行荟萃分析。结果：受试者的平均年龄为 9.8 岁（范围 2-19）。男性受试者的比例为56%。在这些队列中，14% 的样本的 BMI ≥ 95，28% 的样本 ≥ 85%。 Meta 分析在 16q12 基因组区域产生信号，对于 FTO 基因第一个内含子处的 SNP rs8050136 (z = 5.26)，最佳结果为 p = 1.43 × 10-7 [p(rec) = 7.34 × 10-8)，并且队列之间没有异质性 (p = 0.77)。在隐性模型下，该位点上另一个已发表的 SNP rs1421085 产生了最佳结果 [z = 5.782，p(rec) = 8.21 × 10-9]。使用密集的 1000 个基因组和 Hapmap CEU 样本对该区域进行插补，发现 71 个 SNP，p < 10-6，全部位于 FTO 基因座的第一个内含子处。当队列之间允许异质性时，也在先前确定的其他位点中获得信号，包括 MC4R（rs12964056，p = 6.87 × 10-7，z = -4.98）、胆囊收缩素 CCK（rs8192472，p = 1.33 × 10-6，z = -4.85）、白细胞介素 15 (rs2099884，p = 1.27 × 10-5，z = 4.34)、低密度脂蛋白受体相关蛋白 1B [LRP1B (rs7583748，p = 0.00013，z = -3.81)] 和近跨膜蛋白 18 (TMEM18) (rs7561317，p = 0.001，z = -3.17）。我们还在 3 号染色体 COL6A5 处检测到一个新的位点 [最佳 SNP = rs1542829，次要等位基因频率 (MAF) 为 5% p = 4.35 × 10-9，z = 5.89]。结论：一项 EMR 关联队列研究表明，可以成功提取 BMI-Z 测量值并将其与基因组数据关联起来，从而获得有意义的验证结果。我们证实了我们的队列中儿童超重和肥胖率很高（28%）。此外，我们的数据表明，FTO（已知的成人 BMI 遗传风险因素）第一个内含子的遗传变异也与儿科人群的 BMI 密切相关。
Common variations at the loci harboring the fat mass and obesity gene (FTO), MC4R, and TMEM18 are consistently reported as being associated with obesity and body mass index (BMI) especially in adult population. In order to confirm this effect in pediatric population five European ancestry cohorts from pediatric eMERGE-II network (CCHMC-BCH) were evaluated. Method: Data on 5049 samples of European ancestry were obtained from the Electronic Medical Records (EMRs) of two large academic centers in five different genotyped cohorts. For all available samples, gender, age, height, and weight were collected and BMI was calculated. To account for age and sex differences in BMI, BMI z-scores were generated using 2000 Centers of Disease Control and Prevention (CDC) growth charts. A Genome-wide association study (GWAS) was performed with BMI z-score. After removing missing data and outliers based on principal components (PC) analyses, 2860 samples were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and BMI was tested using linear regression adjusting for age, gender, and PC by cohort. The effects of SNPs were modeled assuming additive, recessive, and dominant effects of the minor allele. Meta-analysis was conducted using a weighted z-score approach. Results: The mean age of subjects was 9.8 years (range 2–19). The proportion of male subjects was 56%. In these cohorts, 14% of samples had a BMI ≥95 and 28 ≥ 85%. Meta analyses produced a signal at 16q12 genomic region with the best result of p = 1.43 × 10-7 [p(rec) = 7.34 × 10-8) for the SNP rs8050136 at the first intron of FTO gene (z = 5.26) and with no heterogeneity between cohorts (p = 0.77). Under a recessive model, another published SNP at this locus, rs1421085, generates the best result [z = 5.782, p(rec) = 8.21 × 10-9]. Imputation in this region using dense 1000-Genome and Hapmap CEU samples revealed 71 SNPs with p < 10-6, all at the first intron of FTO locus. When hetero-geneity was permitted between cohorts, signals were also obtained in other previously identified loci, including MC4R (rs12964056, p = 6.87 × 10-7, z = -4.98), cholecystokinin CCK (rs8192472, p = 1.33 × 10-6, z = -4.85), Interleukin 15 (rs2099884, p = 1.27 × 10-5, z = 4.34), low density lipoprotein receptor-related protein 1B [LRP1B (rs7583748, p = 0.00013, z = -3.81)] and near transmembrane protein 18 (TMEM18) (rs7561317, p = 0.001, z = -3.17). We also detected a novel locus at chromosome 3 at COL6A5 [best SNP = rs1542829, minor allele frequency (MAF) of 5% p = 4.35 × 10-9, z = 5.89]. Conclusion: An EMR linked cohort study demonstrates that the BMI-Z measurements can be successfully extracted and linked to genomic data with meaningful confirmatory results. We verified the high prevalence of childhood rate of overweight and obesity in our cohort (28%). In addition, our data indicate that genetic variants in the first intron of FTO, a known adult genetic risk factor for BMI, are also robustly associated with BMI in pediatric population.