Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, P. O. Box 2040, 3000 CA, Rotterdam, The Netherlands,
Hum Genet. 2014 May;133(5):587-97. doi: 10.1007/s00439-013-1394-0. Epub 2013 Nov 20.
Genomic prediction of the extreme forms of adult body height or stature is of practical relevance in several areas such as pediatric endocrinology and forensic investigations. Here, we examine 770 extremely tall cases and 9,591 normal height controls in a population-based Dutch European sample to evaluate the capability of known height-associated DNA variants in predicting tall stature. Among the 180 normal height-associated single nucleotide polymorphisms (SNPs) previously reported by the Genetic Investigation of ANthropocentric Traits (GIANT) genome-wide association study on normal stature, in our data 166 (92.2 %) showed directionally consistent effects and 75 (41.7 %) showed nominally significant association with tall stature, indicating that the 180 GIANT SNPs are informative for tall stature in our Dutch sample. A prediction analysis based on the weighted allele sums method demonstrated a substantially improved potential for predicting tall stature (AUC = 0.75; 95 % CI 0.72-0.79) compared to a previous attempt using 54 height-associated SNPs (AUC = 0.65). The achieved accuracy is approaching practical relevance such as in pediatrics and forensics. Furthermore, a reanalysis of all SNPs at the 180 GIANT loci in our data identified novel secondary association signals for extreme tall stature at TGFB2 (P = 1.8 × 10(-13)) and PCSK5 (P = 7.8 × 10(-11)) suggesting the existence of allelic heterogeneity and underlining the importance of fine analysis of already discovered loci. Extrapolating from our results suggests that the genomic prediction of at least the extreme forms of common complex traits in humans including common diseases are likely to be informative if large numbers of trait-associated common DNA variants are available.
身高极端形式的基因组预测在儿科内分泌学和法医学等多个领域具有实际意义。在这里，我们在基于人群的荷兰欧洲样本中检查了 770 个极高的病例和 9591 个正常身高的对照，以评估已知与身高相关的 DNA 变体预测高身材的能力。在之前由遗传研究人类特质（GIANT）全基因组关联研究报告的 180 个与正常身高相关的单核苷酸多态性（SNP）中，在我们的数据中，166 个（92.2%）显示出方向一致的影响，75 个（41.7%）显示出与高身材的名义显著关联，表明 180 个 GIANT SNP 在我们的荷兰样本中对高身材是有信息的。基于加权等位基因和方法的预测分析表明，与之前使用 54 个与身高相关的 SNP 进行的尝试相比，预测高身材的潜力有了实质性的提高（AUC=0.75；95%CI 0.72-0.79）。所达到的准确性接近实际意义，例如在儿科和法医学中。此外，在我们的数据中对 180 个 GIANT 基因座的所有 SNP 进行重新分析，在 TGFB2（P=1.8×10(-13))和 PCSK5（P=7.8×10(-11)) 发现极端高身材的新次要关联信号，表明存在等位基因异质性，并强调了对已发现基因座的精细分析的重要性。从我们的结果推断，如果有大量与性状相关的常见 DNA 变体可用，则人类至少常见复杂性状的极端形式的基因组预测可能具有信息性，包括常见疾病。
