克罗地亚科尔丘拉岛人体测量特征的全基因组关联研究。
Genome-wide association study of anthropometric traits in Korcula Island, Croatia.
作者信息
Polasek Ozren, Marusić Ana, Rotim Kresimir, Hayward Caroline, Vitart Veronique, Huffman Jennifer, Campbell Susan, Janković Stipan, Boban Mladen, Biloglav Zrinka, Kolcić Ivana, Krzelj Vjekoslav, Terzić Janos, Matec Lana, Tometić Gordan, Nonković Dijana, Nincević Jasna, Pehlić Marina, Zedelj Jurica, Velagić Vedran, Juricić Danica, Kirac Iva, Belak Kovacević Sanja, Wright Alan F, Campbell Harry, Rudan Igor
机构信息
Andrija Stampar School of Public Health, School of Medicine, University of Zagreb, Croatia.
出版信息
Croat Med J. 2009 Feb;50(1):7-16. doi: 10.3325/cmj.2009.50.7.
AIM
To identify genetic variants underlying six anthropometric traits: body height, body weight, body mass index, brachial circumference, waist circumference, and hip circumference, using a genome-wide association study.
METHODS
The study was carried out in the isolated population of the island of Korcula, Croatia, with 898 adult examinees who participated in the larger DNA-based genetic epidemiological study in 2007. Anthropometric measurements followed standard internationally accepted procedures. Examinees were genotyped using HumanHap 370CNV chip by Illumina, with a genome-wide scan containing 316730 single nucleotide polymorphisms (SNP).
RESULTS
A total of 11 SNPs were associated with the investigated traits at the level of P<10(-5), with one SNP (rs7792939 in gene zinc finger protein 498, ZNF498) associated with body weight, hip circumference, and brachial circumference (P=3.59-5.73 x 10(-6)), and another one (rs157350 in gene delta-sarcoglycan, SGCD) with both brachial and hip circumference (P=3.70-6.08 x 10(-6). Variants in CRIM1, a gene regulating delivery of bone morphogenetic proteins to the cell surface, and ITGA1, involved in the regulation of mesenchymal stem cell proliferation and cartilage production, were also associated with brachial circumference (P=7.82 and 9.68 x 10(-6), respectively) and represent interesting functional candidates. Other associations involved those between genes SEZ6L2 and MAX and waist circumference, XTP6 and brachial circumference, and AMPA1/GRIA1 and height.
CONCLUSION
Although the study was underpowered for the reported associations to reach formal threshold of genome-wide significance under the assumption of independent multiple testing, the consistency of association between the 2 variants and a set of anthropometric traits makes CRIM1 and ITGA1 highly interesting for further replication and functional follow-up. Increased linkage disequilibrium between the used markers in an isolated population makes the formal significance threshold overly stringent, and changed allele frequencies in isolate population may contribute to identifying variants that would not be easily identified in large outbred populations.
目的
通过全基因组关联研究，确定影响六项人体测量学特征的基因变异，这些特征包括身高、体重、体重指数、臂围、腰围和臀围。
方法
该研究在克罗地亚科尔丘拉岛的隔离人群中进行，898名成年受试者参与了2007年规模更大的基于DNA的基因流行病学研究。人体测量遵循国际公认的标准程序。受试者使用Illumina公司的HumanHap 370CNV芯片进行基因分型，全基因组扫描包含316730个单核苷酸多态性（SNP）。
结果
共有11个SNP在P<10⁻⁵水平与所研究的特征相关，其中一个SNP（位于锌指蛋白498基因ZNF498中的rs7792939）与体重、臀围和臂围相关（P=3.59 - 5.73×10⁻⁶），另一个（位于δ-肌聚糖基因SGCD中的rs157350）与臂围和臀围均相关（P=3.70 - 6.08×10⁻⁶）。CRIM1基因（一个调节骨形态发生蛋白向细胞表面传递的基因）和ITGA1基因（参与间充质干细胞增殖和软骨生成的调节）中的变异也与臂围相关（分别为P=7.82和9.68×10⁻⁶），是有趣的功能候选基因。其他关联包括SEZ6L2基因和MAX基因与腰围之间、XTP6基因与臂围之间以及AMPA1/GRIA1基因与身高之间的关联。
结论
尽管在独立多重检验假设下，该研究的功效不足以使所报告的关联达到全基因组显著性的正式阈值，但两个变异与一组人体测量学特征之间关联的一致性使得CRIM1和ITGA1基因对于进一步的重复验证和功能后续研究极具吸引力。隔离人群中所用标记之间连锁不平衡的增加使得正式的显著性阈值过于严格，而隔离人群中改变的等位基因频率可能有助于识别在大型非隔离人群中不易识别的变异。
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