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Estimating Uterine Fibroid SNP-Based Heritability in European American Women with Imaging-Confirmed Fibroids.
Human Heredity ( IF 1.8 ) Pub Date : 2019-09-03 , DOI: 10.1159/000501335
Michael J Bray 1, 2 , Lea K Davis 2 , Eric S Torstenson 2 , Sarah H Jones 3 , Todd L Edwards 2, 3, 4, 5, 6 , Digna R Velez Edwards 7, 8, 9, 10, 11
Affiliation  

BACKGROUND Heritability estimates (including twin and single nucleotide polymorphism [SNP]-based heritability studies) for fibroids have been inconsistent across prior studies ranging between 9 and 69%. These inconsistencies are due to variations in study design and included populations. A major design issue has been lack of imaging confirmation to identify controls, where asymptomatic women without imaging confirmation may be misclassified as controls leading to an attenuation of heritability estimates. To reconcile the differences in prior heritability estimates and the impact of misclassification of controls on heritability, we determined SNP-based heritability and characterized the genetic architecture of pelvic image-confirmed fibroid cases and controls. METHODS Analyses were performed among women of European American descent using genome-wide SNP data from BioVU, a clinical database composed of DNA linked to de-identified electronic health records. We estimated the genetic variance explained by all SNPs using Genome-Wide Complex Trait Analysis on imputed data. Fibroid cases and controls were identified using a previously reported phenotyping algorithm that required pelvic imaging confirmation. RESULTS In total, we used 1,067 image-confirmed fibroid cases and 1,042 image-confirmed fibroid controls. The SNP-based heritability estimate for fibroid risk was h2 = 0.33 ± 0.18 (p = 0.040). We investigated the relationship between heritability per chromosome and chromosome length (r2 < 1%), with chromosome 8 explaining the highest proportion of variance for fibroid risk. There was no enrichment for intergenic or genic SNPs for the fibroid SNP-based heritability. Excluding loci previously associated with fibroid risk from genome-wide association study did not attenuate fibroid heritability suggesting that loci associating with fibroid risk are yet to be discovered. CONCLUSIONS We observed that fibroid SNP-based heritability was higher than the previous estimate using genome-wide SNP data that relied on self-reported outcomes, but within the range of prior twin pair studies. Furthermore, these data support that imprecise phenotyping can significantly affect the ability to estimate heritability using genotype data.

中文翻译:

估计患有影像学确认的子宫肌瘤的欧洲美国女性基于子宫肌瘤 SNP 的遗传力。

背景 肌瘤的遗传力估计(包括基于双和单核苷酸多态性 [SNP] 的遗传力研究)在之前的研究中不一致,介于 9% 和 69% 之间。这些不一致是由于研究设计和纳入人群的差异。一个主要的设计问题是缺乏影像学确认来识别对照,其中没有影像学确认的无症状女性可能被错误分类为对照,导致遗传力估计值减弱。为了调和先前遗传力估计的差异和对​​照的错误分类对遗传力的影响,我们确定了基于 SNP 的遗传力,并描述了盆腔图像确认的肌瘤病例和对照的遗传结构。方法 使用来自 BioVU 的全基因组 SNP 数据对欧洲裔美国女性进行分析,BioVU 是一个临床数据库,由与去识别化电子健康记录相关联的 DNA 组成。我们使用全基因组复杂性状分析对估算数据估计了所有 SNP 解释的遗传方差。使用先前报告的需要盆腔成像确认的表型算法来识别肌瘤病例和对照。结果 我们总共使用了 1,067 个图像确认的肌瘤病例和 1,042 个图像确认的肌瘤对照。基于 SNP 的肌瘤风险遗传力估计为 h2 = 0.33 ± 0.18 (p = 0.040)。我们研究了每条染色体的遗传力与染色体长度 (r2 < 1%) 之间的关系,其中 8 号染色体解释了肌瘤风险方差的最高比例。对于基于肌瘤 SNP 的遗传力,基因间或基因 SNP 没有富集。从全基因组关联研究中排除先前与肌瘤风险相关的位点并没有减弱肌瘤遗传力,这表明与肌瘤风险相关的位点尚未被发现。结论 我们观察到基于肌瘤 SNP 的遗传力高于先前使用依赖于自我报告结果的全基因组 SNP 数据的估计,但在先前双胞胎研究的范围内。此外,这些数据支持不精确的表型分析会显着影响使用基因型数据估计遗传力的能力。从全基因组关联研究中排除先前与肌瘤风险相关的位点并没有减弱肌瘤遗传力,这表明与肌瘤风险相关的位点尚未被发现。结论 我们观察到基于肌瘤 SNP 的遗传力高于先前使用依赖于自我报告结果的全基因组 SNP 数据的估计,但在先前双胞胎研究的范围内。此外,这些数据支持不精确的表型分析会显着影响使用基因型数据估计遗传力的能力。从全基因组关联研究中排除先前与肌瘤风险相关的位点并没有减弱肌瘤遗传力,这表明与肌瘤风险相关的位点尚未被发现。结论 我们观察到基于肌瘤 SNP 的遗传力高于先前使用依赖于自我报告结果的全基因组 SNP 数据的估计,但在先前双胞胎研究的范围内。此外,这些数据支持不精确的表型分析会显着影响使用基因型数据估计遗传力的能力。
更新日期:2019-11-01
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