On the use of the transmission disequilibrium test to detect pseudo-autosomal variants affecting traits with sex-limited expression
On the use of the transmission disequilibrium test to detect pseudo-autosomal variants affecting traits with sex-limited expression
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DOI：
10.1111/age.12296
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发表时间：
2015-08-01
期刊：
影响因子：
2.4
通讯作者：
Georges, Michel
中科院分区：
文献类型：
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作者：
Elansary, Mahmoud;Stinckens, Anneleen;Georges, Michel
在此，我们描述了在挪威和比利时的商业猪群体中实现了一项关于阴囊疝气和隐睾症的全基因组关联研究。我们使用了传递不平衡检验来避免由于人口分层而产生的虚假关联。通过这样做，我们获得了两种疾病的全基因组显著信号，SNPs位于伪常染色体区域的伪常染色体边界附近。通过进一步分析这些信号，我们证明了观察到的传输不平衡是人为的。我们确定：(I)当分析性别受限的性状时，以及(Ii)当X和Y染色体标记座位上的等位基因频率不同时，在伪常染色体标记上会发生传递偏差。我们表明，这种偏倚是由于这样一个事实：(I)父本将优先将Y(分别为X)染色体上丰富的等位基因传递给受影响的儿子(分别为女儿)，以及(Ii)母猪将出现优先将富含在Y(分别为X)上的等位基因传递给受影响的儿子(分别为女儿)的事实，因为继承另一个等位基因的后代更有可能是非信息性的。我们定义了缓解这些问题的条件，即：(I)仅从母体减数分裂中提取信息，(Ii)忽略父本和母本具有相同杂合基因的三元组。我们表明，通过将这些规则应用于阴囊疝气和隐睾症，伪常染色体信号消失，证实了它们的虚假性质。
We herein describe the realization of a genome-wide association study for scrotal hernia and cryptorchidism in Norwegian and Belgian commercial pig populations. We have used the transmission disequilibrium test to avoid spurious associations due to population stratification. By doing so, we obtained genome-wide significant signals for both diseases with SNPs located in the pseudo-autosomal region in the vicinity of the pseudo-autosomal boundary. By further analyzing these signals, we demonstrate that the observed transmission disequilibria are artifactual. We determine that transmission bias at pseudo-autosomal markers will occur (i) when analyzing traits with sex-limited expression and (ii) when the allelic frequencies at the marker locus differ between X and Y chromosomes. We show that the bias is due to the fact that (i) sires will preferentially transmit the allele enriched on the Y (respectively X) chromosome to affected sons (respectively daughters) and (ii) dams will appear to preferentially transmit the allele enriched on the Y (respectively X) to affected sons (respectively daughters), as offspring inheriting the other allele are more likely to be non-informative. We define the conditions to mitigate these issues, namely by (i) extracting information from maternal meiosis only and (ii) ignoring trios for which sire and dam have the same heterozygous genotype. We show that by applying these rules to scrotal hernia and cryptorchidism, the pseudo-autosomal signals disappear, confirming their spurious nature.