Increased Power for Detection of Parent-of-Origin Effects via the Use of Haplotype Estimation.
Increased Power for Detection of Parent-of-Origin Effects via the Use of Haplotype Estimation.
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DOI：
10.1016/j.ajhg.2015.07.016
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发表时间：
2015-09-03
影响因子：
9.8
通讯作者：
Cordell HJ
中科院分区：
文献类型：
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作者：
Howey R;Mamasoula C;Töpf A;Nudel R;Goodship JA;Keavney BD;Cordell HJ
亲本的起源（或印迹）效应涉及这样的情况，其中性状受到仅从一个亲本遗传的等位基因的影响，而来自另一个亲本的等位基因几乎没有或没有影响。从病例-亲本三联体中得到的SNP基因型数据，通常可以明确地推断出后代中每个等位基因的亲本来源;然而，当所有三个个体都是杂合子时，这是不正确的。大多数现有的研究亲本起源效应的方法都是基于SNP逐个SNP的基础上进行的，要么对可能的亲本传递进行某种平均，要么丢弃模糊的三重性。如果可以确定SNP的正确起源亲本，这将提供额外的信息并增加检测印记效应的能力。我们建议利用周围的SNP信息，通过单倍型估计，以提高估计父母的起源在一个测试SNP的情况下，父母三人组，母亲二人组，和父亲二人组。然后将这些额外的信息用于多项建模方法中，以估计测试SNP处的起源亲本效应。我们通过计算机模拟表明，我们的方法比以前的方法增加了功率，特别是当数据仅由二人组组成时。我们将我们的方法应用于两个真实的数据集，发现以前被认为可能具有印记效应的基因组区域的p值显著性降低，从而削弱了这些区域实际存在这种效应的证据，尽管有些区域保留了显著效应的证据。
Parent-of-origin (or imprinting) effects relate to the situation in which traits are influenced by the allele inherited from only one parent and the allele from the other parent has little or no effect. Given SNP genotype data from case-parent trios, the parent of origin of each allele in the offspring can often be deduced unambiguously; however, this is not true when all three individuals are heterozygous. Most existing methods for investigating parent-of-origin effects operate on a SNP-by-SNP basis and either perform some sort of averaging over the possible parental transmissions or else discard ambiguous trios. If the correct parent of origin at a SNP could be determined, this would provide extra information and increase the power for detecting the effects of imprinting. We propose making use of the surrounding SNP information, via haplotype estimation, to improve estimation of parent of origin at a test SNP for case-parent trios, case-mother duos, and case-father duos. This extra information is then used in a multinomial modeling approach for estimating parent-of-origin effects at the test SNP. We show through computer simulations that our approach has increased power over previous approaches, particularly when the data consist only of duos. We apply our method to two real datasets and find a decrease in significance of p values in genomic regions previously thought to possibly harbor imprinting effects, thus weakening the evidence that such effects actually exist in these regions, although some regions retain evidence of significant effects.