Howey Richard, Mamasoula Chrysovalanto, Töpf Ana, Nudel Ron, Goodship Judith A, Keavney Bernard D, Cordell Heather J
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK; Institute of Health and Society, Newcastle University, Newcastle upon Tyne, NE2 4AX, UK.
Am J Hum Genet. 2015 Sep 3;97(3):419-34. doi: 10.1016/j.ajhg.2015.07.016. Epub 2015 Aug 27.
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.
亲本来源（或印记）效应涉及这样一种情况：性状仅受来自一方亲本的等位基因影响，而来自另一方亲本的等位基因几乎没有影响或完全没有影响。给定病例 - 亲本三联体的单核苷酸多态性（SNP）基因型数据，后代中每个等位基因的亲本来源通常可以明确推断；然而，当所有三个个体都是杂合子时，情况并非如此。大多数现有的研究亲本来源效应的方法是逐个SNP进行操作的，要么对可能的亲本传递进行某种平均，要么丢弃模糊不清的三联体。如果能够确定SNP处正确的亲本来源，这将提供额外信息并提高检测印记效应的能力。我们建议通过单倍型估计利用周围的SNP信息，以改进对病例 - 亲本三联体、病例 - 母亲二元组和病例 - 父亲二元组中测试SNP的亲本来源估计。然后，这些额外信息用于多项建模方法，以估计测试SNP处的亲本来源效应。我们通过计算机模拟表明，我们的方法比以前的方法具有更高的功效，特别是当数据仅由二元组组成时。我们将我们的方法应用于两个真实数据集，发现在先前认为可能存在印记效应的基因组区域中，p值的显著性降低，从而削弱了这些区域实际存在此类效应的证据，尽管一些区域仍保留显著效应的证据。
