PMC:4564992 / 36967-41522 JSONTXT

{"project":"2_test","denotations":[{"id":"26320892-24571439-2052548","span":{"begin":81,"end":82},"obj":"24571439"},{"id":"26320892-24571439-2052549","span":{"begin":2963,"end":2964},"obj":"24571439"}],"text":"SLI Data\nWe re-analyzed an updated version of the dataset of Nudel et al. (2014),6 who had presented evidence for a maternally inherited parent-of-origin effect on chromosome 5 and a paternally inherited parent-of-origin effect on chromosome 14. Re-analysis of the chromosome 5 data in PREMIM and EMIM without using haplotype estimation in SHAPEIT2 gave a minimum p value of 1.29 × 10−7 at rs10447141, very similar to that seen in the original analysis by Nudel et al. (p value = 1.16 × 10−7). Using PREMIM and EMIM with haplotype estimation in SHAPEIT2 gave a less significant p value of 6.18 × 10−5 at the same SNP. Plots of the two analyses, with and without use of SHAPEIT2 to estimate the parent of origin of alleles, are shown in Figure 5 and show a considerable decrease in significance of the most significant p values. The p values in the implicated region when using estimated parent of origin now provide only weak evidence of association as a result of a maternally inherited imprinting effect.\nRe-analysis of the SLI data on chromosome 14 without use of haplotype estimation in SHAPEIT2 gave a minimum p value of 2.29 × 10−8 at rs4280164, very similar to that seen in the original analysis by Nudel et al. (p value = 3.74 × 10−8). Using PREMIM/EMIM with haplotype estimation in SHAPEIT2 gave a less significant p value of 1.32 × 10−7 at the same SNP. Plots of the two analyses, with and without estimated parent of origin, are shown in Figure 6. These plots show a general decrease in significance of the most significant p values when using haplotype estimation in SHAPEIT2, although the results (see bottom plots of Figure 6) do still provide positive evidence of association due to a paternally inherited imprinting effect.\nTo investigate the cause of the decreases in significance seen in the SLI study when incorporating haplotype estimation, we examined the counts of trios and duos falling into the various categories used in EMIM’s multinomial modeling procedure (see Table 1). Cells 9 (for trios) or 4 (for duos) correspond to the ambiguous categories in which all individuals are heterozygous; when using haplotype estimation in SHAPEIT2, these cells are decomposed into cells 9a and 9b, or 4a and 4b, respectively, in which parent of origin has been (probabilistically) determined. For SNP rs10447141 on chromosome 5, there are 16 ambiguous case-parent trios, which result (when using haplotype estimation) in estimates of six case subjects receiving the risk allele from the father and ten from the mother. There were also ten ambiguous case-mother duos, resulting in estimates of 1.99 case subjects receiving the risk allele from the father and 8.01 from the mother, and four ambiguous case-father duos, resulting in estimates of 3.02 cases receiving the risk allele from the father and 0.98 from the mother. Overall, this resolves the parent of origin in an additional 30 families in comparison to the original analysis of Nudel et al.,6 giving 11.01 new receipts from the father and 18.99 from the mother. This increased number of receipts from the mother might be expected to result in a stronger maternally inherited imprinting effect than seen originally; however, the “risk” allele in this case actually decreases risk, giving an odds ratio of Im = 0.326 in the original analysis and Im = 0.494 when using estimated parent of origin. Therefore, the overall effect is now weakened by having more new receipts from mothers than from fathers. Similar observations can be made for the other SNPs in this region. It therefore seems probable that the original result could represent a statistical false positive due to stochastic sampling variation, which has been better resolved with the addition of 30 new observations. So, although the overall decrease in significance might seem disappointing, it corresponds to the use of more information (an additional 30 families contributing to the analysis) and thus should be considered a more reliable result.\nThe reduction in significance for the paternally inherited imprinting effect on chromosome 14 can also be explained by examining the parent-of-origin resolved cell counts (7.01 new receipts from the father and 15.99 from the mother, see Table 1). The fact that an additional 23 families are contributing to the analysis means that this should again be considered a more reliable result in comparison to the original analysis. However, in this case, the evidence for the presence of a paternally inherited imprinting effect remains relatively strong (p value = 1.32 × 10−7)."}