PMC:4564992 / 43934-48911 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4564992","sourcedb":"PMC","sourceid":"4564992","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4564992","text":"Discussion\nHere, we have demonstrated the improved functionality implemented in the latest version of our software package, PREMIM and EMIM, which has been updated to incorporate haplotype estimation in SHAPEIT2 when modeling parent-of-origin effects. Naturally, computation time is increased as a result of using SHAPEIT2, but the analysis still remains quite feasible for any realistically sized study. Although the focus of this current investigation is on detection of parent-of-origin effects, we note that PREMIM and EMIM offer wider functionality, such as the ability to test for maternal-genotype effects or mother-child genotype interactions, with or without the inclusion of parent-of-origin effects. The software can also be used to increase the power when analyzing an unrelated case-control dataset by incorporating case or control parental data when available.\nThe ability to detect imprinting effects is dependent on determining the parent of origin of alleles in a set of case subjects, which requires parental data as well as data from the case subjects themselves. The most obvious data to gather is a case-parent trio so that the parent of origin of alleles can be determined, except in the one scenario where all individuals are heterozygous. With the use of SHAPEIT2, the parent of origin of alleles can be estimated by using the surrounding SNP information to estimate haplotypes and thus parent of origin. By using these estimates in our multinomial modeling procedure, we found that the power could be increased over the previous versions of PREMIM and EMIM, while still retaining acceptable type I error rates.\nWhen data are restricted to case-mother or case-father duos, the proportion of genotype data with ambiguous parent of origin is greater than that for case-parent trios, thus greatly increasing the benefit of using SHAPEIT2 to estimate the parent of origin of alleles. However, use of case-mother or case-father duos with estimated haplotypes was found to lead to a potential bias in the parent-of-origin assignment (the bias was dependent on which parent was genotyped and the minor allele frequency of the SNP being tested), resulting in an increase in type I error. Fortunately, this could be corrected by adjusting the estimated parent-of-origin cell counts to more closely match the expected distributions under the null hypothesis. This adjustment was performed by fitting an adjustment curve via maximum likelihood methods, which successfully reduced the type I errors to acceptable levels as well as increased the power.\nParent-of-origin effects, particularly if mediated through imprinting, represent a more complex, potentially functionally relevant mechanism than the genetic effects that are typically identified through large-scale case-control GWASs. The requirement for parental data necessarily limits the power of studies designed to detect such effects (except, perhaps, in special populations such as the Icelandic population), owing to the decreased sample sizes that are likely to be available; however, suitable cohorts (particularly of mother-child duos) are often collected, for example, when investigating traits related to pregnancy complications. An attraction of focusing on the detection of parent-of-origin effects (rather than on effects mediated primarily by the case subject’s own genotype) is the greater potential for immediate functional investigation and experimental validation. Our application of the new versions of PREMIM and EMIM to four genomic regions that have been postulated as harboring parent-of-origin effects (in cohorts with two separate disorders) found slightly decreased evidence in three of the four regions and considerably decreased evidence in one region, as a result of a larger number of parent-of-origin resolved transmissions than had previously been available. None of the SNPs investigated lie in regions already known to contain imprinted genes,37,38 so further investigation will be required to determine the underlying cause of the parent-of-origin effects observed. The parent-of-origin effect seen on 14q for SLI does, however, overlap with a region that has previously shown a hint toward genomic imprinting.39 A comparison of individuals with a paternal deletion of 14q11–13 and individuals with maternal uniparental disomy of that region showed that the two groups had some overlapping phenotypes, suggesting that the paternal allele is normally expressed.40 Together, these studies suggest that the region may be maternally imprinted, and thus paternal parent-of-origin effects may be operating there.\nIn conclusion, we recommend that investigators interested in analyzing GWAS data to search for maternally or paternally inherited imprinting effects should use the updated approach implemented in our software package PREMIM and EMIM, which currently provides, to the best of our knowledge, the most convenient and powerful analysis tool for addressing this question.","divisions":[{"label":"title","span":{"begin":0,"end":10}},{"label":"p","span":{"begin":11,"end":874}},{"label":"p","span":{"begin":875,"end":1635}},{"label":"p","span":{"begin":1636,"end":2563}},{"label":"p","span":{"begin":2564,"end":4610}}],"tracks":[{"project":"2_test","denotations":[{"id":"26320892-15990197-2052552","span":{"begin":3949,"end":3951},"obj":"15990197"},{"id":"26320892-16381868-2052552","span":{"begin":3949,"end":3951},"obj":"16381868"},{"id":"26320892-11595025-2052553","span":{"begin":4214,"end":4216},"obj":"11595025"},{"id":"26320892-10951461-2052554","span":{"begin":4464,"end":4466},"obj":"10951461"}],"attributes":[{"subj":"26320892-15990197-2052552","pred":"source","obj":"2_test"},{"subj":"26320892-16381868-2052552","pred":"source","obj":"2_test"},{"subj":"26320892-11595025-2052553","pred":"source","obj":"2_test"},{"subj":"26320892-10951461-2052554","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#ecae93","default":true}]}]}}