Making unused data resources available for imprinting analyses by using new methods to uncover parent-of-origin effects in human and livestock
Final Report Abstract
For imprinting variance component analyses (IVCAs) and the mapping of imprinted loci, large amounts of data are still unused because the existing methods do not allow their full exploitation. Furthermore, there are still large gaps in our knowledge of the relevance of parent-of-origin effects (POEs) for important traits in human and livestock. Therefore, the two ultimate objectives of the project were firstly to develop new methods to make unused data resources accessible for POE analyses and secondly to use these methods to obtain insights into the role of POEs for important traits in human and livestock. The analyses in this project were based on newly introduced methods (objective 1). While gametic models were introduced to the field of human epidemiology for the first time, we published and applied a new statistical model that allowed comprehensive IVCAs of conformation trait data in cattle. The model was referred to as generalised gametic model as it facilitates flexible analyses of POEs based on all kinds of data. Thereby, the model combines the advantages of all earlier introduced imprinting models. Moreover, we developed and published an open-source programme that calculates the inverse of relationship matrices directly from a pedigree. A new mapping approach for imprinted loci has been theoretically derived and will be introduced in connection with the IVCAs of conformation trait data. The first part of objective 2 was to obtain insights into the role of POEs for the development of cancer and autoimmune disorders in human. In this context, we aimed to separate imprinting effects from maternal effects which both contribute to the broader class of POEs. It can be summarised that the separate contributions of each POE was able to delineate the genetic and phenotypic variation in type 1 diabetes and rheumatoid arthritis susceptibility for the first time. Results supported findings that imprinting was of minor importance, but confirmed the role maternal factors played in the occurrence of both diseases. Moreover, new knowledge was gained on the environmental effects on type 1 diabetes and rheumatoid arthritis development. We introduced for the first time how gametic models can be used to investigate and to partition POE (co)variance components in human epidemiology. We experienced that the data needed to be prepared and analysed with great care to provide the best data basis for reliable results. The prospects of fitting complex genetic (co)variance structures can be expected to further improve given the size of good quality epidemiological data and pedigree depth. The second part of objective 2 was to obtain insights into the role of POEs for the development of conformation traits in Holstein cattle. It can be summarised that significant imprinting variances were found and separated from maternal genetic variances for the first time. For example, imprinting effects explained almost 2% and 25% of the additive genetic variance in rump angle and stature. For these traits, the consideration of imprinting effects in the process of breeding value prediction would enhance the breeding progress and facilitate better exploitation of the total genetic variance. In contrast to imprinting, no trait was found that was exclusively controlled by maternal effects. During the IVCA, severe convergence and technical difficulties were encountered. Difficulties in reaching convergence can be possibly justified by the small underlying maternal (co)variance components. It is reasonable to assume that imprinting effects rather than maternal effects accounted for the variation caused by POEs. It can be summarised that some goals declared in the project proposal could not be achieved in their entirety. Especially goals related to the development of a deregression procedure of POEs and the practical application of a newly developed mapping approach were not addressed during the two years of the project period. This can be explained mainly by delays during the IVCA of conformation traits caused by convergence and technical difficulties. However, the two ultimate objectives of the project were successfully achieved. With the development of a generalised model unused data resources were made accessible for POE analyses and insights into the role of POEs for important traits in human and livestock could be obtained.
Publications
- 2019. Genomic imprinting analyses reveal maternal effects to be a cause of genotypic variability in type 1 diabetes and rheumatoid arthritis. 28th Annual Meeting of the International Genetic Epidemiology Society (IGES), Houston, Texas, USA, 10
Blunk, I., H. Thomsen, N. Reinsch, M. Mayer, A. Försti, K. Sundqvist, J. Sundqvist, K. Hemminki
- 2019. Parent-of-origin effect analyses provide evidence for maternal genetic and maternal environmental effects on the genetic variability in type 1 diabetes and rheumatoid arthritis. 69th Annual Meeting of The American Society of Human Genetics (ASHG), Houston, Texas, USA, 2998T
Blunk, I., H. Thomsen, N. Reinsch, M. Mayer, A. Försti, K. Sundqvist, J. Sundqvist, K. Hemminki
- 2020. Generalized gametic relationships for the analysis of parent-of-origin effects on conformation traits in Canadian Holstein cattle. Book of Abstracts of the 71st Annual Meeting of the European Association for Animal Production (EAAP), virtual event from the 1st to 4th December
Blunk, I., G.A. Oliveira Jr., C.F. Baes, N. Reinsch
- 2020. Genomic imprinting analyses identify maternal effects as a cause of phenotypic variability in type 1 diabetes and rheumatoid arthritis. Scientific Reports 10:11562
Blunk, I., H. Thomsen, N. Reinsch, M. Mayer, A. Försti, J. Sundqvist, K. Sundqvist, K. Hemminki
(See online at https://doi.org/10.1038/s41598-020-68212-x) - 2020. Imprinting variance component analyses reveal maternal genetic and shared household effects on the development of rheumatoid arthritis and type 1 diabetes. GMDS & CEN-IBS, 6-11 September 2020, Berlin, Germany
Blunk, I., H. Thomsen, N. Reinsch, M. Mayer, A. Försti, K. Sundqvist, J. Sundqvist, K. Hemminki
- 2021. Generalized gametic relationships for flexible analyses of parent-of-origin effects. G3 (Bethesda, Md.), 10 Mar 2021
Reinsch, N., M. Mayer, I. Blunk
(See online at https://doi.org/10.1093/g3journal/jkab064)
