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FRIMEDBIO-Fri med.,helse,biol

Folate, Paternal Age and De Novo Genetic and Epigenetic Events.

Awarded: NOK 4.5 mill.

De novo mutations are changes in the DNA that occur in germ cells or in early fetal development, and that are new in the sense that they cannot be found in the parents. Epigenetic events are chemical alterations in the genes that determine whether a gene is turned on or off, or up- or down-regulated, i.e., whether the gene is expressed and to what extent it is expressed in the different cell types of the child. The aims of this project were to study the B-vitamin folate, paternal age, and de novo (new) genetic and epigenetic events in children. Results generated will provide information regarding genetic changes commonly found in autism. This will provide a foundation for further research on possible biological mechanisms affected by the genetic variants, and investigations into causality. Our results also concludes that intake of folate in pregnancy modifies risk for autism in the child. The project was a collaborative effort with international partners, and has resulted in several papers in international journals with peer review.

The purpose of this project is to examine the contributions of two factors - the mother's folate metabolic pathway during gestation and the father's age at conception - to the occurrence of de novo genomic and epigenetic events in children. Study subjects will be selected from the Norwegian Mother and Child Cohort Study (MoBa). De novo events are DNA mutations originating in childrem, i.e. mutations which can not be traced back to parents' DNA. Emprical evidence points towards an important role for de n ovo events in the development of human disease. They have recently been found to be increased ten-fold in people with autism. Current observations from genetic and epidemiological research are also consistent with a similar pattern for schizophrenia, but there is no clear empirical evidence yet. Evidence from animal and in vitro studies indicate that low folate, in combination with a genotype causing impaired folate utilization (MTHFR 677 TT) in the mother, increases the risk of de novo events in the of fspring. Likewise, advaned paternal age is demonstrated to increase the risk of de novo point mutations, as well as being a risk factor for autism and schizophrenia. This project aims to combine genetic and epidemiological research in bringing all of th is together. The data generated will allow for extensive analyses of the impact of maternal folate metabolism, paternal age and de novo events on children's health and development. The cohort design of MoBa also enable future follow-up studies of health o utcomes among subjects with de novo events. MoBa is part of the Biohealth I platform, for which FUGE I has provided funding. In our proposed project, the Biohealth I platform will serve as a foundation for using new and emerging genomic technologies in investigating causes of disease and developmental disturbances. The project has partners who are world-leading in the development and utilization of these technologies.

Funding scheme:

FRIMEDBIO-Fri med.,helse,biol