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Genetic imprinting and mental disease

Final Report Summary - GENMED (Genetic imprinting and mental disease)

The theory of kin selection and more recent evolutionary theory of genetic imprinting have helped scientists unravel the likely genetic influences of social competition over shared resources, although application of the latter for understanding conflicts in human reproduction is still in its infancy. This is remarkable as pregnancy disorders and mental diseases are a major source of human suffering where indications of maternal and paternal genetic conflicts altering metabolic and psychological pathways in offspring are increasingly discovered. However, ethical and privacy problems of obtaining relevant data have precluded explicit analyses of large data bases that would have the potential to confirm or refute predictions from genomic imprinting theory for embryonic development and later mental disease. The Nordic registry-based databases such as those located in Denmark offer a unique and untapped opportunity for doing such research.

I proposed to use this data to test the following main questions: Question 1) does the incidence of genetic imprinting markers of parent-offspring conflict during the perinatal period increase the risk of developing psychological disorders later in life? Question 2) how does the expression of genetic conflict between parents and offspring relate to metabolic disorders and other components of offspring morbidity, health and reproductive life history?

Question 1 was based on the need to empirically test Christopher Badcock and Bernie Crespi’s untested imprinted brain theory of psychosis and autism, which was developed in 2008. The theory is an extension of parent-offspring conflict theory; it predicts that risk of autism and psychosis may partially depend on the epigenetic balance of imprinted genes that are tagged for silencing or expression in the developing brain. Some effects of imprinted genes (e.g. IGF2/IGF2r) are well known and have the expected opposite effects on birth weight depending on which parental copy is silenced. In Badcock and Crespi’s extension, large deviations favoring paternal alleles are predicted to result in more resource-costly offspring with higher risks of autism and large deviations favoring maternal alleles in smaller offspring with higher rates of psychosis. Such deviations may arise either because of disturbances to epigenetic markers or because of variations in copy number. Evidence for Badcock and Crespi’s theory includes differences in copy number variants and behavioral syndromes (e.g. Angelman and Prader-Willi syndromes) being caused by maternal or paternal biases of imprinted genes on chromosome 15. My study, which utilised 1.6 million singleton Danish births between 1978-2008 is the first to directly test whether phenotypic markers of parent-offspring conflict during pregnancy that affect birth weight and length are associated with risks of being diagnosed with mental illness later in life. I confirmed the major predictions of Badcock and Crespi’s theory, showing that autistic- and psychotic-type disorders are opposite ends of a single continuum, and that the risk of both types of disorders increases with larger deviations from average birth weight and length. My results are consistent with the idea that imprinting (im)balances are established at conception and induce correlated phenotypic effects via expression in the placenta before birth and expression in the brain after birth. Most significantly, I showed that these effects are significant for the ca. 68% of birth sizes that fall within ± 1 SD from the mean in a single population, i.e. they apply to normal births in Denmark where later cognition is supposed to be normal and no other theories have formulated any expectations of elevated mental disease risks. The results of this study titled “Markers of unbalanced genomic imprinting at birth predict opposing risk patterns for autistic and psychotic disorders”, which are currently in submission as a research article to the journal Proceedings of the National Academy of Sciences USA are particularly timely given the current debate about the new DSM-5 manual that offers no scientific evidence to support discrete categories of psychological disorders. In summary, these results support a new and novel theory that attempts to explain psychological disorders in connection with errors in genomic imprinting occurring early in life and suggest that more direct tests with genomic methods should be pursued to completely validate this theory. My results have the ability to further support the growing recognition that psychological disorders are linked by genes (and variation in their expression) and therefore are connected through a spectrum of mild to severe disorders.

A second component of Question 1 focused on how paternal and maternal age (and their interaction) affects psychological disorders. This manuscript titled “Maternal, paternal and parental age differences affects the risk of most psychological disorders”, which is currently in preparation for publication demonstrated that not only does advancing paternal age contribute to psychological disorders, but advancing maternal age does also. Moreover, the difference between maternal and paternal age contributes to risk of autistic and psychotic type disorders with risk highest when parental age difference is largest. This manuscript builds on Badcock and Crespi’s imprinted brain theory of psychosis and autism by suggesting another axis that influences the risk of offspring developing these disorders. These results are also of interest to general health and may influence family planning.

The results from the main part of Question 2 have been published in PLoS ONE with the title “Parent-Offspring Conflict and the Persistence of Pregnancy-Induced Hypertension in Modern Humans”. The study provides the first encompassing test of David Haig’s genomic imprinting theory in humans. The key hypothesis is that paternal and maternal genes expressed in the placenta have different interests in fetal provisioning: the paternal genes are selected to manipulate the maternal body’s blood pressure so that more resources are invested in the focal child than the mother genes are selected to agree on, given that she has a non-zero probability of having later babies with another partner. I used the database of the Danish National Health system to analyze registered diagnoses since the 1970s of children born to mothers with elevated and normal blood pressure during pregnancy, and found very consistent statistical evidence for hypertension in the first trimester providing general health benefits to children, teenagers, and early adults. However, offspring health effects become negative when hypertension continues, even if this maternal condition does not deteriorate into (pre)eclampsia. These results support David Haig’s theory in that they describe specific timing of hypertension in pregnancy that may incur sufficient offspring health benefits to compensate for the obvious risks for maternal and fetal health towards the end of pregnancy in order to explain why these disorders have not been removed by natural selection in our hunter-gatherer ancestors. These results are also of practical interest to general health and those in the medical community (obstetrics and gynecology) who are concerned with health consequences for mother and child due to the timing and onset of hypertensive disorders of pregnancy.