Genetic nurture: how nontransmitted genes affect offspring's risk of neurodevelopmental outcomes, functional somatic syndromes and somatic traits and diseases.

Most psychiatric and somatic diseases run in families. This holds for depression and related phenotypes (see application form OV18-0454; Van Loo) but also for neurodevelopmental disorders and traits such as autism, ADHD and schizophrenia and reduced neuropsychological functioning. It likewise holds for functional somatic syndromes, such as Chronic Fatique Syndrome, Irritable Bowel Syndrome and Fibromyalgia, as well as for somatic diseases such as asthma, obesity, and cardiovascular outcomes. Both psychiatric and somatic phenotypes have a (partly) genetic origin but the environment plays a role as well. Given the patterns of disease transmission across generations, part of the environmental effects are thought to lie in the (early) family environment. Improved understanding of the multigenerational transmission of psychiatric and somatic phenotypes through the environment facilitates the identification of causal factors that are amenable to change. Currently these are insufficiently known, hampering the development of prevention and treatment strategies. 

One of the understudied pathways of familial transmission is "genetic nurture" or "indirect genetic effects". In daily life we tend to think of risk factors for disease and symptoms as either reflecting the actions of genes ("nature") or the environment ("nurture"). However, nature and nature are highly entangled. One way in which nature and nurture are entangled is through what has become known as GxE correlation or genetic nurture. GxE correlation or genetic nurture exists if the offspring's disease risk is influenced by parental genes that affect the child indirectly, via the phenotype of the parents and the rearing environment they create such as their parenting styles or feeding practices (Moore et al., 1997; Wolf et al., 1998). It is likely that genetic nurture effects exist for a broad domain of diseases and symptoms. 

Although it has been known for a long time from twin and adoption studies that environmental variables are (partly) genetically driven. In other observational study designs, it has for long been difficult to study genetic nurture effects or the environment without such genetic confounding. Recently, with increasing success of genome wide association studies (GWA), methods to directly study genetic nurture effects have been developed. These methods are based on the partitioning of transmitted (direct genetic effect) and non-transmitted (indirect genetic effect) alleles from parents to offspring. Building on successful GWA studies of educational attainment, the first two studies used this partitioning to study familial transmission of educational attainment from parent to offspring (Bates et al., 2018; Kong et al., 2018). In both studies, parental non-transmitted alleles independently predicted their offspring's educational achievements through 'genetic nurture', constituting roughly one third of the direct genetic effect. Genetic nurture effects were much stronger for educational attainment - a behavioral trait - than for physical traits such as body mass index and height (Kong et al., 2018). Possibly, indirect genetic effects may be more important for behavioral and emotional outcomes including psychiatric phenotypes than for physical health traits and diseases, although this remains to be tested. Another possibility is that indirect genetic effects are more important for less heritable outcomes (e.g. depression: heritability ~30-40%; ADHD, schizophrenia, autism ~70-80%). Yet even these highly heritable phenotypes (ADHD, autism, schizophrenia) are thought to be importantly influenced by the environment, facilitating their onset and influencing the course. Cleary, more research is needed. 

Both educational attainment and BMI are prototypical examples in terms of successful identification of associated loci through GWA studies. Recently, GWA studies have also become successful for psychiatric disease outcomes, including depression, ADHD, autism, and schizophrenia. It is to be expected that this success will extend to other phenotypes, including functional somatic syndromes. 

Identifying genetic nurture effects for aforementioned outcomes may in the longer run have important consequences for prediction and prevention of psychiatric disorders in clinical practice. Taking indirect genetic effects into account could lead to more precise estimates of outcome risk in offspring. For instance, a high or low parental risk might enhance or reduce our expected risk for offspring, independent of their own polygenic risk for the outcome. A better understanding of mechanisms of familial transmission may aid in improving prevention efforts. Disentangling genetic nurture effects from true environmental effects may be an important part of this. That is, while parents cannot influence the genes they transmit to their offspring, they may be supported to provide healthy rearing environments, thus lowering offspring risk.