Glanville, K. | bioRxiv Science

bioRxiv2019

Investigating the role of behaviour in the genetic risk for schizophrenia

The notion that behaviour may be on a causal path from genetics to psychiatric disorders, such as schizophrenia, highlights a potential for practical interventions. Motivated by this, we test the association between schizophrenia (SCZ) polygenic risk scores (PRS) and 420 behavioural traits (personality, psychological, lifestyle, nutritional) in a psychiatrically healthy sub-cohort of the UK Biobank. Higher schizophrenia PRS was associated with a range of traits, including lower verbal-numerical reasoning (P = 6x10-61), higher nervous feelings (P = 2x10-51) and higher self-reported risk-taking (P = 2x10-41). We follow-up the risk-taking association, hypothesising that the association may be due to a genetic propensity for risk-taking leading to greater migration, urbanicity or drug-taking - reported environmental risk factors for schizophrenia, and all positively associated with risk-taking in these data. However, schizophrenia PRS was also associated with traits, such as tea drinking (P = 2x10-34), that are highly unlikely to be on a causal path to schizophrenia. We depict four causal relationships that may in theory underlie such PRS-trait associations and illustrate ways of testing for each. For example, we contrast PRS-trait trends in the healthy sub-cohort to the corresponding trait values of medicated and non-medicated individuals diagnosed with schizophrenia, allowing some differentiation of mediation-by-behaviour, disease-onset effects and treatment effects. However, dedicated follow-up studies and new methods are required to fully disentangle these relationships. Thus, while we urge caution in interpretation of simple PRS cross-trait associations, we propose that well-designed PRS analyses can contribute to identifying behaviours on the causal path from genetics to disease.

genetics↗

bioRxiv2019

Familial influences on Neuroticism and Education in the UK Biobank

Genome-wide studies often exclude family members, even though they are a valuable source of information. We identified parent-offspring pairs, siblings and couples in the UK Biobank and implemented a family-based DNA-derived heritability method to capture additional genetic effects and multiple sources of environmental influence on neuroticism and years of education. Compared to estimates from unrelated individuals, heritability increased from 10% to 27% and from 19% to 57% for neuroticism and education respectively by including family-based genetic effects. We detected no family environmental influences on neuroticism, but years of education was substantially influenced by couple similarity (38%). Overall, our genetic and environmental estimates closely replicate previous findings from an independent sample, but more research is required to dissect contributions to the additional heritability, particularly rare and structural genetic effects and residual environmental confounding. The latter is especially relevant for years of education, a highly socially-contingent variable, for which our heritability estimate is at the upper end of twin estimates in the literature. Family-based genetic effects narrow the gap between twin and DNA-based heritability methods, and could be harnessed to improve polygenic prediction.

genomics↗