Genetic Overlap and Causal Mediation Relationship Between Psychiatric and Non-Psychiatric Phenotypes

Abstract

Genome-wide genotyping studies are providing evidence that psychiatric disorders are truly polygenic, that is they have a genetic architecture of many genetic variants. Cross-trait polygenic analysis has been applied to identifying genetic correlations between psychiatric and non-psychiatric phenotypes. However, causal models between shared genetic factors and the genetically-correlated phenotypes are mostly unclear. We used cross-trait polygenic risk score (PRS) association analysis to examine the genetic overlap between two phenotypes. We then performed causal mediation analysis to identify the causal relationship between common genetic variants and two genetically correlated traits. We examined if the effect of polygenic risk on one trait (i.e., the outcome) was mediated by the other trait (i.e., the mediator).

In Chapter 1, we examined the relationship between PRS for psychotic illness or cognitive ability, event-related potential (ERP), and severity of psychotic symptoms. A phenotype of global impairment on multiple ERP measures is associated with positive symptoms of psychosis as well as polygenic influences on educational attainment and, to a lesser extent, schizophrenia. We also observed a positive association between education PRS and positive symptoms that was almost entirely mediated by effects on the globally impaired ERP phenotype.

In Chapter 2, we examined the relationship between PRS for Alzheimer’s dementia, vascular pathologies, and late-life cognitive function. Our findings support the hypothesis of a genetic overlap, mostly due to APOE, between vascular pathologies and AD dementia. The polygenic genetic effect on late-life cognition is partially but significantly mediated by cerebral microbleeds, white matter lesion load, and coronary artery calcification.

In Chapter 3, we examined the relationship between PRS for coronary heart disease, psychological attitudes, and liability to coronary heart disease. Our findings suggest a genetic overlap between optimism and CHD in older women of European ancestry. The polygenic genetic effect on CHD is modestly though significantly mediated by optimism.