Gene-by-environment interactions in Alzheimer's disease and Parkinson's disease

Abstract

Diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) arise from complex interactions of genetic and environmental factors, with genetic variants regulating individual responses to environmental exposures (i.e. gene-by-environment interactions). Identifying gene-by-environment interactions will be critical to fully understanding disease mechanisms and developing personalized therapeutics, though these interactions are still poorly understood and largely under-studied. Candidate gene approaches have shown that known disease risk variants often regulate response to environmental factors. However, recent improvements in exposome- and genome-wide association and interaction studies in humans and mice are enabling discovery of novel genetic variants and pathways that predict response to a variety of environmental factors. Here, we highlight recent approaches and ongoing developments in human and rodent studies to identify genetic modulators of environmental factors using AD and PD as exemplars. Identifying gene-by-environment interactions in disease will be critical to developing personalized intervention strategies and will pave the way for precision medicine.

Keywords: Alzheimer’s disease; Exposome; Gene-Environment; Genetic reference panel; Genome; Parkinson’s disease.

Figure 1.. Recent approaches to identify GxE interactions in neurological disease.

(A) Candidate gene analyses, genome-wide interaction and association studies (GWAIS), and genome-wide and exposome-wide association studies (GxEWAS) are valuable in approaching GxE analyses. Candidate gene analyses ask whether an exposure or exposures results in differential disease risk in carriers (e.g. “T/T” individuals) or non-carriers (e.g. “A/A” individuals) of a particular known disease risk allele. GWAIS ask which genetic variants and genomic loci correlate with disease risk given individuals’ exposure to a known disease-relevant environmental factor. Finally, GxEWAS take an integrated approach of measuring and determining which exposome-wide and genome-wide factors contribute to risk of a variety of diseases, and how these factors interact across time in order to determine individual risk for any number of diseases. (B) AD-BXD and Ntg-BXD mice underwent extensive cognitive and metabolic phenotyping on chow and after eight weeks of high-fat diet. We performed ANOVA and removed the residual variation resulting from unknown sources to calculate the remaining relative contribution of diet, genetic background, and gene-by-diet interactions on each of these traits. Interestingly, we found a wide range of contributions from genetic background, diet, and gene-by-diet interactions depending on phenotype. In general, energy expenditure is highly dependent on genetic background, whereas food intake and weight are highly dependent on diet. Other traits, such as glucose tolerance and working memory show a substantial interaction between genetic background and diet, suggesting that the effects of diet on these traits are dependent on genetic variants within this population.