Measuring the exposome in bipolar disorder

Although bipolar disorder is highly heritable, the identified genetic variants explain only a small portion of phenotypic variation and overall disease risk. Contemporaries of Kraepelin delineate environmental exposure to disease, in part, by developmental age and whether exposures are modifiable (i.e., diet, alcohol, and drug use) or non-modifiable (i.e., childhood maltreatment, head trauma, and infection-associated immune activation) risk factors.^{1, 2} Exposures can be studied at the individual level and population level. For example, in comparison to age-matched controls, individuals with bipolar disorder, in particular those with a history of psychotic mania and non-early onset illness, had significantly increased long-term IgG antibody response to cytomegalovirus.³ In another study utilizing two large datasets from the United States and Denmark, air quality was identified as the strongest predictor of a bipolar disorder diagnosis among environmental quality indices.⁴ These examples provide a compelling illustration of how quantifying environmental exposure at both the individual and population levels has merit in enhancing our understanding of bipolar disorder and its putative subphenotypes. Achieving a more comprehensive and precise assessment of such environmental factors is critical for future clinical research initiatives.

Introduced in 2005, the exposome concept illustrated the need to assess environmental exposures more holistically.⁵ It encompasses all exposures an individual encounters, from conception to end of life. The exposome is broadly categorized into three interactive and potentially overlapping domains of general external exposures (geographic, social, and economic), specific external exposures (diet, tobacco, alcohol, substance use, pharmacotherapy, skin care products, pollutants, radiation, and contaminants), and internal exposures which include biological effects of external exposures (metabolism, hormones, gut microflora, inflammation, and oxidative stress). Importantly, these domains are not necessarily mutually exclusive and inevitably interact as exogenous factors influence internal factors. Advances in exposome research will likely facilitate greater breadth and depth of environmental risk quantification to disease and relapse.

Measuring the exposome is a challenging task due to the vast array and dynamic fluctuations of environmental exposures individuals encounter throughout their lives. Initial models for estimating the exposome score have been proposed for psychiatric disorders, particularly schizophrenia, with the potential to enhance risk prediction and stratification.⁶ However, these models are currently limited to considering only external exposures and do not account for the internal biological response to environmental exposures, ultimately failing to capture the entirety of non-genetic exposures. Achieving a more comprehensive understanding is possible with emerging technologies, such as enhanced gas or liquid chromatography with ultrahigh-accuracy mass spectrometry, as well as high-throughput technologies that now allow for the collective characterization and quantification of nutrients, metabolites, proteins, toxicants, and pollutants in human blood. Recent studies have demonstrated the feasibility of measuring the exposome, including cumulative lifelong exposure to over one million commercial, occupational, and environmental chemicals.⁷ Importantly, more than half of these small molecules were not part of human metabolic pathways, illustrating the importance of going beyond endogenous metabolomics.⁸ Multi-omics investigation can integrate various omics disciplines, including but not limited to, epigenomics (reversible modifications in DNA and associated proteins), transcriptomics (RNA transcripts), proteomics (proteins), metabolomics (metabolites), lipidomics (lipids), and adductomics (chemical adducts found in biological macromolecules like proteins, RNA, or DNA). Furthermore, in contrast to single biomarker studies, this multi-omics approach provides greater systems biology-level understanding of biochemical functions paving the way for a deeper molecular phenotyping of illnesses.⁹

Many diseases such as cancer, diabetes, or bipolar disorder fall in the middle of a gene–environment interplay. A deeper understanding of an individual's exposome composition—that is, the body's internal environment that includes biological responses to exposures, external agents, and surrounding social, cultural, and ecological factors—can shed light on the factors that shape their health outcomes by uncovering the interaction between their environment and genome (Figure 1). By investigating the entirety of genetic predisposition and environmental exposures, we will improve our understanding of disease risk and develop personalized treatments. Incorporating exposome measurements into future research is critical and has the potential to lead to breakthrough discoveries that are much needed in bipolar disorder.

ME's spouse is an employee of Sanofi, neither ME nor his spouse hold stock in Sanofi. BS received grant support from Mayo Clinic, the National Network of Depression Centers (NNDC), and Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2). MAF received grant support from Assurex Health, Mayo Foundation and Breakthrough Discoveries for thriving with Bipolar Disorder (BD2), received CME travel and honoraria from Carnot Laboratories and American Physician Institute, and has Financial Interest/Stock ownership/Royalties from Chymia LLC. All other authors report no financial relationships with commercial interests.