How can the interplay of genetics and environment can shape human health?

By: Stanley Wu

Imagine a box filled with thousands of puzzles mixed with an unknown number of pieces, and a person attempted to solve each puzzle separately. Solving these would be analogous to the complexity of understanding the etiology of disease. This is why, after centuries, the etiology of many diseases remains unknown. Despite the expeditious progressions of technological advancements, scientists and clinicians are still seeking definitive answers. While some diseases can be traced to a single factor, the etiology of complex diseases is more difficult to discern, in part due to its nature of multiple contributing factors (1). 

The slightest difference in one person’s genes can result in a different response in an identical environment to another person. This, accompanied by minute factors ranging from chemicals in the air to grooming products may contribute to the development of a disease in one person but not another (2). Especially during childhood, disrupted gene expression can induce lifelong determinants in brain function and morphology. The mildest genetic variations may affect pre-puberty neurological development, increasing risks for psychiatric conditions as people age (3). In this essay, I review two of the world's most common neurological diseases - Parkinson’s (PD) and Tourrete (TS) - both with undetermined and incomplete etiologies. 

PD is now a leading cause of neurological disability for individuals over 60, affecting an estimated 4.5 million people across the world’s 10 most populous countries (5). This neuropsychiatric disorder includes symptoms of tremor, rigidity, akinesia, and postural instability - all involuntary. The most common motor symptom of PD are tremors; however, PD can be distributed to multiple subtypes, such as akinetic-rigid type (ART), which hinder muscle movement, and tremor-dominant type (TDT), which induces uncontrollable shaking (9). 

Involuntary movements of PD can be stimulated by environmental changes combined with genetic factors, influencing the onset of human disease through structural alteration of deoxyribonucleic acid (DNA) (6). Genetic factors contribute to approximately 10-15% of PD cases, with mutations in genes such as SNCA and LRRK2 implicated in familial forms of the disease (15). While some gene-environment interactions are considered a major underlying cause of idiopathic PD (4), a loss of dopamine in the substantia nigra is also a commonly suggested factor. Chemicals such as caffeine can increase dopamine neurotransmission, thus temporarily ameliorating tremblings. Pesticides and heavy metals exacerbate PD symptoms and display PD-associated mechanisms varying from mitochondrial dysfunction to protein degradation impairment (4). This is further demonstrated in various epidemiologic studies with many of these solvents, metals, and pesticides recapitulating PD pathology in animal models (7). As a result of these environmental factors, genetic variations often induce worsened effects. For instance, when polymorphism occurs, affecting nitric oxide production, a neuron-damaging molecule, chances of developing PD after pesticide exposure greatly increase (8). 

TS, similar to PD, was uncommon during the 1800s; it is now estimated to affect 1-10 in every 1000 children (5). While the etiology and pathogenesis of TD have not been completely elucidated, it is thought that TD results from interactions between genetic and environmental risk factors (12). TS occurs with symptoms of abrupt, quick, repetitive motions and/or vocalizations (10). Those movements and vocalizations are called tics, which are often “semi-involuntary” but can be suppressed periodically (11). This suppression can be easily overwhelmed through environmental stimulation. Environmental factors, such as pre-, peri-, and postnatal events, psychological stress, and infections, not only contribute to gene environment interactions, but also to brain development and the severity of TD symptoms (12). Furthermore, genes including SLITRK1 and HDC have been implicated in TS, although no single gene can fully explain its development (14). While psychosocial stress most significantly impacts the intensity of tics, major changes in a Tourrete patient’s surroundings can stimulate symptoms (13). 

Since most diseases have a combination of genetic and environmental causal factors, it is imperative for scientists to continue to research connections between genes and the environment (2). Scientists are trying to pursue new approaches in preventing and treating disease through genetic code, but genetic risk factors only represent a fraction of the likely genetic risk for PD and TS (16, 17). Furthermore, it would be necessary to perform genetic studies across ancestral groups, taking into account historical environmental factors. Larger study cohorts would allow for several genetic loci to be implicated, fostering further therapeutic plans in ameliorating PD and TS (16, 17). Through fine mapping of discovered loci in neuropsychiatric diseases, genetic discoveries will be made, opening the doors for accurate predictions of disease and defining etiological subtypes. 

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