March/April 2017

Research Review: GCH1 Gene Mutation Linked to Early Onset of Parkinson's Disease in Caucasians
By Auriel A. Willette, PhD, MS, and Joseph Webb, BS
Today's Geriatric Medicine
Vol. 10 No. 2 P. 30

Parkinson's disease (PD) was originally thought to be a primarily nonhereditary disease. However, advances in the molecular genetics of PD have revealed it to be a complex disorder with a clear genetic component. These advances have also revealed unexpected clinical and genetic heterogeneity in PD, highlighting the importance of better characterizing the mechanisms resulting in PD pathology. PD is believed to be due to alpha-synuclein aggregation,1 decreasing dopamine production whereby many genetic risk factors act individually or in concert to impact disease pathogenesis.2

It is first important to recognize that PD primarily affects the central nervous system, specifically a region of the brain known as the substantia nigra that is responsible for producing dopamine, controlling movement, and coordinating balance.3 Disruption of the substantia nigra typically results in the hallmark symptoms of PD including trembling in the extremities, torso rigidity with limb stiffness, slow movement, and impaired balance.4 PD also can affect emotions, increase the risk of developing depression, and predispose individuals to developing dementia. If these symptoms manifest after the age of 50, it is called late onset PD as opposed to symptoms appearing before the age of 50, which is known as early onset PD.

In the clinical setting, these advancements in the genetic underpinnings of PD are reflected in increased demand for genetic analysis of PD-associated genes by physicians, highlighting the need to improve the understanding of the beneficial and adverse effects of PD genes. It is important to determine which genetic factors will improve PD diagnosis and highlight pathways to guide more drug and nondrug-related therapies to ameliorate PD-related brain atrophy, decreased motor function, and memory decline.

Selecting Genomic Variants
The authors initially collected publicly available cognitive, demographic, genetic, and biological data from the Parkinson's Progression Markers Initiative (PPMI),5 a public-private partnership sponsored by the Michael J. Fox Foundation for Parkinson's Research. PPMI is a longitudinal observational study to comprehensively evaluate PD by examining factors that increase the risk of developing the disease, with the goal of identifying biomarkers that predict the progression of PD. PPMI collects clinical and behavioral assessments, neuroimaging data, genetic data, and biofluids to compare subjects with newly diagnosed untreated PD subjects against healthy age-matched controls.5

The authors then began to examine baseline clinical, genetic, neuropsychological, volumetric imaging, and dopaminergic imaging data among 289 de novo PD and 233 age-matched healthy controls. After reading a 2014 meta-analysis that highlighted new genetic loci that were associated with increased risk of developing PD6 across multiple genomicwide association studies, the researchers selected a novel single nucleotide polymorphism that was located in the gene coding for Guanosine triphosphate cyclohydrolase-1 (GCH1; OMIM 600225), on chromosome 14 (14q22.1-q22.2) encoding for the rate-limiting enzyme catalyzing the first step in tetrahydrobiopterin (BH4) synthesis.7 BH4 is a required cofactor for tyrosine hydroxylase, which ultimately leads downstream to the production of dopamine.8

The analysis focused on genetic variations that would result in a biological change, which could be evaluated using the data collected in the PPMI cohort that were relevant to developing PD. The researchers ultimately selected the genetic variant RS11158026 based on disease etiology and previous studies linking this gene locus with dopamine production and PD risk. The study compared subjects who were homozygous for the major allele (C/C; n=151) with individuals carrying one or two copies of the minor allele (C/T or T/T; n=171). Statistical analyses were conducted to determine how subjects carrying the defect in the GCH1 gene affected cognitive, biological, and imaging indices.

Results
First, the authors noted there was not a big difference between the number of subjects with PD who had this genetic defect compared with their healthy controls. While this defect was present not only in subjects with PD, carriers of the T allele showed a 23% increased risk of developing PD compared with subjects who did not have the minor allele. Examination followed to determine whether there were differences in the age at disease onset. Carriers of the T allele displayed an earlier age of onset by five years compared with noncarriers.

To understand the possible underlying reasons these subjects were developing PD earlier, the researchers turned to imaging data to shed light on the topic. T allele carriers demonstrated lower striatal DAT uptake, which is a marker for how readily dopamine is taken up in the substantia nigra. This result was sensible because if subjects with the genetic defect were unable to produce as much dopamine, they should also have less dopamine uptake in the region of the brain responsible for dopamine production. Subsequent examination explored how this genetic variant altered grey matter volume in the brain. However, the researchers saw no differences in grey matter volume between carriers and noncarriers.

Because this single-nucleotide polymorphism was not changing grey matter, the authors examined how it influenced other biological indices associated with developing PD. First they examined alpha-synuclein in the cerebrospinal fluid, which they hypothesized would be lower in subjects with the risk allele. Researchers were surprised when they found that subjects with the risk allele had substantially higher alpha-synuclein than their counterparts with the common allele. Normally in PD, subjects with the disease have lower alpha-synuclein compared with healthy controls, but this association was not observed in this cohort. Another biological factor that is known to influence dopamine uptake is cholesterol, and examination of plasma cholesterol levels showed that carriers had higher LDL cholesterol and total cholesterol. The minor allele drastically affected cholesterol levels but was dependent on whether subjects were PD or control.

Finally, the researchers sought to examine whether this genetic variant affected motor and cognitive outcomes. Utilizing the Unified Parkinson's Disease Rating Scale, a cross-validated measure to assess severity of the multiple facets affected by PD, researchers noted that carriers of the T allele had worse motor function. Similarly evaluated were neuropsychiatric outcomes, including anxiety, where carriers of the minor allele displayed higher anxiety on the State-Trait Anxiety Inventory. Carriers of the minor allele also demonstrated decreased executive function relative to noncarriers, where executive function is defined as a set of cognitive processes such as attentional control, inhibitory control, working memory, problem solving, and judgment.

To determine whether this genetic variant was associated with early onset PD or late onset PD, the authors followed up these analyses by stratifying the subjects based on those who were above or below the age of 50. Subjects who were under the age of 50 showed stronger correlations than the initial analyses, while subjects over the age of 50 no longer displayed significant correlations.

Overall these results suggested that alterations in the GCH1 gene can increase the risk of developing early onset PD by altering dopamine production through decreased BH4 synthesis.

The biggest takeaway message from this study is that individuals with the defective gene, regardless of age, were more anxious and struggled more with daily activities. This genetic variant is not as strong a predictor for developing Parkinson's disease in people over the age of 50 because as people age, they progressively make less dopamine, and this effect strongly outweighs the genetic influences from the "bad version" of this gene. During normal aging, dopamine production decreases to the point that the effects from a mutation in this gene are not noticeable in older adults but make a big difference in younger populations. Because this study was cross-sectional, it is important to note that causal attribution cannot be inferred.

Treatment Implications
These findings have the potential to further personalize medical care for people with a family history of PD, similar to testing for the BRCA gene for women at risk for breast cancer. By examining how genetic variants affect different populations, we can develop a more comprehensive understanding of how genes related to PD may differently affect an individual's risk of developing a disease at different points throughout the lifetime. Through genetic testing, we can determine an individual's risk for illness while accounting for age, gender, weight, and other intervening factors that might modify the disease process.

Current medical approaches try to apply one-size-fits-all solutions that are based on population averages that may not be effective on an individual level. Because everyone is unique when it comes to genetic makeup, these differences can affect how individuals respond to medical treatment or even improve the ability to recover from illness.

Understanding these differences in the genetic makeup of different populations can move medicine toward more precise health care customized for individual patients. With the growing understanding of how genetics drives health, disease, and medicinal responses, health care providers will be able to provide improved advice to prevent disease, facilitate more precise diagnoses, and develop more effective treatments for conditions diminishing human health.

Even though many studies highlight the role of genetic factors predisposing people to developing a disease, most of the time our genetic makeup may alter our risk by only 1% to 15%, whereas lifestyle plays a major role in disease development. Often it is said that genetics loads the gun and the contributions of our actions/environment are responsible for pulling the trigger. One method of delaying disease onset and decreasing disease risk is proper weight maintenance. The beneficial effects from exercise have been shown to improve brain health and function while preventing cognitive decline.

In closing, genetic mechanisms that regulate the brain are complicated, so careful consideration should be given when determining genetic predisposition to developing a disease or providing disease resistance. Hopefully, future studies will evaluate genetic mechanisms highlighting opportunities for targeting pathways to treat disease and corroborate the authors' findings on GCH1's role in PD.

— Auriel A. Willette, PhD, MS, is a researcher in the department of food science and human nutrition, as well as the neuroscience graduate program, at Iowa State University in Ames, Iowa. He also has an adjunct appointment in the department of neurology at University of Iowa.

— Joseph Webb, BS, is a graduate student working in Dr. Willette's laboratory in the department of food science and human nutrition at Iowa State University.

References
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2. Lesage S, Brice A. Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet. 2009;18(R1):R48-R59.

3. Goetz CG, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): process, format, and clinimetric testing plan. Mov Disord. 2007;22(1):41-47.

4. Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79(4):368-376.

5. Marek K, Jennings D, Lasch S, et al. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol. 2011;95(4):629-635.

6. Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014;46(9):989-993.

7. Mencacci NE, Isaias IU, Reich MM, et al. Parkinson's disease in GTP cyclohydrolase 1 mutation carriers. Brain. 2014;137(Pt 9):2480-2492.

8. Opladen T, Hoffmann G, Hörster F, et al. Clinical and biochemical characterization of patients with early infantile onset of autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia. Mov Disord. 2011;26(1):157-161.