Genetic variants tied to mortality, motor progression in Parkinson’s
Six variants identified in genome-wide studies
Six genetic variants associated with mortality and motor progression have been discovered in people with Parkinson’s disease.
These newly detected genetic factors that influenced disease progression were largely different from those that increased Parkinson’s risk, researchers found.
“This work will help us to better understand the biology of [Parkinson’s] progression and develop new disease-modifying treatments,” they wrote in the study, “Genome-wide determinants of mortality and motor progression in Parkinson’s disease,” published in npj Parkinson’s Disease.
Although the cause of Parkinson’s disease remains unclear, genetics are known to play a role.
Previous genome-wide association studies (GWAS) — which find single genetic changes at specific locations in the genome associated with a disease — have identified 90 variants linked to a risk of Parkinson’s. Still, few variants have been tied to disease progression. It’s “important to study the genetics and biology of disease progression” because it “will enable the development of potential disease-modifying treatments,” the team, based across Europe and the U.S., wrote.
Large-scale studies collected data over several years
The researchers carried out two GWASs to identify genetic variants associated with progression to mortality and a Hoehn and Yahr stage of 3 or greater. Stage 3 represents physical independence despite mild to moderate involvement on both sides of the body with some postural instability. Higher stages indicate worse disability.
Data from 6,766 Parkinson’s patients were collected over a mean follow-up time of 4.2 years to 15.7 years.
Of the 5,744 patients in the mortality analysis, 1,846 (32.1%) individuals had died. Across the entire genome of these patients, the team looked for single genetic changes called single nucleotide polymorphisms, or SNPs, associated with a progression to mortality.
The most significant mortality-associated SNP (rs429358) was linked with APOE epsilon 4, one of three versions of the APOE gene, which encodes apolipoprotein E, a protein that facilitates the transport of fat-like lipids in the bloodstream. This SNP’s effect on Parkinson’s mortality was stronger in women than in men. It was also in linkage disequilibrium with 12 other SNPs, meaning these genetic markers were likely inherited together.
Variants in APOE have been tied to faster cognitive decline and a higher risk of cognitive impairment in Parkinson’s patients, and are the strongest genetic risk factor for Alzheimer’s disease.
Another SNP (rs4726467) significantly associated with mortality was in the TBXAS1 gene, with five additional SNPs in linkage disequilibrium. This gene carries instructions for thromboxane A synthase 1, an enzyme involved in the production of fat-like lipids. This SNP appeared to reduce TBXAS1’s activity in blood, but not in other tissues, or affect its activity in brain regions.
Only one mortality-related SNP (rs35749011) was found in the GBA1 gene, a known genetic risk factor for Parkinson’s.
Signals for motor issues
Among the 3,331 individuals analyzed for progression, 753 (22.6%) met the outcome of motor progression to the Hoehn and Yahr stage of 3 or greater. This outcome was associated with four SNPs in or near the genes MORN1 (rs115217673), ASNS (rs145274312), PDE5A (rs113120976), and XPO1 (rs141421624).
The top SNP for MORN1, which encodes a protein of unknown function, did not appear to affect its activity across different tissues, similar to the top SNP nearest to the ASNS gene. This gene provides instructions for asparagine synthetase, an enzyme that produces asparagine, a protein building block.
The third most significant SNP was closest to the PDE5A gene, which lowered the activity of another gene called USP53 in blood but not in other tissues. The fourth top SNP, and nine associated SNPs, spanned several genes: XPO1, USP34, KIAA1841, and C2orf74, although only the top XPO1-linked SNP of these reached significance. This SNP altered other genes in the blood and increased C2orf74 activity in the brain.
“We conducted two large-scale GWASs of [Parkinson’s] progression, including the first GWAS of mortality in [Parkinson’s],” the team concluded. “We identified six significant genome-wide signals, including TBXAS1.”
The researchers said their work “will help us to better understand the biology of [Parkinson’s] progression and develop new disease-modifying treatments, though they noted the need for more studies “to understand the links between these genomic variants and the underlying disease biology.”
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