The role of common genetic risk variants in Parkinson disease


Eng-King Tan, MD, FRCP, Department of Neurology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore.
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Despite the discovery of at least five pathogenic genes in Parkinson disease (PD), the genetic etiology in the vast majority of PD remains to be clarified. Common genetic variants could act as susceptibility risk factors. Our previous meta-analysis of PD genetic association studies, over a 30-year period yielded four genes (N-acetylcysteine 2, monoamine oxidase B, glutathione transferase, and mitochondrial tRNA), as their common variants were found to be associated with PD. More recently, international collaborative studies and meta-analysis have identified the S18Y variant of ubiquitin carboxy-terminal hydrolase L1, Rep 1 variant of alpha-synuclein and tau H1 haplotype to be genetic susceptibility risk/protective factors. However, the most significant, common genetic risk factor in PD has been its association with the leucine-rich repeat kinase-2 (LRRK2) G2385R variant. We conducted an analysis of independent studies involving 2205 PD and 1817 controls and found the average carrier rate of G2385R variant to be about 9% in PD and 4% in controls (p < 0.001; odds ratio: 2.27; 95% confidence interval: 1.78–2.9). A higher frequency of G2385R carriers has been observed in familial PD when compared with sporadic patients. Based on current evidence, certain common genetic variants are likely to modulate the risk of PD.