Association between the number of CAG repeats in polymerase gamma and Parkinson disease in the Norwegian population

Abstract

Parkinson disease (PD) is a common neurodegenerative movement disorder that increases in prevalence with age. It is characterized clinically by resting tremor, rigidity, bradykinesia, and failing balance, and is due to the gradual loss of the dopaminergic neurons in the substantia nigra of the midbrain. Different factors including environmental (1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6- hydroxydopamine (6-OHDA), etc.) and genetic (PINK1, DJ1 and LRRK2) have been found to cause the loss of the dopaminergic neurons in the substantia nigra. In addition, deficiency of respiratory chain complexes (complex I, II and IV) and increased levels of mtDNA deletions have been identified in PD patients. All of these factors, from the environmental to the genetic and the biochemical converge on one site, namely the mitochondrion: MPTP poisons complex I of the respiratory chain, PINK1, DJ1 and LRRK2 have all been linked to mitochondrial and lastly, mutations in the catalytic subunit of the mitochondrial DNA polymerase, POLG1, are known to cause Parkinsonism. The POLG1 gene also contains a trinucleotide (CAG) repeat region and while the majority of individuals have 10 CAG repeats (10Q) this region is also unstable and both longer and shorter repeats are seen. Previous studies have highlighted an association between CAG length in POLG1 and the development of PD. This has been done in different population such as England and United states, also for Nordic population (Finland and Sweden). In most populations studied, an association has been found, but in one population (England) no association was seen. The aim of this study was, therefore, to ascertain whether the length polymorphism of the CAG tract in POLG1 was associated with PD in the Norwegian population. In order to do this we studied cohort of Norwegian patients and age-matched controls that had been collected and clinically characterized as part of the ParkVest study. We found a significant association between the non 10Q alleles (P= 0.027; OR 1.53), especially 12Q (P= 0.031; OR 2.38), and PD. In addition, meta- analysis of all available studies confirmed a highly significant association between the non 10Q alleles (P= 0.0004; OR 1.27) particularly 12Q (P= 0.0047; OR 1.55) and PD. This pooled analysis also showed significant association between 9Q and PD (P= 0.0427; OR 1.21). Our results suggest that CAG repeat polymorphism in the POLG1 can be a risk factor or marker for PD.