Mutations for Gaucher disease linked to high risk of Parkinson’s disease

What’s the connection between Gaucher disease, a rare single gene disorder of metabolism that appears during childhood, and Parkinson’s disease, a common multifactorial disorder of the nervous system that occurs late in life?

The answer lies in just a single gene (glucocerebrosidase or GBA), which encodes an enzyme required for lipid metabolism and storage within the lysosome. Numerous pathogenic mutations in this gene have been characterised, which result in Gaucher disease if present in both copies of the gene; these recessive mutations are generally assumed to be relatively harmless to the carrier.

However, numerous studies have linked pathogenic mutations within GBA with increased susceptibility to Parkinson’s disease. In the most definitive work to date [Mitsui J et al. (2009) Arch Neurol 66(5):571-576], researchers resequenced the GBA gene in over 500 cases of Parkinson’s disease and matched controls; whilst only 2 of the control subjects had any of the pathogenic mutations associated with Gaucher disease, 50 of the cases were heterozygous for one of 11 mutations in the gene. Having one of these mutations therefore confers a substantial and significant increased risk of developing Parkinson’s disease of nearly 30-fold (OR = 28.0, 95% confidence intervals 7.3-238.3). In addition, patients with mutations in GBA were significantly younger at the age of onset of Parkinson’s disease than those without. In contrast, there was no statistically significant association between non-pathogenic mutations in GBA and Parkinson’s disease.

Comment: This research is important for three different reasons. First, by combining numerous pathogenic mutations in the GBA gene in a relatively large study, the work unifies various earlier and smaller studies linking the gene with Parkinson’s disease.

Second, it highlights a general paradigm shift from the common disease-common variant hypothesis within human genetics, which underlies the recent plethora of genome-wide association (GWA) studies, to the common disease-rare variant hypothesis. If the majority of genetic risk for common diseases is actually located in rare variants, not common polymorphisms, conducting resequencing analysis of specific susceptibility genes is the logical next step in the hunt for the genetic basis for all common diseases. Adopting such a strategy could therefore be substantially more fruitful than conducting ever larger GWA studies.

Third, and perhaps most significantly, the work raises serious ethical concerns over carrier screening for Gaucher disease, particularly within the Ashkenazi Jewish population (see previous news). According to the National Gaucher Foundation, the carrier status may be as high as 1 in 15 amongst Jewish people of Eastern European ancestry (and 1 in 100 amongst the general population). The current policy of the UK National Screening Committee is that carrier testing for Gaucher disease should not be offered, as it is treatable and can be relatively mild. However, those who are considering getting tested privately prior to becoming pregnant may now want to think again; a relative risk of ~30 is one of the largest genetic risks known, and may even be useful as a predictor of the disease (though further research is needed here). As Parkinson’s disease has a UK population prevalence of around 1% in the over 65’s (based on data from the Parkinson’s Disease Society), such information could potentially have enormous personal and societal consequences. Additionally, authorities face an even greater challenge – should people who have already had carrier testing be informed of the associated risk of Parkinson’s disease, or not?

Such ethical conundrums are only likely to increase as more and more genetic susceptibilities are discovered that have relevance to multiple diseases. To date, this has been a relatively small problem, as most of the susceptibilities discovered through GWA studies have been associated with extremely low risks (OR<2) and have very limited predictive ability. However, if the common disease-rare variant hypothesis is correct, we can expect significantly more issues of this nature to surface over the coming years. Policymakers and clinicians will need to bear this in mind when forming national guidance regarding genetic testing and screening.