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This a short thread about PRKN mutations and #parkinson's disease. It seems to some people that there are contradictory results between my team's paper and a paper by @vuvuzelo1 and @pdgenetics (in which I am a proud member). So here's why I think there's no real contradiction:
In our paper, we fully sequenced PRKN and performed a comprehensive analysis of CNV in 2,807 Parkinson's disease patients and 3,627 controls. The aim was to examine whether HETEROZYGOUS carriage of PRKN mutations is associated with PD. https://www.medrxiv.org/content/10.1101/2020.05.07.20072728v2
We found no evidence for association of any type of PRKN mutations with Parkinson's disease. The three cohorts we included were all sequenced at the same time, the same place using the same method, so no risk of bias there.
In the paper by @vuvuzelo1 and @pdgenetics, they performed an analysis of much larger dataset, from different sources using different methodologies. https://www.medrxiv.org/content/10.1101/2020.06.26.20138172v1
They reported that "Overall, after exclusion of biallelic carriers, single PARK2 mutations were more common in PD than controls conferring a >1.5-fold increase in risk of PD (P=0.035), with meta-analysis (19,574 PD cases and 468,488 controls) confirming increased risk."
But then, they also explained that: "Studies that did not assess biallelic PARK2 mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR=1.23, P=0.614; n=4)."
And: "Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PARK2 mutations we found that 44% had biallelic mutations suggesting that previous estimates may be influenced by cryptic biallelic mutation status."
In other words, there is a very good chance that the association that they have initially observed was due to unidentified carriers of homozygous or compound heterozygous carriers of PRKN variants.
And this is why they carefully conclude that: "While this study supports the association of single PARK2 mutations with PD, it highlights confounding effects therefore caution is needed when interpreting current risk estimates."
And that: "Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PARK2 mutations."
One thing that supports this, is the observed risk for heterozygous carriers (who probably include undetected biallelic carriers) that was about 1.5 fold. Which is very similar to many common SNPs, and less than the E326K GBA polymorphism, for example.
Now, biallelic carriers of pathogenic PRKN mutations, to the best of knowledge, have 100% penetrance. Or in other words, they will all get the disease. So carriers of 2 mutations have 100% chance to have PD, and carriers of 1 mutation have about 1.5-3% chance? Not very likely.
Not saying it's impossible, just not very likely.
So my interpretation, based on our study as well as on the larger study is that heterozygous PRKN mutations are not likely to cause PD or to be a risk factor for PD.
And if they are a risk factor, they are a very weak risk factor, with similar magnitude to that of common SNPs.
And if they are a risk factor, they are a very weak risk factor, with similar magnitude to that of common SNPs.
On the same topic, throughout this thread I called it "PD", but it is my opinion that those with biallelic PRKN mutations have a distinct disease, which may be clinically similar to PD. Same same but different.
