Rare TMEM230 Variants are Potentially Associated With Early Onset Parkinson's Disease
Konstantin Senkevich1, Eric Yu1, Uladzislau Rudakou1, Jamil Ahmad1, Jennifer Ruskey1, Farnaz Asayesh1, Dan Spiegelman1, Stanley Fahn2, Cheryl Waters2, Oury Monchi1, Yves Dauvilliers3, Nicolas Dupre4, Irina Miliukhina5, Alla Timofeeva6, Daria Kulabukhova6, Anton Emelyanov6, Sofya Pchelina6, Lior Greenbaum7, Sharon Hassin8, Roy Alcalay9, Ziv Gan-Or1
1McGill University, 2Columbia University Medical Center, 3Hopital Gui De Chaulliac, 4CHU de Quebec - U Laval, 510. Institute of the Human Brain of RAS, 6First Pavlov State Medical University of St. Petersburg, 7Sackler Faculty of Medicine, 8Chaim Sheba Medical Center, 9Columbia University
Objective:
In the current study, we assessed whether rare variants in TMEM230 and LRP10 are associated with Parkinson’s disease (PD) and early onset PD (EOPD,≤50 years).
Background:
Several studies reported an association between PD and variants in TMEM230 and LRP10. However, this association remains controversial, as limited evidence supports the overrepresentation of rare variants in these genes in PD.
Design/Methods:
To study the association of rare variants in LRP10 and TMEM230 with PD, we performed an analysis in four cohorts sequenced at McGill with a total of 3,302 PD patients and 1,938 controls. Targeted sequencing was performed by molecular inversion probes. We then analyzed whole-genome and whole-exome sequencing data from two publicly available cohorts, the Accelerating Medicines Partnership-PD cohort (AMP-PD) and UK-Biobank(UKBB) with a total of 2,943 PD cases and 18,486 controls. Standard quality control was performed on individual and variant levels for each cohort separately. For the analysis of rare variants (minor allele frequency<1%), we applied an optimized sequence Kernel association test (SKAT-O). Meta-analysis of SKAT-O results between cohorts sequenced at McGill with AMP-PD and UKBB cohorts was done using the MetaSKAT package in R.
Results:
In a meta-analysis of all six cohorts, we found an association between rare non-synonymous and variants with high Combined annotation‐dependent depletion score(>20) in TMEM230 and EOPD with p=0.002 and p=0.007, respectively (threshold after Bonferroni correction p=0.003). We did not find any role of rare TMEM230 variants in PD when studied patients of all ages together. We also did not find any association between LRP10 variants and PD.
Conclusions:
Rare TMEM230 variants are associated with EOPD in our data. These results should be considered with caution as their statistical significance is borderline. Our results do not support an association of rare LRP10 variants with PD. However, we cannot exclude the role of very rare pathogenic LRP10 mutations in PD.