Konstantin Senkevich (Canada)
McGill University
The Neuro (Montreal Neurological Institute-Hospital) Department of Neurology & Neurosurgery
Konstantin Senkevich, MD, PhD, is a neurologist who completed his MD at the First Pavlov State Medical University of St. Petersburg, Russia and his PhD at the Institute of Experimental Medicine in St. Petersburg, Russia. He is currently working as a postdoctoral fellow at McGill University, Canada in the Neurogenomics And Precision Medicine (NAP-Med) lab, led by Dr. Ziv Gan-Or. His research focuses on the genetics of neurodegenerative disorders. In his current main project, he is studying the role of lysosomal genes in synucleinopathies. He is an author and co-author of >40 publications. Dr. Senkevich applies various bioinformatical approaches. He is well versed in programming using different languages and tools, including R, Python, and Linux/Bash. He is a member of numerous professional and scientific associations, including MDS, AAN, EAN, IPDGC.

Moderator of 1 Session

 Conference Calendar
SYMPOSIUM

GENETICS OF NEURODEGENERATION 4

Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
05:15 PM - 06:45 PM
Room
ONSITE: 133-134
Chair(s)

Presenter of 1 Presentation

 Conference Calendar

GALC VARIANTS ARE ASSOCIATED WITH PARKINSON’S DISEASE AND WITH CHANGES IN ENZYMATIC ACTIVITY

Session Name
1720 - GENETICS OF NEURODEGENERATION 4 (ID 208)
Session Type
SYMPOSIUM
Date
Sat, 19.03.2022
Session Time
05:15 PM - 06:45 PM
Room
ONSITE: 133-134
Lecture Time
05:30 PM - 05:45 PM
Presenter

Abstract

Aims

To identify the functional role of PD genome-wide association study (GWAS) top hit locus near GALC, encoding the lysosomal enzyme galactosylcerebrosidase(GALC).

Methods

GALC activity was measured in two cohorts, from Columbia University (N=1229) and PPMI (N=470). GALC activity measurements were performed at Sanofi laboratories by liquid chromatography-tandem/mass-spectrometry from dried blood spots. Using genotyping data from the Columbia University cohort (Illumina-OmniExpress array/NeuroX) and the PPMI cohort (NeuroX/Immunochip), we performed a GWAS to examine the effect of genetic variants on GALC activity. We further performed full sequencing of GALC in three independent cohorts at McGill University (PD,N=2421; controls,N=1625) to study the effects of rare variants. We performed Mendelian randomization to study the potential causal relationship between GALC activity and PD risk. Finally, we examined the effects of GALC variants on GALC structure in silico.

Results

The known PD risk variant rs979812 near GALC is associated with increased GALC activity (b=1.2; SE=0.06; p=5.10E-95). We did not find any variant significantly associated with GALC activity outside the GALC locus. Mendelian randomization suggested that increased GALC activity may be causal in PD (IVW; b=0.025; se=0.007; p=0.0008). Burden analyses did not identify an association of rare GALC variants in PD. Finally, structural analysis demonstrated that the common variant p.I562T can lead to improper maturation of GALC affecting its activity.

Conclusions

The risk of PD associated with the GALC locus is potentially driven by increased GALC activity. Furthermore, GALC activity may be causal in PD, and should therefore be studied as a potential therapeutic target.

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