TY  - CONF
AU  - Garai, Nemanja
AU  - Petrović, Kristina
AU  - Karanović, Jelena
AU  - Dejanović, Ivana
AU  - Perić, Stojan
AU  - Basta, Ivana
AU  - Jovanović, Vladimir
AU  - Savić-Pavićević, Dušanka
PY  - 2023
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2196
AB  - Introduction: Genome-wide association studies (GWAS) identify genomic loci that contain genetic determinants
of complex diseases. Subsequent functional genomic approaches, such as bioinformatic finemapping
and transcriptome-wide association studies (TWAS), can reveal potentially causal single
nucleotide variants (SNVs) that can be tested on patient samples. We applied this approach to study
causal SNVs for acetylcholine receptor (AChR) seropositive myasthenia gravis (MG). We focused on
CHRNA1 and CHRNB1 loci, coding AChR subunits, and CTLA-4 locus, coding protein transmitting an inhibitory
signal to T cells.
Methods: CHRNA1 was fine-mapped by PAINTOR using data from GWAS summary statistics, 1000
genome and RegulomeDB. Alongside, rs4151121 identified by TWAS in CHRNB1, and rs231735 and
rs231770 identified by fine-mapping in CTLA-4 were studied. SNVs were genotyped using allele discrimination
assays in 447 Serbian AChR-MG patients (183 early-onset and 264 late-onset) and 447 sex- and
age-matched controls.
Results: CHRNA1 rs35274388 was fine-mapped as a potentially causal variant (PIP2=92%) exhibiting
transcription factor binding and chromatin accessibility peaks. CHRNA1 rs35274388 minor allele A and
CHRNAB1 rs4151121 minor allele G increased the risk for late-onset MG (OR=1.669, 95% CI=1.05-2.638,
p=0.027, p10e6 permutation=0.031 and OR=1.322, 95% CI=1.063-1.644, p10e6 permutation=0.014, respectively).
On the other hand, CTLA-4 rs231735 recessive genotype TT decreased, while rs231735-
rs231770 haplotype GC increased the susceptibility to early-onset MG (OR=0.548, 95% CI=0.339-0.888,
p=0.014, p10e6 permutation=0.014 and OR=1.360, p=0.027, p10e6 permutation=0.027, respectively).
Conclusion: CHRNA1 rs35274388 and CHRNAB1 rs4151121 loci could be causal genetic factors for lateonset
MG while CTLA-4 rs231735 and rs231770 could be causal genetic factors for early-onset MG in Serbian
population.
PB  - Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade
C3  - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
T1  - Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study
EP  - 39
SP  - 39
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2196
ER  - 

@conference{
author = "Garai, Nemanja and Petrović, Kristina and Karanović, Jelena and Dejanović, Ivana and Perić, Stojan and Basta, Ivana and Jovanović, Vladimir and Savić-Pavićević, Dušanka",
year = "2023",
abstract = "Introduction: Genome-wide association studies (GWAS) identify genomic loci that contain genetic determinants
of complex diseases. Subsequent functional genomic approaches, such as bioinformatic finemapping
and transcriptome-wide association studies (TWAS), can reveal potentially causal single
nucleotide variants (SNVs) that can be tested on patient samples. We applied this approach to study
causal SNVs for acetylcholine receptor (AChR) seropositive myasthenia gravis (MG). We focused on
CHRNA1 and CHRNB1 loci, coding AChR subunits, and CTLA-4 locus, coding protein transmitting an inhibitory
signal to T cells.
Methods: CHRNA1 was fine-mapped by PAINTOR using data from GWAS summary statistics, 1000
genome and RegulomeDB. Alongside, rs4151121 identified by TWAS in CHRNB1, and rs231735 and
rs231770 identified by fine-mapping in CTLA-4 were studied. SNVs were genotyped using allele discrimination
assays in 447 Serbian AChR-MG patients (183 early-onset and 264 late-onset) and 447 sex- and
age-matched controls.
Results: CHRNA1 rs35274388 was fine-mapped as a potentially causal variant (PIP2=92%) exhibiting
transcription factor binding and chromatin accessibility peaks. CHRNA1 rs35274388 minor allele A and
CHRNAB1 rs4151121 minor allele G increased the risk for late-onset MG (OR=1.669, 95% CI=1.05-2.638,
p=0.027, p10e6 permutation=0.031 and OR=1.322, 95% CI=1.063-1.644, p10e6 permutation=0.014, respectively).
On the other hand, CTLA-4 rs231735 recessive genotype TT decreased, while rs231735-
rs231770 haplotype GC increased the susceptibility to early-onset MG (OR=0.548, 95% CI=0.339-0.888,
p=0.014, p10e6 permutation=0.014 and OR=1.360, p=0.027, p10e6 permutation=0.027, respectively).
Conclusion: CHRNA1 rs35274388 and CHRNAB1 rs4151121 loci could be causal genetic factors for lateonset
MG while CTLA-4 rs231735 and rs231770 could be causal genetic factors for early-onset MG in Serbian
population.",
publisher = "Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade",
journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia",
title = "Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study",
pages = "39-39",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2196"
}

Garai, N., Petrović, K., Karanović, J., Dejanović, I., Perić, S., Basta, I., Jovanović, V.,& Savić-Pavićević, D.. (2023). Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia
Institute of Molecular Genetics and Genetic Engineering (IMGGE), University of Belgrade., 39-39.
https://hdl.handle.net/21.15107/rcub_imagine_2196

Garai N, Petrović K, Karanović J, Dejanović I, Perić S, Basta I, Jovanović V, Savić-Pavićević D. Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia. 2023;:39-39.
https://hdl.handle.net/21.15107/rcub_imagine_2196 .

Garai, Nemanja, Petrović, Kristina, Karanović, Jelena, Dejanović, Ivana, Perić, Stojan, Basta, Ivana, Jovanović, Vladimir, Savić-Pavićević, Dušanka, "Identification of potentally causal variants for myasthenia gravis: a bioinformatics-driven fine-mapping approach combined with genetic association study" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia, Abstract Book – Trends in Molecular Biology, Special issue 06-08 October 2023, Belgrade, Serbia (2023):39-39,
https://hdl.handle.net/21.15107/rcub_imagine_2196 .