TY - JOUR
T1 - Genome-wide case-only analysis of gene-gene interactions with known Parkinson's disease risk variants reveals link between LRRK2 and SYT10
AU - International Parkinson Disease Genomics Consortium
AU - Aleknonytė-Resch, Milda
AU - Trinh, Joanne
AU - Leonard, Hampton
AU - Delcambre, Sylvie
AU - Leitão, Elsa
AU - Lai, Dongbing
AU - Smajić, Semra
AU - Orr-Urtreger, Avi
AU - Thaler, Avner
AU - Blauwendraat, Cornelis
AU - Sharma, Arunabh
AU - Makarious, Mary B
AU - Kim, Jonggeol Jeff
AU - Lake, Julie
AU - Rahmati, Pegah
AU - Freitag-Wolf, Sandra
AU - Seibler, Philip
AU - Foroud, Tatiana
AU - Singleton, Andrew B
AU - Grünewald, Anne
AU - Kaiser, Frank
AU - Klein, Christine
AU - Krawczak, Michael
AU - Dempfle, Astrid
N1 - © 2023. The Author(s).
PY - 2023/6/29
Y1 - 2023/6/29
N2 - The effects of one genetic factor upon Parkinson's disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the 'missing heritability' of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson's Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p-value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65-1.95, p = 2.7 × 10-43). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2, its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.
AB - The effects of one genetic factor upon Parkinson's disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the 'missing heritability' of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson's Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p-value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65-1.95, p = 2.7 × 10-43). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2, its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.
U2 - 10.1038/s41531-023-00550-9
DO - 10.1038/s41531-023-00550-9
M3 - Journal articles
C2 - 37386035
SN - 2373-8057
VL - 9
SP - 102
JO - NPJ Parkinson's disease
JF - NPJ Parkinson's disease
IS - 1
ER -