Genome-wide case-only analysis of gene-gene interactions with known Parkinson's disease risk variants reveals link between LRRK2 and SYT10

Milda Aleknonytė-Resch; Joanne Trinh; Hampton Leonard; Sylvie Delcambre; Elsa Leitão; Dongbing Lai; Semra Smajić; Avi Orr-Urtreger; Avner Thaler; Cornelis Blauwendraat; Arunabh Sharma; Mary B Makarious; Jonggeol Jeff Kim; Julie Lake; Pegah Rahmati; Sandra Freitag-Wolf; Philip Seibler; Tatiana Foroud; Andrew B Singleton; International Parkinson Disease Genomics Consortium; Anne Grünewald; Frank Kaiser; Christine Klein; Michael Krawczak; Astrid Dempfle

doi:10.1038/s41531-023-00550-9

Genome-wide case-only analysis of gene-gene interactions with known Parkinson's disease risk variants reveals link between LRRK2 and SYT10

NPJ Parkinsons Dis. 2023 Jun 29;9(1):102. doi: 10.1038/s41531-023-00550-9.

Authors

Milda Aleknonytė-Resch^{1

2}, Joanne Trinh³, Hampton Leonard^{4

5

6}, Sylvie Delcambre⁷, Elsa Leitão⁸, Dongbing Lai⁹, Semra Smajić⁷, Avi Orr-Urtreger¹⁰, Avner Thaler¹⁰, Cornelis Blauwendraat^{4

6}, Arunabh Sharma¹, Mary B Makarious^{4

11

12}, Jonggeol Jeff Kim⁴, Julie Lake⁴, Pegah Rahmati¹, Sandra Freitag-Wolf¹, Philip Seibler³, Tatiana Foroud⁹, Andrew B Singleton^{4

6}; International Parkinson Disease Genomics Consortium; Anne Grünewald^{3

7}, Frank Kaiser⁸, Christine Klein³, Michael Krawczak^#¹, Astrid Dempfle^#¹³

Affiliations

¹ Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany.
² Department of Computer Science, Kiel University, Kiel, Germany.
³ Institute of Neurogenetics, University of Lübeck, University Medical Center Schleswig-Holstein, Campus Lübeck, Germany.
⁴ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
⁵ Data Tecnica International LLC, Glen Echo, MD, USA.
⁶ Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD, USA.
⁷ Molecular and Functional Neurobiology Group, Luxembourg Centre for Systems Biomedicine, Esch-sur-Alzette, Luxembourg.
⁸ Institute of Human Genetics, University Hospital Essen, Essen, Germany.
⁹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰ Neurological Institute, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
¹¹ Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK.
¹² UCL Movement Disorders Centre, University College London, London, UK.
¹³ Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany. dempfle@medinfo.uni-kiel.de.

^# Contributed equally.

Abstract

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.

Abstract

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