Plasticity-related gene 3 (LPPR1) and age at diagnosis of Parkinson disease

Zachary D Wallen; Honglei Chen; Erin M Hill-Burns; Stewart A Factor; Cyrus P Zabetian; Haydeh Payami

doi:10.1212/NXG.0000000000000271

Plasticity-related gene 3 (LPPR1) and age at diagnosis of Parkinson disease

Neurol Genet. 2018 Oct 5;4(5):e271. doi: 10.1212/NXG.0000000000000271. eCollection 2018 Oct.

Authors

Zachary D Wallen¹, Honglei Chen¹, Erin M Hill-Burns¹, Stewart A Factor¹, Cyrus P Zabetian¹, Haydeh Payami¹

Affiliation

¹ Department of Neurology (Z.D.W., E.M.H.-B., H.P.), University of Alabama at Birmingham, Birmingham, AL; Department of Epidemiology and Biostatistics (H.C.), Michigan State University, East Lansing, MI; Department of Neurology (S.A.F.), Jean & Paul Amos Parkinson's Disease and Movement Disorder Program, Emory University School of Medicine, Atlanta, GA; VA Puget Sound Health Care System and Department of Neurology (C.P.Z.), University of Washington, Seattle, WA; and Center for Genomic Medicine (H.P.), HudsonAlpha Institute for Biotechnology, Huntsville, AL.

Abstract

Objective: To identify modifiers of age at diagnosis of Parkinson disease (PD).

Methods: Genome-wide association study (GWAS) included 1,950 individuals with PD from the NeuroGenetics Research Consortium (NGRC) study. Replication was conducted in the Parkinson's, Genes and Environment study, including 209 prevalent (PAGE_P) and 517 incident (PAGE_I) PD cases. Cox regression was used to test association with age at diagnosis. Individuals without neurologic disease were used to rule out confounding. Gene-level analysis and functional annotation were conducted using Functional Mapping and Annotation of GWAS platform (FUMA).

Results: The GWAS revealed 2 linked but seemingly independent association signals that mapped to LPPR1 on chromosome 9. LPPR1 was significant in gene-based analysis (p = 1E-8). The top signal (rs17763929, hazard ratio [HR] = 1.88, p = 5E-8) replicated in PAGE_P (HR = 1.87, p = 0.01) but not in PAGE_I. The second signal (rs73656147) was robust with no evidence of heterogeneity (HR = 1.95, p = 3E-6 in NGRC; HR = 2.14, p = 1E-3 in PAGE_P + PAGE_I, and HR = 2.00, p = 9E-9 in meta-analysis of NGRC + PAGE_P + PAGE_I). The associations were with age at diagnosis, not confounded by age in patients or in the general population. The PD-associated regions included variants with Combined Annotation Dependent Depletion (CADD) scores = 10-19 (top 1%-10% most deleterious mutations in the genome), a missense with predicted destabilizing effect on LPPR1, an expression quantitative trait locus (eQTL) for GRIN3A (false discovery rate [FDR] = 4E-4), and variants that overlap with enhancers in LPPR1 and interact with promoters of LPPR1 and 9 other brain-expressed genes (Hi-C FDR < 1E-6).

Conclusions: Through association with age at diagnosis, we uncovered LPPR1 as a modifier gene for PD. LPPR1 expression promotes neuronal regeneration after injury in animal models. Present data provide a strong foundation for mechanistic studies to test LPPR1 as a driver of response to damage and a therapeutic target for enhancing neuroregeneration and slowing disease progression.

Grants and funding

I01 BX000531/BX/BLRD VA/United States