Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study

doi:10.1016/j.neurobiolaging.2016.09.022

Neurobiology of Aging

Volume 49, January 2017, Pages 217.e1-217.e4

https://doi.org/10.1016/j.neurobiolaging.2016.09.022 Get rights and content

Abstract

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted.

Introduction

Genetic discoveries made over the years either by using linkage, array, and/or exome-based approaches have helped in advancing our knowledge of the genetic underpinnings of Parkinson's disease (PD) (International Parkinson Disease Genomics Consortium et al., 2011, Lesage and Brice, 2009, Trinh and Farrer, 2013). As we discover new loci relevant to idiopathic PD pathogenesis, it has become imperative to also understand the gene–gene interaction effect in modulating PD risk in population (see Supplementary Information) (Elbaz et al., 2011). Although the results of most gene–gene interactions studies in PD to date have pointed toward independent effects for PD susceptibility variants, an exception to this has been an assessment of functional-genetic interaction between the LRRK2 and PARK16 loci in which overexpression of RAB7L1, a candidate gene for PARK16 locus, reversed the effects of the LRRK2 mutation and rescued the phenotypes (MacLeod et al., 2013). Therefore, this study aims to evaluate the interaction between several different LRRK2 and PARK16 variants in determining PD risk using a Caucasian series with more than 10,000 subjects from 14 different centers, and an Asian series with more than 5000 subjects from 5 different centers.

Section snippets

Methods

The Genetic Epidemiology of Parkinson's Disease (GEoPD) consortium includes investigators from 59 sites, across 30 countries and 6 continents, as of 2016. A total of 19 sites representing 17 countries and 4 continents agreed to contribute DNA samples and clinical data for the present study. In total, 15,976 subjects were included in this study, divided into a Caucasian series (5769 PD patients, 4988 controls) and an Asian series (1946 PD patients, 3273 controls). We selected 5 SNPs for the

Results

Of the 10 interactions that were examined between the PARK16 and LRRK2 variants, nonsignificant evidence of gene–gene interaction was observed between LRRK2 rs1491942 and PARK16 rs11240572 in the combined series (interaction OR: 0.97, 95% CI: 0.74–1.01, p = 0.07, Supplementary Table 1). PARK16 rs11240572 appeared to have no effect on PD risk for individuals with the common GG genotype for LRRK2 rs1491942, but a slight protective effect for those with GC and CC LRRK2 rs1491942 genotypes (see

Discussion

The identification of genetic mutations in genes linked to familial forms of PD (e.g., LRRK2, VPS35, and DNAJC13), and genetic variability within the PARK16 locus in genome wide association studies strongly implicates the role of retromer and lysosomal pathway in PD pathogenesis (Heckman et al., 2014, Soto-Ortolaza et al., 2013). Therefore, to understand the impact of interaction in world-wide populations, we performed a large multicenter study to assess the genetic evidence of interaction

Disclosure statement

The institution of L. Wang and M. Sharma is financially supported by the Courage-PD, an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND-www.jpnd.eu: the Medical Research Council, United Kingdom, the French National Research Agency, the German Bundesministerium für Bildung und Forschung, the Italian Ministry of Health/Ministry of Education, the Israeli Ministry of Health, the

Acknowledgements

The Mayo Clinic Jacksonville is a Morris K. Udall Center of Excellence in Parkinson's Disease Research (grant number P50 NS072187) and was supported by the gift from the family of Carl Edward Bolch, Jr., and Susan Bass Bolch (RJU, ZKW, OAR). Owen A. Ross, PhD, acknowledges funding support from the National Institutes of Health (grant number R01 NS78086). M. J. Farrer reports grants from the Canadian Federal Government, Cunhill Foundation, BC Leading Edge Endowment, during the conduct of the

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There are more references available in the full text version of this article.

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LRRK2: Genetic mechanisms vs genetic subtypes
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In 2004, the identification of pathogenic variants in the LRRK2 gene across several families with autosomal dominant late-onset Parkinson's disease (PD) revolutionized our understanding of the role of genetics in PD. Previous beliefs that genetics in PD was limited to rare early-onset or familial forms of the disease were quickly dispelled. Currently, we recognize LRRK2 p.G2019S as the most common genetic cause of both sporadic and familial PD, with more than 100,000 affected carriers across the globe. The frequency of LRRK2 p.G2019S is also highly variable across populations, with some regions of Asian or Latin America reporting close to 0%, contrasting to Ashkenazi Jews or North African Berbers reporting up to 13% and 40%, respectively. Patients with LRRK2 pathogenic variants are clinically and pathologically heterogeneous, highlighting the age-related variable penetrance that also characterizes LRRK2-related disease. Indeed, the majority of patients with LRRK2-related disease are characterized by a relatively mild Parkinsonism with less motor symptoms with variable presence of α-synuclein and/or tau aggregates, with pathologic pleomorphism widely described. At a functional cellular level, it is likely that pathogenic variants mediate a toxic gain-of-function of the LRRK2 protein resulting in increased kinase activity perhaps in a cell-specific manner; by contrast, some LRRK2 variants appear to be protective reducing PD risk by decreasing the kinase activity. Therefore, employing this information to define appropriate patient populations for clinical trials of targeted kinase LRRK2 inhibition strategies is very promising and demonstrates a potential future application for PD using precision medicine
What have we learned from genome-wide association studies (GWAS) in Parkinson's disease?
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Citation Excerpt :
Recognising this unmet need to diversify genomic research in PD, large multi-national consortia have recently initiated an effort to catalogue genomic diversity (International Parkinson Disease Genomics Consortium (IPDGC), 2020). These include the LARGE-PD consortium (Latin American Research Consortium on the Genetics of Parkinson’s Disease), (Zabetian and Mata, 2017) the Luxembourg-German-Indian Alliance on Neurodegenerative diseases (Lux-GIANT)106, or recent efforts in Southeast Asia, (Foo et al., 2017) China, and Africa spearheaded by the International Parkinson Disease Genomics Consortium98 (IPDGC) and the Genetic Epidemiology of Parkinson disease (GEoPD) consortium (Wang et al., 2017). Such initiatives are making significant progress in integrating ethnic diversity in PD GWAS.
After fifteen years of genome-wide association studies (GWAS) in Parkinson's disease (PD), what have we learned? Addressing this question will help catalogue the progress made towards elucidating disease mechanisms, improving the clinical utility of the identified loci, and envisioning how we can harness the strides to develop translational GWAS strategies. Here we review the advances of PD GWAS made to date while critically addressing the challenges and opportunities for next-generation GWAS. Thus, deciphering the missing heritability in underrepresented populations is currently at the reach of hand for a truly comprehensive understanding of the genetics of PD across the different ethnicities. Moreover, state-of-the-art GWAS designs hold a true potential for enhancing the clinical applicability of genetic findings, for instance, by improving disease prediction (PD risk and progression). Lastly, advanced PD GWAS findings, alone or in combination with clinical and environmental parameters, are expected to have the capacity for defining patient enriched cohorts stratified by genetic risk profiles and readily available for neuroprotective clinical trials. Overall, envisioning future strategies for advanced GWAS is currently timely and can be instrumental in providing novel genetic readouts essential for a true clinical translatability of PD genetic findings.
Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease
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Editorial: Celebrating the Diversity of Genetic Research to Dissect the Pathogenesis of Parkinson's Disease
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Genetic and environmental factors influence the pleomorphy of lrrk2 parkinsonism
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Selective LRRK2 kinase inhibition reduces phosphorylation of endogenous Rab10 and Rab12 in human peripheral mononuclear blood cells
2017, Scientific Reports

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Neurobiology of Aging

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Disclosure statement

Acknowledgements

References (8)

Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

Neurobiol. Aging

RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk

Neuron

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

Proc. Natl. Acad. Sci. U. S. A.

Independent and joint effects of the MAPT and SNCA genes in Parkinson disease

Ann. Neurol.

Cited by (6)

LRRK2: Genetic mechanisms vs genetic subtypes

What have we learned from genome-wide association studies (GWAS) in Parkinson's disease?

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Editorial: Celebrating the Diversity of Genetic Research to Dissect the Pathogenesis of Parkinson's Disease

Genetic and environmental factors influence the pleomorphy of lrrk2 parkinsonism

Selective LRRK2 kinase inhibition reduces phosphorylation of endogenous Rab10 and Rab12 in human peripheral mononuclear blood cells

Genetic report abstractNegative resultsEvaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Disclosure statement

Acknowledgements

Neurobiol. Aging

Neuron

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

Proc. Natl. Acad. Sci. U. S. A.

Independent and joint effects of the MAPT and SNCA genes in Parkinson disease

Ann. Neurol.

Genetic report abstract
Negative results
Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study