Identification of <i>LRRK2</i> missense variants in the accelerating medicines partnership Parkinson’s disease cohort

Bryant, Nicole; Malpeli, Nicole; Ziaee, Julia; Blauwendraat, Cornelis; Li, Yong; West, Andrew B.

doi:10.1093/hmg/ddab058

Cited by 27 publications

(37 citation statements)

References 47 publications

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“…In a recent analysis of whole‐genome sequencing data from the Accelerating Medicines Partnership‐Parkinson's Disease cohort, Bryant and colleagues found that the 5′ variant rs76904798 was associated with LRRK2 p.R1514Q and p.N2081D 33 . We confirmed the co‐inheritance of these variants with rs76904798 in a data set that is ~20 times larger and also found a significant difference in the allele distribution of p.S1647T after removing rs76904798 carriers.…”

Section: Discussionsupporting

confidence: 74%

Coding and Noncoding Variation in LRRK2 and Parkinson's Disease Risk

et al. 2021

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A BS TRACT: Background: The leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (eg, p.G2019S) and common noncoding variants (eg, rs76904798) with lower effect sizes that are associated with Parkinson's disease (PD) risk.Objectives: This study aimed to investigate in a large metaanalysis whether the LRRK2 Genome-Wide Association Study (GWAS) signal represented by rs76904798 is independently associated with PD risk from LRRK2 coding variation and whether complex linkage disequilibrium structures with p.G2019S and the 5 0 noncoding haplotype account for the association of LRRK2 coding variants. Methods: We performed a meta-analysis using imputed genotypes from 17,838 patients, 13,404 proxy patients, and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798, and p.N2081D.Results: LRRK2 rs76904798 remained significantly associated with PD after excluding the carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p. N2081D were frequently co-inherited with rs76904798, and the allele distribution of p.S1647T significantly changed among patients after removing rs76904798 carriers. Conclusions: These data suggest that the LRRK2 coding variants previously related to PD (p.N551K, p.R1398H, p. M1646T, and p.N2081D) do not drive the 5 0 noncoding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551Kp.R1398H and p.M1646T with altered disease risk.

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Section: Discussionsupporting

confidence: 74%

Coding and Noncoding Variation in LRRK2 and Parkinson's Disease Risk

et al. 2021

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“…All the definite LRRK2 mutations are in the catalytic domains and may result in hyperactivation of the kinase domain [ 3 , 53 ]. LRRK2 is involved in a large array of cell biological processes, and the disease mechanism may reflect important roles in microtubule function and Rab proteins as phosphorylation substrates [ 2 , 54 ].…”

Section: Autosomal Dominant Formsmentioning

confidence: 99%

Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

Jia

Fellner

Kumar

2022

Genes

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Parkinson’s disease may be caused by a single pathogenic variant (monogenic) in 5–10% of cases, but investigation of these disorders provides valuable pathophysiological insights. In this review, we discuss each genetic form with a focus on genotype, phenotype, pathophysiology, and the geographic and ethnic distribution. Well-established Parkinson’s disease genes include autosomal dominant forms (SNCA, LRRK2, and VPS35) and autosomal recessive forms (PRKN, PINK1 and DJ1). Furthermore, mutations in the GBA gene are a key risk factor for Parkinson’s disease, and there have been major developments for X-linked dystonia parkinsonism. Moreover, atypical or complex parkinsonism may be due to mutations in genes such as ATP13A2, DCTN1, DNAJC6, FBXO7, PLA2G6, and SYNJ1. Furthermore, numerous genes have recently been implicated in Parkinson’s disease, such as CHCHD2, LRP10, TMEM230, UQCRC1, and VPS13C. Additionally, we discuss the role of heterozygous mutations in autosomal recessive genes, the effect of having mutations in two Parkinson’s disease genes, the outcome of deep brain stimulation, and the role of genetic testing. We highlight that monogenic Parkinson’s disease is influenced by ethnicity and geographical differences, reinforcing the need for global efforts to pool large numbers of patients and identify novel candidate genes.

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“…In a recent analysis of whole-genome sequencing data from the Accelerating Medicines Partnership-Parkinson's Disease (AMP-PD) cohort, Bryant et al found that the 5' variant rs76904798 was associated with LRRK2 p.R1514Q and p.N2081D 33 . We confirmed the coinheritance of these variants with rs76904798 in a dataset that is ~20 times larger and also found a significant difference in the allele distribution of p.S1647T after removing rs76904798 carriers.…”

Section: Discussionmentioning

confidence: 99%

LRRK2 coding variants and the risk of Parkinson’s disease

Lake

Reed

et al. 2021

Preprint

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BackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (e.g. p.G2019S) and common non-coding variants (e.g. rs76904798) with lower effect sizes that are associated with Parkinson’s disease risk.ObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 GWAS signal represented by rs76904798 is independently associated with Parkinson’s disease risk from LRRK2 coding variation, and whether complex linkage disequilibrium structures with p.G2019S and the 5’ non-coding haplotype account for the association of LRRK2 coding variants.MethodsWe performed a meta-analysis using imputed genotypes from 17,838 cases, 13,404 proxy-cases and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk, and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798 and p.N2081D.ResultsLRRK2 rs76904798 remained significantly associated with Parkinson’s disease after excluding carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798 and the allele distribution of p.S1647T significantly changed among cases after removing rs76904798 carriers.ConclusionsThese data suggest that the LRRK2 coding variants previously linked to Parkinson’s disease (p.N551K, p.R1398H, p.M1646T and p.N2081D) do not drive the 5’ non-coding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk.

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Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson’s disease cohort

Cited by 27 publications

References 47 publications

Coding and Noncoding Variation in LRRK2 and Parkinson's Disease Risk

Coding and Noncoding Variation in LRRK2 and Parkinson's Disease Risk

Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

LRRK2 coding variants and the risk of Parkinson’s disease

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