Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Nalls, Mike A.; Pankratz, Nathan; Lill, Christina M.; Chuong, B.; Hernandez, Dena G.; Saad, Mohamad; DeStefano, Anita L.; Kara, Eleanna; Brás, José; Sharma, Manu; Schulte, Claudia; Keller, Margaux F.; Arepalli, Sampath; Letson, Christopher T.; Edsall, Connor; Stefánsson, Hreinn; Liu, Xinmin; Pliner, Hannah A.; Lee, Joseph H.; Cheng, Rong; Ikram, M. Arfan; Ioannidis, John P. A.; Hadjigeorgiou, Georgios M.; Bis, Joshua C.; Martínez, María; Perlmutter, Joel S.; Goate, Alison M.; Marder, Karen; Fiske, Brian; Sutherland, Margaret; Xiromerisiou, Georgia; Myers, Richard H.; Clark, Lorraine N.; Stefánsson, Kāri; Hardy, John; Heutink, Peter; Chen, Honglei; Wood, Nicholas W.; Houlden, Henry; Payami, Haydeh; Brice, Alexis; Scott, William K.; Gasser, Thomas; Bertram, Lars; Eriksson, Nicholas; Foroud, Tatiana; Singleton, Andrew B.

doi:10.1038/ng.3043

Cited by 1,742 publications

(1,904 citation statements)

References 36 publications

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“…In DATATOP, the eligibility criteria required a diagnosis of early, idiopathic PD (Hoen & Yahr [HY] stages 1 or 2) not on antiparkinsonian medications23. Detailed eligibility criteria for the cohorts have been previously reported 10, 13, 14, 16, 22, 23, 24, 25. For all cohorts, diagnostic certainty was increased by confirming the clinical diagnosis of PD during longitudinal follow‐up visits 26.…”

Section: Methodsmentioning

confidence: 99%

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Liu

Boot

Locascio

et al. 2016

Annals of Neurology

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ObjectiveWe hypothesized that specific mutations in the β‐glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non‐neuropathic GD mutations confer intermediate progression rates.MethodsA total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models.ResultsOverall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non‐neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance.InterpretationMutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685

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Section: Methodsmentioning

confidence: 99%

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Liu

Boot

Locascio

et al. 2016

Annals of Neurology

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235

240

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“…We obtained GWAS summary statistics for three neurodegenerative diseases: AD,1 ALS,2 and PD 3. We used MS33 as a positive control, as it is a disease affecting the brain with known immune etiology.…”

Section: Methodsmentioning

confidence: 99%

“…In the latest AD meta‐analysis, 19 loci in addition to the well‐established APOE locus were pinpointed 1. The latest ALS meta‐analysis identified three ALS‐associated loci2 and the latest PD meta‐analysis brought the total number of established PD loci to 26 3. Despite progress in identifying genetic hits in these neurodegenerative diseases, the underlying processes or cell types mediating the pathology remain uncertain.…”

Section: Introductionmentioning

confidence: 99%

“…For AD, Yokoyama et al22 showed that eight variants were associated with both AD and immune‐mediated diseases, and there is further evidence from pathway analysis1, 23, 24 and from animal models 25. For PD, the role of the immune system has been suggested through pathway analyses,26, 27 animal models,28 and variants in the Human Leukocyte Antigen (HLA) region reaching statistical significance in GWASs 3, 29. For ALS, there is evidence of immune abnormalities 30.…”

Section: Introductionmentioning

confidence: 99%

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Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Gagliano

Pouget

Hardy

et al. 2016

Ann Clin Transl Neurol

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ObjectivesWe assessed the current genetic evidence for the involvement of various cell types and tissue types in the etiology of neurodegenerative diseases, especially in relation to the neuroinflammatory hypothesis of neurodegenerative diseases.MethodsWe obtained large‐scale genome‐wide association study (GWAS) summary statistics from Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We used multiple sclerosis (MS), an autoimmune disease of the central nervous system, as a positive control. We applied stratified LD score regression to determine if functional marks for cell type and tissue activity, and gene‐set lists were enriched for genetic heritability. We compared our results to those from two gene‐set enrichment methods (Ingenuity Pathway Analysis and enrichr).ResultsThere were no significant heritability enrichments for annotations marking genes active within brain regions, but there were significant heritability enrichments for annotations marking genes active within cell types that form part of both the innate and adaptive immune systems. We found this for MS (as expected) and also for AD and PD. The strongest signals were from the adaptive immune system (e.g., T cells) for PD, and from both the adaptive (e.g., T cells) and innate (e.g., CD14: a marker for monocytes, and CD15: a marker for neutrophils) immune systems for AD. Annotations from the liver were also significant for AD. Pathway analysis provided complementary results.InterpretationFor AD and PD, we found significant enrichment of heritability in annotations marking gene activity in immune cells.

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“…LRRK2‐PD has an almost indistinguishable clinico‐pathological phenotype from sporadic PD regarding age of onset, the presence of Lewy bodies (although a minority of cases have been reported without Lewy bodies) 5 and responsiveness to dopamine replacement therapy. These observations, paired with the identification of LRRK2 polymorphisms associated with increased lifetime risk for developing sporadic PD 6, suggested that LRRK2 may provide a deep understanding of the molecular mechanisms of PD. The exact physiological role of LRRK2 is still unknown, although it has been implicated in many cellular functions.…”

Section: Introductionmentioning

confidence: 96%

Cellular processes associated with LRRK2 function and dysfunction

Wallings¹,

2015

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Mutations in the leucine‐rich repeat kinase 2 (LRRK2)‐encoding gene are the most common cause of monogenic Parkinson's disease. The identification of LRRK2 polymorphisms associated with increased risk for sporadic Parkinson's disease, as well as the observation that LRRK2‐Parkinson's disease has a pathological phenotype that is almost indistinguishable from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic Parkinson's disease cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with Parkinson's disease reside within the enzymatic core of LRRK2, suggesting that modification of its activity impacts greatly on disease onset and progression. Although progress has been made since its discovery in 2004, there is still much to be understood regarding LRRK2′s physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review discusses the state of current knowledge on the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. In addition, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function are also discussed.

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Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Cited by 1,742 publications

References 36 publications

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Cellular processes associated with LRRK2 function and dysfunction

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