Nature Genetics. 2021, May 6.
Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease
Ganqiang Liu, Jiajie Peng, Zhixiang Liao, Joseph J. Locascio, Jean-Christophe Corvol, Frank Zhu, Xianjun Dong, Jodi Maple-Grødem, Meghan C. Campbell, Alexis Elbaz, Suzanne Lesage, Alexis Brice, Graziella Mangone, John H. Growdon, Albert Y. Hung, Michael A. Schwarzschild, Michael T. Hayes, Anne-Marie Wills, Todd M. Herrington, Bernard Ravina, Ira Shoulson, Pille Taba, Sulev Kõks, Thomas G. Beach, Florence Cormier-Dequaire, Guido Alves, Ole-Bjørn Tysnes, Joel S. Perlmutter, Peter Heutink, Sami S. Amr, Jacobus J. van Hilten, Meike Kasten, Brit Mollenhauer, Claudia Trenkwalder, Christine Klein, Roger A. Barker, Caroline H. Williams-Gray, Johan Marinus, International Genetics of Parkinson Disease Progression (IGPP) Consortium & Clemens R. ScherzerRead more
A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10−11), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10−8) and WWOX (HR = 2.12, P = 2.37 × 10−8) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.
Neurology. 2020 Aug 11, e685-e696.
β-Glucocerebrosidase activity in GBA-linked Parkinson disease: The type of mutation matters
Young Eun Huh, Ming Sum Ruby Chiang, Joseph J Locascio, Zhixiang Liao, Ganqiang Liu, Karbi Choudhury, Yuliya I Kuras, Idil Tuncali, Aleksandar Videnovic, Ann L Hunt, Michael A Schwarzschild, Albert Y Hung, Todd M Herrington, Michael T Hayes, Bradley T Hyman, Anne-Marie Wills, Stephen N Gomperts, John H Growdon, Sergio Pablo Sardi, Clemens R ScherzerRead more
OBJECTIVE: To test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and β-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies.
METHODS: A total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson’s Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1-2 years).
RESULTS: β-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual β-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/L/h (95% confidence interval, -1.17, -0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in β-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02).
CONCLUSIONS: Residual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.
Lancet Neurology, 2017; 16: 620-629.
Prediction of cognition in Parkinson’s disease with a clinical–genetic score: a longitudinal analysis of nine cohorts
Ganqiang Liu, Joseph J Locascio, Jean-Christophe Corvol, Brendon Boot, Zhixiang Liao, Kara Page, Daly Franco, Kyle Burke, Iris E Jansen, Ana Trisini-Lipsanopoulos, Sophie Winder-Rhodes, Caroline M Tanner, Anthony E Lang, Shirley Eberly, Alexis Elbaz, Alexis Brice, Graziella Mangone, Bernard Ravina, Ira Shoulson, Florence Cormier-Dequaire, Peter Heutink, Jacobus J van Hilten, Roger A Barker, Caroline H Williams-Gray, Johan Marinus, Clemens R Scherzer
BACKGROUND Cognitive decline is a debilitating manifestation of disease progression in Parkinson’s disease. We aimed to develop a clinical–genetic score to predict global cognitive impairment in patients with the disease.
METHODS In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson’s disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox’s proportional hazards analysis using the Akaike’s information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population.
FINDINGS 3200 patients with Parkinson’s disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6–4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β–glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1–7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82–0·90) and replication (95% CI 0·78–0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4–36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79–0·94) and a negative predictive value of 0·92 (95% 0·88–0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets.
INTERPRETATION Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson’s disease. This model could improve trials of cognitive interventions and inform on prognosis.
FUNDING National Institutes of Health, US Department of Defense.
Annals of Neurology, 2016; 80: 674-685.
Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s.
Liu G, Boot B, Locascio JJ, Jansen IE, Winder-Rhodes S, Eberly S, Elbaz A, Brice A, Ravina B, van Hilten JJ, Cormier-Dequaire F, Corvol JC, Barker RA, Heutink P, Marinus J, Williams-Gray CH, Scherzer CR; International Genetics of Parkinson Disease Progression (IGPP) Consortium.
OBJECTIVE: We 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.
METHODS: A 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.
RESULTS: Overall, 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.
Mutations 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.
©2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
Brain, 2015; 138: 2659–2671.
Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson’s disease.
Locascio JJ, Eberly S, Liao Z, Liu G, Hoesing AN, Duong K, Trisini-Lipsanopoulos A, Dhima K, Hung AY, Flaherty AW, Schwarzschild MA, Hayes MT, Wills AM, Shivraj Sohur U, Mejia NI, Selkoe DJ, Oakes D, Shoulson I, Dong X, Marek K, Zheng B, Ivinson A, Hyman BT, Growdon JH, Sudarsky LR, Schlossmacher MG, Ravina B, Scherzer CR.
There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson’s disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson’s disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: firstname.lastname@example.org.[/expand] [/av_textblock] [/av_three_fifth] [av_hr class='custom' height='50' shadow='no-shadow' position='center' custom_border='av-border-thin' custom_width='100%' custom_border_color='#e0e0e0' custom_margin_top='5px' custom_margin_bottom='5px' icon_select='no' custom_icon_color='' icon='ue808' font='entypo-fontello' av_uid='av-6pu4w' admin_preview_bg=''] [av_two_fifth first min_height='' vertical_alignment='' space='' custom_margin='' margin='0px' row_boxshadow='' row_boxshadow_color='' row_boxshadow_width='10' link='' linktarget='' link_hover='' padding='0px' highlight='' highlight_size='' border='' border_color='' radius='0px' column_boxshadow='' column_boxshadow_color='' column_boxshadow_width='10' background='bg_color' background_color='' background_gradient_color1='' background_gradient_color2='' background_gradient_direction='vertical' src='' background_position='top left' background_repeat='no-repeat' animation='' mobile_breaking='' mobile_display='' av_uid='av-lf79qo'] [av_hr class='invisible' height='10' shadow='no-shadow' position='center' custom_border='av-border-thin' custom_width='50px' custom_border_color='' custom_margin_top='30px' custom_margin_bottom='30px' icon_select='yes' custom_icon_color='' icon='ue808' font='entypo-fontello' av_uid='av-k76cg4hc' admin_preview_bg=''] [av_image src='https://www.bwhparkinsoncenter.org/wp-content/uploads/2020/02/Santiago.png' attachment='3171' attachment_size='full' align='center' styling='' hover='' link='' target='' caption='' font_size='' appearance='' overlay_opacity='0.4' overlay_color='#000000' overlay_text_color='#ffffff' copyright='' animation='no-animation' av_uid='av-k6v3awxg' admin_preview_bg=''][/av_image] [/av_two_fifth] [av_three_fifth min_height='' vertical_alignment='' space='' custom_margin='' margin='0px' row_boxshadow='' row_boxshadow_color='' row_boxshadow_width='10' link='' linktarget='' link_hover='' padding='0px' highlight='' highlight_size='' border='' border_color='' radius='0px' column_boxshadow='' column_boxshadow_color='' column_boxshadow_width='10' background='bg_color' background_color='' background_gradient_color1='' background_gradient_color2='' background_gradient_direction='vertical' src='' background_position='top left' background_repeat='no-repeat' animation='' mobile_breaking='' mobile_display='' av_uid='av-9hcqeo'] [av_textblock size='' font_color='' color='' av-medium-font-size='' av-small-font-size='' av-mini-font-size='' av_uid='av-k6v3553l' admin_preview_bg=''] Proceedings of the National Academy of Sciences of the United States of America, 2015; 112: 2257–2262.
Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease
Jose A. Santiago and Judith A. Potashkin
Cellular and Molecular Pharmacology Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
Environmental and genetic factors are likely to be involved in the pathogenesis of Parkinson’s disease (PD), the second most prevalent neurodegenerative disease among the elderly. Network-based metaanalysis of four independent microarray studies identified the hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most down-regulated gene. Quantitative PCR assays revealed that HNF4A and PTBP1 mRNAs were up- and down-regulated, respectively, in blood of 51 PD patients and 45 controls nested in the Diagnostic and Prognostic Biomarkers for Parkinson’s Disease. These results were confirmed in blood of 50 PD patients compared with 46 healthy controls nested in the Harvard Biomarker Study. Relative abundance of HNF4A mRNA correlated with the Hoehn and Yahr stage at baseline, suggesting its clinical utility to monitor disease severity. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y follow-up period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD.
Neurology, 2013; 81: 1531-1537.
Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker Study.
Ding H, Dhima K, Lockhart KC, Locascio JJ, Hoesing AN, Duong K, Trisini-Lipsanopoulos A, Hayes MT, Sohur US, Wills AM, Mollenhauer B, Flaherty AW, Hung AY, Mejia N, Khurana V, Gomperts SN, Selkoe DJ, Schwarzschild MA, Schlossmacher MG, Hyman BT, Sudarsky LR, Growdon JH, Scherzer CR.
From the Neurogenomics Laboratory (H.D., K.D., K.C.L., A.N.H., K.D., A.T.-L., C.R.S.), Harvard Medical School and Brigham & Women’s Hospital, Cambridge; Biomarkers Program (K.D., K.C.L., A.N.H., K.D., A.T.-L., M.T.H., U.S.S., B.M., N.M., V.K., S.N.G., D.J.S., M.A.S., M.G.S., B.T.H., J.H.G., C.R.S.), Harvard NeuroDiscovery Center, Boston; Department of Neurology (J.J.L., U.S.S., A.-M.W., A.W.F., A.Y.H., N.M., V.K., S.N.G., M.A.S., B.T.H., J.H.G., C.R.S.), Massachusetts General Hospital, Boston; Department of Neurology (M.T.H., A.Y.H., D.J.S., L.R.S., C.R.S.), Brigham and Women’s Hospital, Boston, MA; Paracelsus-Elena-Klinik (B.M.), Kassel, Germany; and Division of Neurology, the Ottawa Hospital, University of Ottawa (M.G.S.), Canada.
OBJECTIVE: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD).
METHODS: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study.
RESULTS: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson’s Disease Rating Scale scores at baseline and during follow-up.
CONCLUSIONS: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D-deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.
Cerebrospinal fluid proteomics implicates the granin family in Parkinson’s disease
Melissa S. Rotunno, Monica Lane, Wenfei Zhang, Pavlina Wolf, Petra Oliva, Catherine Viel, Anne-Marie Wills, Roy N. Alcalay, Clemens R. Scherzer, Lamya S. Shihabuddin, Kate Zhang, & S. Pablo SardiRead more
Parkinson’s disease, the most common age-related movement disorder, is a progressive
neurodegenerative disease with unclear etiology. Better understanding of the underlying disease
mechanism(s) is an urgent need for the development of disease-modifying therapeutics. Limited
studies have been performed in large patient cohorts to identify protein alterations in cerebrospinal
fluid (CSF), a proximal site to pathology. We set out to identify disease-relevant protein changes in
CSF to gain insights into the etiology of Parkinson’s disease and potentially assist in disease biomarker
identification. In this study, we used liquid chromatography-tandem mass spectrometry in dataindependent
acquisition (DIA) mode to identify Parkinson’s-relevant biomarkers in cerebrospinal
fluid. We quantified 341 protein groups in two independent cohorts (n = 196) and a longitudinal cohort
(n = 105 samples, representing 40 patients) consisting of Parkinson’s disease and healthy control
samples from three different sources. A first cohort of 53 Parkinson’s disease and 72 control samples
was analyzed, identifying 53 proteins with significant changes (p < 0.05) in Parkinson’s disease relative to healthy control. We established a biomarker signature and multiple protein ratios that differentiate Parkinson’s disease from healthy controls and validated these results in an independent cohort. The second cohort included 28 Parkinson’s disease and 43 control samples. Independent analysis of these samples identified 41 proteins with significant changes. Evaluation of the overlapping changes between the two cohorts identified 13 proteins with consistent and significant changes (p < 0.05). Importantly, we found the extended granin family proteins as reduced in disease, suggesting a potential common mechanism for the biological reduction in monoamine neurotransmission in Parkinson’s patients. Our study identifies several novel protein changes in Parkinson’s disease cerebrospinal fluid that may be exploited for understanding etiology of disease and for biomarker development. [/expand] [/av_textblock] [/av_three_fifth]