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Molecular Markers of Early Parkinson's Disease Based on Gene Expression in Blood

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Molecular Markers of Early Parkinson's Disease Based on Gene Expression in Blood Molecular markers of early Parkinson’s disease based on gene expression in blood Clemens R. Scherzer*†‡§, Aron C. Eklund*, Lee J. Morse*, Zhixiang Liao*, Joseph J. Locascio†, Daniel Fefer*, Michael A. Schwarzschild†‡, Michael G. Schlossmacher*‡, Michael A. Hauser¶, Jeffery M. Vance¶, Lewis R. Sudarsky‡, David G. Standaert†‡, John H. Growdon†‡, Roderick V. Jensenʈ, and Steven R. Gullans* *Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Cambridge, MA 02139; †Neurology Service, Massachusetts General Hospital, Boston, MA 02114; ‡Partners Parkinson and Movement Disorders Center, Boston, MA 02114; ¶Center for Human Genetics, Duke University Medical Center, Durham, NC 27710; and ʈDepartment of Physics, University of Massachusetts, Boston, MA 02125 Communicated by Gregory A. Petsko, Brandeis University, Waltham, MA, November 24, 2006 (received for review March 12, 2006) Parkinson’s disease (PD) progresses relentlessly and affects five For a biomarker to be clinically useful, noninvasive detection in million people worldwide. Laboratory tests for PD are critically peripheral blood is desirable. The power of this approach for needed for developing treatments designed to slow or prevent identifying disease-associated candidates in a neurodegenerative progression of the disease. We performed a transcriptome-wide disease is precedented by an expression screen of lymphoblasts scan in 105 individuals to interrogate the molecular processes of patients with Alzheimer’s disease (AD), in which we detected perturbed in cellular blood of patients with early-stage PD. The abnormally low signals of the neuronal sorting receptor LR11/ molecular multigene marker here identified is associated with risk SorLa (20). Subsequent analyses of LR11/SorLa’s mechanistic of PD in 66 samples of the training set comprising healthy and role in AD demonstrated that LR11/sorLA modulates APP disease controls [third tertile cross-validated odds ratio of 5.7 (P for trafficking and its processing to amyloid-␤ (21, 22). trend 0.005)]. It is further validated in 39 independent test samples Here, first, a risk marker for PD was built based on a [third tertile odds ratio of 5.1 (P for trend 0.04)]. Insights into systematic scan of genome-wide expression changes in blood of disease-linked processes detectable in peripheral blood are offered individuals with early PD. Second, this screen identified genes by 22 unique genes differentially expressed in patients with PD differentially transcribed in PD patients versus normal controls. versus healthy individuals. These include the cochaperone ST13, which stabilizes heat-shock protein 70, a modifier of ␣-synuclein Results misfolding and toxicity. ST13 messenger RNA copies are lower in Identification of a Molecular Signature of PD in Blood. To identify a patients with PD (mean ؎ SE 0.59 ؎ 0.05) than in controls (0.96 ؎ transcriptional profile associated with PD we probed RNA in two independent populations. Thus, gene extracted from whole blood of 50 PD patients predominantly at (0.002 ؍ P) (0.09 expression signals measured in blood can facilitate the develop- early disease stages (mean Hoehn and Yahr stage 2.3, range 1–4) ment of biomarkers for PD. [supporting information (SI) Table 2] and 55 age-matched controls with 22,283 oligonucleotide probe sets on microarrays. risk markers ͉ biomarkers ͉ heat shock protein 70-interacting protein The disease controls included patients with AD that may be MEDICAL SCIENCES (ST13) ͉ microarray misclassified as PD (23), as well as with progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration, any fundamental decisions in medical practice are based which closely mimic the clinical features of PD (23) but differ in Mon laboratory risk markers (1). For example, cholesterol etiology, prognosis, and treatment response. We carefully as- levels, although not diagnostic, are a standard biomarker that sayed for shifts in differential blood counts that could bias gene correlate with risk for coronary heart disease and trigger inter- expression changes and found no significant difference between ventions to prevent heart attacks (2). PD and controls (SI Table 2). Parkinson’s disease (PD) is a slowly progressive disease. A subset of the patient samples was randomly chosen to build Tremor and slow movements develop only after Ϸ70% of the risk marker (SI Methods). This ‘‘training set’’ included Ϸ60% vulnerable dopaminergic neurons in the substantia nigra have of the subjects (66/105), including 31 PD patients, 17 healthy already died (3). No laboratory test that correlates with PD risk subjects, and 18 disease controls with AD or progressive su- is available. This curtails our ability to test disease-modifying drugs and other neuroprotective strategies (4). Genes mutated in rare monogenic variants of PD (5) are transcribed in blood Author contributions: C.R.S. designed research; C.R.S., L.J.M., Z.L., D.F., M.A.S., M.G.S., cells (6, 7). In PARK9, a donor splice site mutation in the M.A.H., J.M.V., L.R.S., D.G.S., and J.H.G. performed research; C.R.S., A.C.E., Z.L., J.J.L., and predominantly neuronal gene ATP13A2, leads to skipping of R.V.J. analyzed data; and C.R.S., A.C.E., R.V.J., and S.R.G. wrote the paper. Conflict of interest statement: C.R.S., S.R.G., and R.V.J. are listed as coinventors on a U.S. exon 13 during RNA processing (8). The aberrant mRNA Letters Patent application for identification of dysregulated genes in patients with neu- isoform can be detected in whole blood (8). Furthermore, studies rologic diseases held by Brigham and Women’s Hospital. C.R.S. is a consultant to Link in platelets (9) or lymphocytes (10–13) of patients with sporadic Medicine Corporation. PD have detected subtle abnormalities in dopamine biosynthesis/ Freely available online through the PNAS open access option. signaling and mitochondrial function, two hallmarks of PD. The Abbreviations: PD, Parkinson’s disease; AD, Alzheimer’s disease; C.I., confidence interval; etiology of these changes remains unexplained and might reflect ROC curve, receiver-operating-characteristics curve; FDR, false discovery rate; CT, threshold disease mechanisms, allele-specific gene expression, or reactive cycle. responses (14, 15). Data deposition: The data reported in this paper have been deposited in the Gene Instead of testing one gene at a time, microarrays can inter- Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE6613). rogate in parallel expression levels of thousands of genes in §To whom correspondence should be addressed at: Laboratory for Functional Neurog- enomics, Center for Neurologic Diseases, Harvard Medical School and Brigham and tissues from patients with PD. This allows to rapidly scan for Women’s Hospital, 65 Landsdowne Street, Suite 301A, Cambridge, MA 02139. E-mail: candidate genes and candidate biomarkers (15). In the substantia [email protected]. nigra of individuals affected by PD and in PD models, we (16, This article contains supporting information online at www.pnas.org/cgi/content/full/ 17) and others (18, 19) found profound expression changes of 0610204104/DC1. genes involved in cellular quality control and energy metabolism. © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0610204104 PNAS ͉ January 16, 2007 ͉ vol. 104 ͉ no. 3 ͉ 955–960 Downloaded by guest on September 26, 2021 Fig. 1. Molecular marker associated with PD risk. (a) Expression data matrix of eight marker genes of 66 blood samples from PD and control subjects. Each row represents a blood sample, and each column represents a gene. As shown in the color bar, overexpression is displayed in red, and underexpression is displayed in green. Blood samples are ordered by their risk score (shown on the left), which is defined as the correlation with the average profile of the PD group minus the correlation with the average profile of the controls. Twenty of 22 individuals with high risk scores ranked in the top third of the list have PD (third tertile). Twenty-one of 22 individuals with low risk scores ranked in the bottom third of the list are controls (first tertile). Solid lines designate tertiles of risk score values. The clinical diagnosis for each individual is shown on the right. (b) Validation of the risk marker on independent test samples confirms that high scores are significantly associated with increased PD risk (P for trend ϭ 0.04). The expression data matrix is as in a, except that b uses 39 independent samples. (c) The ROC curve in the test set (blue curve) is highly consistent with the ROC curve for the leave-one-out cross-validated (LOOCV) marker in the training set (gray) confirming the risk prediction observed for different cutoffs. The nominal ROC curve in the training set represents an upper limit (red). (d) Dopamine replacement medication does not bias the risk score. There is no difference in risk scores of PD patients on dopamine medication versus unmedicated de novo patients (mean Ϯ SE 0.06 Ϯ 0.04 and 0.11 Ϯ 0.1, respectively; P ϭ 0.96). The average risk score for the overall PD group is 0.07 Ϯ 0.03 (data not shown). Average risk scores are low (negative) in healthy controls (Ϫ0.24 Ϯ 0.04) and neurodegenerative disease controls [AD, Ϫ0.25 Ϯ 0.05; progressive supranuclear palsy, Ϫ0.19 Ϯ 0.06; multiple system atrophy (MSA), Ϫ0.34 Ϯ 0.17; corticobasal degeneration (CBD), Ϫ0.26; essential tremor (ET), Ϫ0.15]. Individual scores range from Ϫ0.43 to 0.6 for PD patients, Ϫ0.62 to 0.12 for healthy controls, and Ϫ0.59 to 0.37 for neurodegenerative disease controls. ND, neurodegenerative disease control; H, healthy control. Error bars indicate standard errors. pranuclear palsy. We used a powerful four-step supervised lated, which was defined as the correlation with the PD templates prediction method, similar to those used previously (24), to build minus the correlation with the non-PD template.
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