16 results on '"Benjamin Saef"'
Search Results
2. Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology
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Satria P. Sajuthi, Jamie L. Everman, Nathan D. Jackson, Benjamin Saef, Cydney L. Rios, Camille M. Moore, Angel C. Y. Mak, Celeste Eng, Ana Fairbanks-Mahnke, Sandra Salazar, Jennifer Elhawary, Scott Huntsman, Vivian Medina, Deborah A. Nickerson, Soren Germer, Michael C. Zody, Gonçalo Abecasis, Hyun Min Kang, Kenneth M. Rice, Rajesh Kumar, Noah A. Zaitlen, Sam Oh, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, José Rodríguez-Santana, Esteban G. Burchard, and Max A. Seibold
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Science - Abstract
Understanding regulation of genes associated to disease can reveal insights into disease mechanisms. Here, the authors perform an airway epithelial transcriptome-wide association analysis to elucidate genetic determinants of airway dysfunction in asthma, identifying genetic mechanisms of mucus pathobiology.
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- 2022
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3. Expression of SMARCD1 interacts with age in association with asthma control on inhaled corticosteroid therapy
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Michael J. McGeachie, Joanne E. Sordillo, Amber Dahlin, Alberta L. Wang, Sharon M. Lutz, Kelan G. Tantisira, Ronald Panganiban, Quan Lu, Satria Sajuthi, Cydney Urbanek, Rachel Kelly, Benjamin Saef, Celeste Eng, Sam S. Oh, Alvin T. Kho, Damien C. Croteau-Chonka, Scott T. Weiss, Benjamin A. Raby, Angel C. Y. Mak, Jose R. Rodriguez-Santana, Esteban G. Burchard, Max A. Seibold, and Ann Chen Wu
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Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Global gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context. Methods We used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments & Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age. Results The SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10− 9), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10− 8). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells. Conclusion Focusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids.
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- 2020
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4. Parkinson disease polygenic risk score is associated with Parkinson disease status and age at onset but not with alpha-synuclein cerebrospinal fluid levels
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Laura Ibanez, Umber Dube, Benjamin Saef, John Budde, Kathleen Black, Alexandra Medvedeva, Jorge L. Del-Aguila, Albert A. Davis, Joel S. Perlmutter, Oscar Harari, Bruno A. Benitez, and Carlos Cruchaga
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Parkinson disease ,Genetics ,Age at onset ,Biomarkers ,Polygenic risk score ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background The genetic architecture of Parkinson’s Disease (PD) is complex and not completely understood. Multiple genetic studies to date have identified multiple causal genes and risk loci. Nevertheless, most of the expected genetic heritability remains unexplained. Polygenic risk scores (PRS) may provide greater statistical power and inform about the genetic architecture of multiple phenotypes. The aim of this study was to test the association between PRS and PD risk, age at onset and cerebrospinal fluid (CSF) biomarkers (α-synuclein, Aβ1–42, t-tau and p-tau). Methods The weighted PRS was created using the genome-wide loci from Nalls et al., 2014 PD GWAs meta-analysis. The PRS was tested for association with PD status, age at onset and CSF biomarker levels in 829 cases and 432 controls of European ancestry. Results The PRS was associated with PD status (p = 5.83×10−08) and age at onset (p = 5.70×10−07). The CSF t-tau levels showed a nominal association with the PRS (p = 0.02). However, CSF α-synuclein, amyloid beta and phosphorylated tau were not found to be associated with the PRS. Conclusion Our study suggests that there is an overlap in the genetic architecture of PD risk and onset, although the different loci present different weights for those phenotypes. In our dataset we found a marginal association of the PRS with CSF t-tau but not with α-synuclein CSF levels, suggesting that the genetic architecture for the CSF biomarker levels is different from that of PD risk.
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- 2017
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5. CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease
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Nicolas R. Barthélemy, Benjamin Saef, Yan Li, Brian A. Gordon, Yingxin He, Kanta Horie, Erik Stomrud, Gemma Salvadó, Shorena Janelidze, Chihiro Sato, Vitaliy Ovod, Rachel L. Henson, Anne M. Fagan, Tammie L. S. Benzinger, Chengjie Xiong, John C. Morris, Oskar Hansson, Randall J. Bateman, and Suzanne E. Schindler
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Aging ,Neuroscience (miscellaneous) ,Geriatrics and Gerontology - Abstract
Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman’s ρ = 0.69) than Aβ42/Aβ40 (ρ = −0.42, P n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD.
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- 2023
6. Effect of Race on Prediction of Brain Amyloidosis by Plasma Aβ42/Aβ40, Phosphorylated Tau, and Neurofilament Light
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Suzanne E. Schindler, Thomas K. Karikari, Nicholas J. Ashton, Rachel L. Henson, Kevin E. Yarasheski, Tim West, Mathew R. Meyer, Kristopher M. Kirmess, Yan Li, Benjamin Saef, Krista L. Moulder, David Bradford, Anne M. Fagan, Brian A. Gordon, Tammie L.S. Benzinger, Joyce Balls-Berry, Randall J. Bateman, Chengjie Xiong, Henrik Zetterberg, Kaj Blennow, and John C. Morris
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Amyloid ,Amyloid beta-Peptides ,Apolipoprotein E4 ,Intermediate Filaments ,Brain ,tau Proteins ,Amyloidosis ,Peptide Fragments ,Alzheimer Disease ,Humans ,Neurology (clinical) ,Phosphorylation ,Biomarkers ,Aged - Abstract
Background and ObjectivesTo evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231), and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.MethodsIndividuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age,APOEε4 carrier status, and cognitive status. Each participant underwent blood and CSF collection, and amyloid PET was performed in 103 participants (68%). Plasma Aβ42/Aβ40 was measured by a high-performance immunoprecipitation–mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aβ42/Aβ40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively.ResultsThere were 76 matched pairs of AA and NHW participants (n = 152 total). For both AA and NHW groups, the median age was 68.4 years, 42% wereAPOEε4 carriers, and 91% were cognitively normal. AA were less likely than NHW participants to have brain amyloidosis by CSF Aβ42/Aβ40 (22% vs 43% positive;p= 0.003). The receiver operating characteristic area under the curve of CSF Aβ42/Aβ40 status with the plasma biomarkers was as follows: Aβ42/Aβ40, 0.86 (95% CI 0.79–0.92); p-tau181, 0.76 (0.68–0.84); p-tau231, 0.69 (0.60–0.78); and NfL, 0.64 (0.55–0.73). In models predicting CSF Aβ42/Aβ40 status with plasma Aβ42/Aβ40 that included covariates (age, sex,APOEε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aβ42/Aβ40 positivity. In similar models based on plasma p-tau181, p-tau231, or NfL, AA participants had a lower probability of CSF Aβ42/Aβ40 positivity (odds ratio 0.31 [95% CI 0.13–0.73], 0.30 [0.13–0.71], and 0.27 [0.12–0.64], respectively). Models of amyloid PET status yielded similar findings.DiscussionModels predicting brain amyloidosis using a high-performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA individuals.
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- 2022
7. CSF tau phosphorylation at T217 and T205 are improved biomarkers of amyloid and tau pathology in Alzheimer disease
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Nicolas Barthélemy, Benjamin Saef, Yan Li, Brian Gordon, Yingxin He, Kanta Horie, Erik Stomrud, Gemma Salvado, Shorena Janelidze, Chihiro Sato, Vitaliy Ovod, Rachel Henson, Anne Fagan, Tammie Benzinger, Chengjie Xiong, John Morris, Oskar Hansson, Randall Bateman, and Suzanne Schindler
- Abstract
CSF Aβ42/Aβ40 and tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer disease (AD). This study used mass spectrometry to measure concentrations of 9 phosphorylated and 5 non-phosphorylated species, and phosphorylation occupancies (phosphorylated/non-phosphorylated [%]) at 10 sites. In 750 individuals with a median age of 71.2 years, CSF pT217/T217 (%) predicted amyloid PET status slightly better than Aβ42/Aβ40 (p=0.02). In amyloid PET positive individuals (n=263), CSF pT217/T217 (%) was more strongly correlated with amyloid PET Centiloid (Spearman ρ=0.69) than Aβ42/Aβ40 (ρ = -0.42, p
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- 2022
8. Nasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology
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Satria P, Sajuthi, Jamie L, Everman, Nathan D, Jackson, Benjamin, Saef, Cydney L, Rios, Camille M, Moore, Angel C Y, Mak, Celeste, Eng, Ana, Fairbanks-Mahnke, Sandra, Salazar, Jennifer, Elhawary, Scott, Huntsman, Vivian, Medina, Deborah A, Nickerson, Soren, Germer, Michael C, Zody, Gonçalo, Abecasis, Hyun Min, Kang, Kenneth M, Rice, Rajesh, Kumar, Noah A, Zaitlen, Sam, Oh, José, Rodríguez-Santana, Esteban G, Burchard, and Max A, Seibold
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Metaplasia ,Mucus ,Humans ,Mucin 5AC ,Child ,Transcriptome ,Asthma ,Epithelium - Abstract
To identify genetic determinants of airway dysfunction, we performed a transcriptome-wide association study for asthma by combining RNA-seq data from the nasal airway epithelium of 681 children, with UK Biobank genetic association data. Our airway analysis identified 95 asthma genes, 58 of which were not identified by transcriptome-wide association analyses using other asthma-relevant tissues. Among these genes were MUC5AC, an airway mucin, and FOXA3, a transcriptional driver of mucus metaplasia. Muco-ciliary epithelial cultures from genotyped donors revealed that the MUC5AC risk variant increases MUC5AC protein secretion and mucus secretory cell frequency. Airway transcriptome-wide association analyses for mucus production and chronic cough also identified MUC5AC. These cis-expression variants were associated with trans effects on expression; the MUC5AC variant was associated with upregulation of non-inflammatory mucus secretory network genes, while the FOXA3 variant was associated with upregulation of type-2 inflammation-induced mucus-metaplasia pathway genes. Our results reveal genetic mechanisms of airway mucus pathobiology.
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- 2021
9. Identification of blood eQTLs for AD risk loci
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Fabiana H.G. Farias, Carlos Cruchaga, John P. Budde, Joseph Bradley, Richard Davenport, Zeran Li, Alzheimer’s Disease Neuroimaging Initiative, Yuetiva Deming, Benjamin Saef, Oscar Harari, and Fengxian Wang
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Genetics ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Identification (biology) ,Neurology (clinical) ,Disease ,Geriatrics and Gerontology ,Biology - Published
- 2020
10. Polygenic risk score of sporadic late‐onset Alzheimer's disease reveals a shared architecture with the familial and early‐onset forms
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Carlos Cruchaga, John P. Budde, Anne M. Fagan, Giuseppe Tosto, Kathleen Black, Manav Kapoor, Oscar Harari, Randall J. Bateman, Alison Goate, Yuetiva Deming, John C. Morris, Richard Mayeux, Benjamin Saef, Maria Victoria Fernandez, Jorge Del aguila, David M. Holtzman, and Laura Ibanez
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Male ,0301 basic medicine ,Oncology ,Apolipoprotein E ,Multifactorial Inheritance ,Epidemiology ,Disease ,Cohort Studies ,0302 clinical medicine ,PSEN2 ,PSEN1 ,Early-onset Alzheimer's disease ,Age of Onset ,Aged, 80 and over ,Genetics ,Health Policy ,Middle Aged ,Psychiatry and Mental health ,Female ,Psychology ,Adult ,medicine.medical_specialty ,Genotype ,tau Proteins ,Late onset ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Apolipoproteins E ,Developmental Neuroscience ,Alzheimer Disease ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Aged ,Family Health ,Amyloid beta-Peptides ,Odds ratio ,medicine.disease ,Databases, Bibliographic ,Peptide Fragments ,Genetic architecture ,Logistic Models ,030104 developmental biology ,ROC Curve ,Mutation ,Neurology (clinical) ,Geriatrics and Gerontology ,030217 neurology & neurosurgery - Abstract
Objective To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD). Methods Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk. Results We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10 −7 ) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10 −7 ) and sLOAD (OR = 1.40; P = 1.21 × 10 −3 ). The PRS was associated with cerebrospinal fluid ptau 181 -Aβ 42 on eADAD ( P = 4.36 × 10 −2 ). Conclusion Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.
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- 2017
11. Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers
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Yuetiva, Deming, Zeran, Li, Manav, Kapoor, Oscar, Harari, Jorge L, Del-Aguila, Kathleen, Black, David, Carrell, Yefei, Cai, Maria Victoria, Fernandez, John, Budde, Shengmei, Ma, Benjamin, Saef, Bill, Howells, Kuan-Lin, Huang, Sarah, Bertelsen, Anne M, Fagan, David M, Holtzman, John C, Morris, Sungeun, Kim, Andrew J, Saykin, Philip L, De Jager, Marilyn, Albert, Abhay, Moghekar, Richard, O'Brien, Matthias, Riemenschneider, Ronald C, Petersen, Kaj, Blennow, Henrik, Zetterberg, Lennart, Minthon, Vivianna M, Van Deerlin, Virginia Man-Yee, Lee, Leslie M, Shaw, John Q, Trojanowski, Gerard, Schellenberg, Jonathan L, Haines, Richard, Mayeux, Margaret A, Pericak-Vance, Lindsay A, Farrer, Elaine R, Peskind, Ge, Li, Antonio F, Di Narzo, John S K, Kauwe, Alison M, Goate, and Carlos, Cruchaga
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Adult ,0301 basic medicine ,Genotype ,Endophenotypes ,Amyloid beta ,tau Proteins ,Genome-wide association study ,Locus (genetics) ,Disease ,Quantitative trait locus ,Pathology and Forensic Medicine ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Apolipoproteins E ,0302 clinical medicine ,Alzheimer Disease ,Risk Factors ,Humans ,Genetic Predisposition to Disease ,INPP5D ,Aged ,Genetic association ,Aged, 80 and over ,Genetics ,Amyloid beta-Peptides ,biology ,Middle Aged ,Phenotype ,030104 developmental biology ,Genetic Loci ,Disease Progression ,biology.protein ,Neurology (clinical) ,Biomarkers ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10−2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10−2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.
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- 2017
12. Parkinson disease polygenic risk score is associated with Parkinson disease status and age at onset but not with alpha-synuclein cerebrospinal fluid levels
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John P. Budde, Albert A. Davis, Joel S. Perlmutter, Alexandra Medvedeva, Oscar Harari, Umber Dube, Benjamin Saef, Bruno A. Benitez, Jorge L. Del-Aguila, Laura Ibanez, Kathleen Black, and Carlos Cruchaga
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0301 basic medicine ,Oncology ,Male ,Risk ,medicine.medical_specialty ,Pathology ,Neurology ,Genome-wide association study ,tau Proteins ,Disease ,lcsh:RC346-429 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cerebrospinal fluid ,Polygenic risk score ,Internal medicine ,medicine ,Genetics ,Humans ,Neurochemistry ,Phosphorylation ,lcsh:Neurology. Diseases of the nervous system ,Aged ,Alpha-synuclein ,Amyloid beta-Peptides ,business.industry ,Age at onset ,Parkinson Disease ,General Medicine ,Heritability ,Middle Aged ,Genetic architecture ,3. Good health ,030104 developmental biology ,Phenotype ,chemistry ,alpha-Synuclein ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Biomarkers ,Research Article ,Genome-Wide Association Study - Abstract
Background The genetic architecture of Parkinson’s Disease (PD) is complex and not completely understood. Multiple genetic studies to date have identified multiple causal genes and risk loci. Nevertheless, most of the expected genetic heritability remains unexplained. Polygenic risk scores (PRS) may provide greater statistical power and inform about the genetic architecture of multiple phenotypes. The aim of this study was to test the association between PRS and PD risk, age at onset and cerebrospinal fluid (CSF) biomarkers (α-synuclein, Aβ1–42, t-tau and p-tau). Methods The weighted PRS was created using the genome-wide loci from Nalls et al., 2014 PD GWAs meta-analysis. The PRS was tested for association with PD status, age at onset and CSF biomarker levels in 829 cases and 432 controls of European ancestry. Results The PRS was associated with PD status (p = 5.83×10−08) and age at onset (p = 5.70×10−07). The CSF t-tau levels showed a nominal association with the PRS (p = 0.02). However, CSF α-synuclein, amyloid beta and phosphorylated tau were not found to be associated with the PRS. Conclusion Our study suggests that there is an overlap in the genetic architecture of PD risk and onset, although the different loci present different weights for those phenotypes. In our dataset we found a marginal association of the PRS with CSF t-tau but not with α-synuclein CSF levels, suggesting that the genetic architecture for the CSF biomarker levels is different from that of PD risk. Electronic supplementary material The online version of this article (10.1186/s12883-017-0978-z) contains supplementary material, which is available to authorized users.
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- 2017
13. Polygenic Risk Score of Sporadic late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms
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Richard Mayeux, Kathleen Black, Manav Kapoor, John P. Budde, John C. Morris, Laura Ibanez, Giuseppe Tosto, Alison Goate, David M. Holtzman, Anne M. Fagan, Benjamin Saef, Oscar Harari, Jorge Del aguila, Randall J. Bateman, Carlos Cruchaga, and Maria Victoria Fernandez
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Genetics ,0303 health sciences ,business.industry ,Late Onset Alzheimer Disease ,Familial clustering ,Disease ,medicine.disease ,Genetic architecture ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Polygenic risk score ,Alzheimer's disease ,business ,030217 neurology & neurosurgery ,030304 developmental biology ,Early onset - Abstract
Objective:To determine whether the genetic architecture of sporadic late-onset Alzheimer’s Disease (sLOAD) has an effect on familial late-onset AD (fLOAD), sporadic early-onset (sEOAD) and autosomal dominant early-onset (eADAD).Methods:Polygenic risk scores (PRS) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.Results:We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. sEOAD showed the highest odds for the PRS (OR=2.27; p=1.29×10-7), followed by fLOAD (OR=1.75; p=1.12×10-7) and sLOAD (OR=1.40; p=1.21×10-3). PRS is associated with cerebrospinal fluid ptau181-Aβ42on eADAD.Conclusion:Our analysis confirms that the genetic factors identified for sLOAD also modulate risk in fLOAD and sEOAD cohorts. Furthermore, our results suggest that the burden of these risk variants is associated with familial clustering and earlier-onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.
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- 2017
14. [O1–11–03]: CEREBROSPINAL FLUID ENDOPHENOTYPES PROVIDE INSIGHT INTO BIOLOGY UNDERLYING ALZHEIMER'S DISEASE
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Ronald C. Petersen, Kuan-lin Huang, Henrik Zetterberg, Jordi Clarimón, Yefei Cai, Carlos Cruchaga, Andrew J. Saykin, David M. Holtzman, Shengmei Ma, John S. K. Kauwe, John P. Budde, Richard Mayeux, Manav Kapoor, Bill Howells, Elaine R. Peskind, Lindsay A. Farrer, Lennart Minthon, Maria Victoria Fernandez, Margaret A. Pericak-Vance, Antonio Fabio Di Narzo, Oscar Harari, Kaj Blennow, Benjamin Saef, Abhay Moghekar, Laura Piccio, Sarah Bertelsen, John Q. Trojanowski, Jonathan L. Haines, David Carrell, Alberto Lleó, Ge Li, Virginia M.-Y. Lee, Richard O'Brien, Philip L. De Jager, Zeran Li, Gerard D. Schellenberg, Pau Pastor, John C. Morris, Sungeun Kim, Vivianna M. Van Deerlin, Leslie M. Shaw, Matthias Riemenschneider, Alison Goate, Anne M. Fagan, Kathleen Black, Jorge L. Del-Aguila, José Luis Molinuevo, Marilyn S. Albert, and Yuetiva Deming
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Cerebrospinal fluid ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Endophenotype ,Neurology (clinical) ,Disease ,Geriatrics and Gerontology ,Psychology ,Neuroscience - Published
- 2017
15. Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits
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Jenny Lord, John P. Budde, John C. Morris, Shengmei Ma, Kelly R. Bales, Yefei Cai, Laura Piccio, Alison Goate, Kathleen Black, Yuetiva Deming, Benjamin Saef, Perry G. Ridge, John S. K. Kauwe, Holtzman David M, Jorge L. Del-Aguila, Carlos Cruchaga, Maria Victoria Fernandez, Laura Heitsch, Matthew H. Bailey, Jian Xia, Sarah Bertelsen, Bill Howells, Jin-Moo Lee, Eve H. Pickering, and David Carrell
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0301 basic medicine ,Genetics ,Apolipoprotein E ,Multidisciplinary ,Multiple sclerosis ,Locus (genetics) ,Type 2 diabetes ,Biology ,medicine.disease ,Blood proteins ,Article ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,ABO blood group system ,Endophenotype ,medicine ,030217 neurology & neurosurgery ,Genetic association - Abstract
Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects and complex disease associations in the same locus.
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- 2016
16. Chitinase-3-like 1 protein (CHI3L1) locus influences cerebrospinal fluid levels of YKL-40
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Kuan-lin Huang, Yefei Cai, Holtzman David M, John P. Budde, Maria Victoria Fernandez, Benjamin Saef, Kathleen Black, Joseph D. Dougherty, Rawan Tarawneh, John C. Morris, Bill Howells, Carlos Cruchaga, Sarah Bertelsen, David Carrell, Alison Goate, Yuetiva Deming, Courtney L. Sutphen, Anne M. Fagan, Jorge L. Del-Aguila, and Shengmei Ma
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0301 basic medicine ,Male ,musculoskeletal diseases ,Pathology ,medicine.medical_specialty ,YKL-40 ,Amyloid beta ,Clinical Neurology ,Locus (genetics) ,tau Proteins ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Genetic variation ,medicine ,Humans ,CHI3L1 ,Chitinase-3-Like Protein 1 ,Cognitive decline ,Allele ,Aged ,Amyloid beta-Peptides ,biology ,business.industry ,General Medicine ,medicine.disease ,3. Good health ,030104 developmental biology ,Cerebrospinal fluid ,Genetic Loci ,Expression quantitative trait loci ,Immunology ,biology.protein ,Disease Progression ,Linear Models ,Biomarker (medicine) ,Female ,Neurology (clinical) ,Alzheimer's disease ,business ,030217 neurology & neurosurgery ,Biomarkers ,Research Article - Abstract
Background Alzheimer’s disease (AD) pathology appears several years before clinical symptoms, so identifying ways to detect individuals in the preclinical stage is imperative. The cerebrospinal fluid (CSF) Tau/Aβ42 ratio is currently the best known predictor of AD status and cognitive decline, and the ratio of CSF levels of chitinase-3-like 1 protein (CHI3L1, YKL-40) and amyloid beta (Aβ42) were reported as predictive, but individual variability and group overlap inhibits their utility for individual diagnosis making it necessary to find ways to improve sensitivity of these biomarkers. Methods We used linear regression to identify genetic loci associated with CSF YKL-40 levels in 379 individuals (80 cognitively impaired and 299 cognitively normal) from the Charles F and Joanne Knight Alzheimer’s Disease Research Center. We tested correlations between YKL-40 and CSF Tau/Aβ42 ratio, Aβ42, tau, and phosphorylated tau (ptau181). We used studentized residuals from a linear regression model of the log-transformed, standardized protein levels and the additive reference allele counts from the most significant locus to adjust YKL-40 values and tested the differences in correlations with CSF Tau/Aβ42 ratio, Aβ42, tau, and ptau181. Results We found that genetic variants on the CH13L1 locus were significantly associated with CSF YKL-40 levels, but not AD risk, age at onset, or disease progression. The most significant variant is a reported expression quantitative trait locus for CHI3L1, the gene which encodes YKL-40, and explained 12.74 % of the variance in CSF YKL-40 in our study. YKL-40 was positively correlated with ptau181 (r = 0.521) and the strength of the correlation significantly increased with the addition of genetic information (r = 0.573, p = 0.006). Conclusions CSF YKL-40 levels are likely a biomarker for AD, but we found no evidence that they are an AD endophenotype. YKL-40 levels are highly regulated by genetic variation, and by including genetic information the strength of the correlation between YKL-40 and ptau181 levels is significantly improved. Our results suggest that studies of potential biomarkers may benefit from including genetic information. Electronic supplementary material The online version of this article (doi:10.1186/s12883-016-0742-9) contains supplementary material, which is available to authorized users.
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