Publications by authors named "Jaeyoon Chung"

35 Publications

Cytokine Levels in Human Vitreous in Proliferative Diabetic Retinopathy.

Cells 2021 Apr 30;10(5). Epub 2021 Apr 30.

Department of Ophthalmology, Boston University School of Medicine & Boston Medical Center, Boston, MA 02118, USA.

In this study, we compare the vitreous cytokine profile in patients with proliferative diabetic retinopathy (PDR) to that of patients without PDR. The identification of novel cytokines involved in the pathogenesis of PDR provides candidate therapeutic targets that may stand alone or work synergistically with current therapies in the management of diabetic retinopathy. Undiluted vitreous humor specimens were collected from 74 patients undergoing vitrectomy for various vitreoretinal disorders. Quantitative immunoassay was performed for a panel of 36 neuroinflammatory cytokines in each specimen and assessed to identify differences between PDR ( = 35) and non-PDR ( = 39) patients. Levels of interleukin-8 (IL-8), IL-15, IL-16, vascular endothelial growth factor (VEGF), VEGF-D, c-reactive protein (CRP), serum amyloid-A (SAA), and intracellular adhesion molecule-1 (ICAM1) were significantly increased in the vitreous of PDR patients compared to non-PDR patients ( < 0.05). We report novel increases in IL-15 and IL-16, in addition to the expected VEGF, in the human vitreous humor of patients with PDR. Additionally, we confirm the elevation of ICAM-1, VCAM-1, SAA, IL-8 and CRP in the vitreous of patients with PDR, which has previously been described.
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http://dx.doi.org/10.3390/cells10051069DOI Listing
April 2021

Cell-type-specific expression quantitative trait loci associated with Alzheimer disease in blood and brain tissue.

Transl Psychiatry 2021 Apr 27;11(1):250. Epub 2021 Apr 27.

Bioinformatics Graduate Program, Boston University, Boston, MA, USA.

Because regulation of gene expression is heritable and context-dependent, we investigated AD-related gene expression patterns in cell types in blood and brain. Cis-expression quantitative trait locus (eQTL) mapping was performed genome-wide in blood from 5257 Framingham Heart Study (FHS) participants and in brain donated by 475 Religious Orders Study/Memory & Aging Project (ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within 1 Mb of genes was evaluated using linear regression models for unrelated subjects and linear-mixed models for related subjects. Cell-type-specific eQTL (ct-eQTL) models included an interaction term for the expression of "proxy" genes that discriminate particular cell type. Ct-eQTL analysis identified 11,649 and 2533 additional significant gene-SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 386 unique target eGenes of significant eQTLs shared between blood and brain were enriched in apoptosis and Wnt signaling pathways. Five of these shared genes are established AD loci. The potential importance and relevance to AD of significant results in myeloid cell types is supported by the observation that a large portion of GWS ct-eQTLs map within 1 Mb of established AD loci and 58% (23/40) of the most significant eGenes in these eQTLs have previously been implicated in AD. This study identified cell-type-specific expression patterns for established and potentially novel AD genes, found additional evidence for the role of myeloid cells in AD risk, and discovered potential novel blood and brain AD biomarkers that highlight the importance of cell-type-specific analysis.
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http://dx.doi.org/10.1038/s41398-021-01373-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079392PMC
April 2021

Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract.

Commun Biol 2020 Dec 11;3(1):755. Epub 2020 Dec 11.

Institute of Molecular and Cell Biology, 138673, Singapore, Singapore.

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10), TMPRSS5 (rs4936279, P = 2.5 × 10), LINC01412 (rs16823886, P = 1.3 × 10), GLTSCR1 (rs1005911, P = 9.8 × 10), and COMMD1 (rs62149908, P = 1.2 × 10). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.
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http://dx.doi.org/10.1038/s42003-020-01421-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733496PMC
December 2020

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

JAMA Neurol 2021 Jan;78(1):102-113

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.

Design, Setting, And Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.

Main Outcomes And Measures: Diagnosis of Alzheimer disease.

Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.

Conclusions And Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
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http://dx.doi.org/10.1001/jamaneurol.2020.3536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573798PMC
January 2021

Neurofilament light chain in the vitreous humor of the eye.

Alzheimers Res Ther 2020 09 17;12(1):111. Epub 2020 Sep 17.

Boston University Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA.

Background: Neurofilament light chain (NfL) is a promising biomarker of neurodegeneration in the cerebrospinal fluid and blood. This study investigated the presence of NfL in the vitreous humor and its associations with amyloid beta, tau, inflammatory cytokines and vascular proteins, apolipoprotein E (APOE) genotypes, Mini-Mental State Examination (MMSE) scores, systemic disease, and ophthalmic diseases.

Methods: This is a single-site, prospective, cross-sectional cohort study. Undiluted vitreous fluid (0.5-1.0 mL) was aspirated during vitrectomy, and whole blood was drawn for APOE genotyping. NfL, amyloid beta (Aβ), total Tau (t-Tau), phosphorylated Tau (p-Tau181), inflammatory cytokines, chemokines, and vascular proteins in the vitreous were quantitatively measured by immunoassay. The main outcome measures were the detection of NfL levels in the vitreous humor and its associations with the aforementioned proteins. Linear regression was used to test the associations of NfL with other proteins, APOE genotypes, MMSE scores, and ophthalmic and systemic diseases after adjustment for age, sex, education level, and other eye diseases.

Results: NfL was detected in all 77 vitreous samples. NfL was not found to be associated with ophthalmic conditions, APOE genotypes, MMSE scores, or systemic disease (p > 0.05). NfL levels were positively associated with increased vitreous levels of Aβ (p = 7.7 × 10), Aβ (p = 2.8 × 10), and t-tau (p = 5.5 × 10), but not with p-tau181 (p = 0.53). NfL also had significant associations with inflammatory cytokines such as interleukin-15 (IL-15, p = 5.3 × 10), IL-16 (p = 2.2 × 10), monocyte chemoattractant protein-1 (MCP1, p = 4.1 × 10), and vascular proteins such as vascular endothelial growth factor receptor-1 (VEGFR1, p = 2.9 × 10), Vegf-C (p = 8.6 × 10), vascular cell adhesion molecule-1 (VCAM-1, p = 5.0 × 10), Tie-2 (p = 6.3 × 10), and intracellular adhesion molecular-1 (ICAM-1, p = 1.6 × 10).

Conclusion: NfL is detectable in the vitreous humor of the eye and significantly associated with amyloid beta, t-tau, and select inflammatory and vascular proteins in the vitreous. Additionally, NfL was not associated with patients' clinical eye condition. Our results serve as a foundation for further investigation of NfL in the ocular fluids to inform us about the potential utility of its presence in the eye.
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http://dx.doi.org/10.1186/s13195-020-00677-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500015PMC
September 2020

Genetic overlap and causal inferences between kidney function and cerebrovascular disease.

Neurology 2020 06 21;94(24):e2581-e2591. Epub 2020 May 21.

From the Center for Genomic Medicine (S.M., J.C., J.Q.A.H., J.R., C.D.A.), Department of Neurology (J.R., C.D.A.), and Henry and Allison McCance Center for Brain Health (J.R., C.D.A.), Massachusetts General Hospital, Boston; Institute for Stroke and Dementia Research (M.K.G., M.D., R.M.), University Hospital of Ludwig-Maximilians-University; Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-University, Munich, Germany; Department of Medicine (Biomedical Genetics) (J.C.), Boston University School of Medicine, MA; Munich Cluster for Systems Neurology (SyNergy) (M.D.); German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany; and Program in Medical and Population Genetics (J.R., C.D.A.), Broad Institute of Harvard and MIT, Cambridge, MA.

Objective: Leveraging large-scale genetic data, we aimed to identify shared pathogenic mechanisms and causal relationships between impaired kidney function and cerebrovascular disease phenotypes.

Methods: We used summary statistics from genome-wide association studies (GWAS) of kidney function traits (chronic kidney disease diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]) and cerebrovascular disease phenotypes (ischemic stroke and its subtypes, intracerebral hemorrhage [ICH], and white matter hyperintensities [WMH] on brain MRI). We (1) tested the genetic overlap between them with polygenic risk scores (PRS), (2) searched for common pleiotropic loci with pairwise GWAS analyses, and (3) explored causal associations by employing 2-sample Mendelian randomization.

Results: A PRS for lower eGFR was associated with higher large artery stroke (LAS) risk ( = 1 × 10). Multiple pleiotropic loci were identified between kidney function traits and cerebrovascular disease phenotypes, with 12q24 associated with eGFR and both LAS and small vessel stroke (SVS), and 2q33 associated with UACR and both SVS and WMH. Mendelian randomization revealed associations of both lower eGFR (odds ratio [OR] per 1-log decrement, 2.10; 95% confidence interval [CI], 1.38-3.21) and higher UACR (OR per 1-log increment, 2.35; 95% CI, 1.12-4.94) with a higher risk of LAS, as well as between higher UACR and higher risk of ICH.

Conclusions: Impaired kidney function, as assessed by decreased eGFR and increased UACR, may be causally involved in the pathogenesis of LAS. Increased UACR, previously proposed as a marker of systemic small vessel disease, is involved in ICH risk and shares a genetic risk factor at 2q33 with manifestations of cerebral small vessel disease.
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http://dx.doi.org/10.1212/WNL.0000000000009642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455337PMC
June 2020

Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.

Ann Neurol 2020 07 7;88(1):56-66. Epub 2020 May 7.

Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK.

Objective: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH.

Methods: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses.

Results: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively.

Interpretation: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.
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http://dx.doi.org/10.1002/ana.25740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523882PMC
July 2020

Influence of Genetic Variation in on Endothelial Function and Stroke.

Hypertension 2020 02 23;75(2):365-371. Epub 2019 Dec 23.

From the Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (M.T., A.A.A.O., H.S.M.).

We aimed to characterize the genetics of endothelial function and how this influences risk for cardiovascular diseases such as ischemic stroke. We integrated genetic data from a study of ultrasound flow-mediated dilatation of brachial artery in adolescents from ALSPAC (Avon Longitudinal Study of Parents and Children; n=5214) with a study of ischemic stroke (MEGASTROKE: n=60 341 cases and 452 969 controls) to identify variants that confer risk of ischemic stroke through altered endothelial function. We identified a variant in (Phosphodiesterase 3A), encoding phosphodiesterase 3A, which was associated with flow-mediated dilatation in adolescents (9-12 years of age; β[SE], 0.38 [0.070]; =3.8×10) and confers risk of ischemic stroke (odds ratio, 1.04 [95% CI, 1.02-1.06]; =5.2×10). Bayesian colocalization analyses showed the same underlying variation is likely to lead to both associations (posterior probability, 97%). The same variant was associated with flow-mediated dilatation in a second study in young adults (age, 24-27 years; β[SE], 0.47 [0.23]; =0.047) but not in older adults (β[SE], -0.012 [0.13]; =0.89). We conclude that a genetic variant in influences endothelial function in early life and leads to increased risk of ischemic stroke. Subtle, measurable changes to the vasculature that are influenced by genetics also influence risk of ischemic stroke.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055937PMC
February 2020

Con: Preoperative Echocardiography Should Be Reviewed Before Cardiac Surgery.

J Cardiothorac Vasc Anesth 2020 03 24;34(3):830-831. Epub 2019 Oct 24.

Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson University Hospital, Philadelphia, PA. Electronic address:

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http://dx.doi.org/10.1053/j.jvca.2019.10.032DOI Listing
March 2020

Genome-wide association study of cerebral small vessel disease reveals established and novel loci.

Brain 2019 10;142(10):3176-3189

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.
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http://dx.doi.org/10.1093/brain/awz233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763741PMC
October 2019

Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype.

JAMA Neurol 2019 Sep;76(9):1099-1108

Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, Massachusetts.

Importance: Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles.

Objective: To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing.

Design, Setting, And Participants: The discovery stage included 10 441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018.

Main Outcomes And Measures: Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ε4 carriers and noncarriers. Results with P ≤ 1 × 10-5 were further evaluated in the replication data sets and combined by meta-analysis.

Results: Among 3145 patients with AD and 4213 controls lacking ε4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10-8). GPAA1 was also associated with expression in the brain of GPAA1 (β = -0.08; P = .03) and its repressive transcription factor, FOXG1 (β = 0.13; P = .003), and global cognition function (β = -0.53; P = .009). Significant gene-wide associations (threshold P ≤ 6.35 × 10-7) were observed for OR8G5 (P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16), and SLC24A3 (P = 2.67 × 10-12) in 2377 patients with AD and 706 controls with ε4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women).

Conclusions And Relevance: The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ε4 alleles that reinforce known and suggest additional pathways leading to AD.
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http://dx.doi.org/10.1001/jamaneurol.2019.1456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563544PMC
September 2019

CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease.

Aging Cell 2019 08 29;18(4):e12964. Epub 2019 May 29.

Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.

CpG-related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome-wide association study using a sliding-window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue of the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood of Framingham Heart Study participants (FHS). Genome-wide significant (p < 5 × 10 ) associations were identified with 171 1.0 kb-length windows spanning 932 kb in the APOE region (top p < 2.2 × 10 ), five windows at BIN1 (top p = 1.3 × 10 ), two windows at MS4A6A (top p = 2.7 × 10 ), two windows near MS4A4A (top p = 6.4 × 10 ), and one window at PICALM (p = 6.3 × 10 ). The total number of CGS-derived CpG dinucleotides in the window near MS4A4A was associated with AD risk (p = 2.67 × 10 ), brain DNA methylation (p = 2.15 × 10 ), and gene expression in brain (p = 0.03) and blood (p = 2.53 × 10 ). Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at MS4A4A (cg14750746) showed an enrichment of methyltransferase functions. We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage-derived genetic score to predict AD risk.
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http://dx.doi.org/10.1111/acel.12964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612647PMC
August 2019

Cross-Field Ventilation for Treatment of Harlequin Syndrome in Traumatic Tracheobronchial Injury Repair Using Intraoperative Venoarterial Extracorporeal Membrane Oxygenation.

J Cardiothorac Vasc Anesth 2019 Nov 18;33(11):3090-3094. Epub 2019 Mar 18.

Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA.

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http://dx.doi.org/10.1053/j.jvca.2019.03.033DOI Listing
November 2019

Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry.

JAMA Netw Open 2019 03 1;2(3):e191350. Epub 2019 Mar 1.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.

Importance: Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations.

Objective: To identify genetic variants associated with AD risk using a nonstatistical approach.

Design, Setting, And Participants: Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018.

Main Outcomes And Measures: Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative.

Results: Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006).

Conclusions And Relevance: Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.1350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450321PMC
March 2019

Association of Cognitive Function with Amyloid-β and Tau Proteins in the Vitreous Humor.

J Alzheimers Dis 2019 ;68(4):1429-1438

Department of Ophthalmology, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA.

Background: The eye may serve as source for diagnostic testing for early detection of Alzheimer's disease (AD). Examination of amyloid-β (Aβ) and tau protein content in human vitreous and its correlation to neuro-cognition may improve ocular-based AD detection methods.

Objective: To evaluate levels of Aβ and tau protein in human vitreous humor and investigate the clinical predictive role of these proteins as early diagnostic markers of AD.

Methods: A prospective, single-center, multi-surgeon cohort study. Vitreous humor samples from 80 eyes were measured quantitatively for Aβ40-42, pTau, and tTau. Linear regression was used to test associations between AD biomarker levels, Mini-Mental State Exam (MMSE), and serum apolipoprotein E (APOE) allele status, with adjustment for age, sex, and education level of patients.

Results: Lower MMSE scores were significantly associated with lower levels of vitreous Aβ40 (p = 0.015), Aβ42 (p = 0.0066), and tTau (p = 0.0085), and these biomarkers were not associated with any pre-existing eye conditions. Presence of the ɛ4 allele and the ɛ2 allele approached significance with reduced Aβ40 level (p = 0.053) and increased p-Tau level (p = 0.056), respectively.

Conclusion: Patients with poor cognitive function have significantly lower vitreous humor levels of AD-related biomarkers Aβ40, Aβ42, and tTau. These biomarkers do not correlate with underlying eye conditions, suggesting their specificity in association with cognitive change. This is the first study to our knowledge to correlate cognition with AD-related proteins in the vitreous humor. Results suggest ocular proteins may have a role for early dementia detection in individuals at risk for AD.
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http://dx.doi.org/10.3233/JAD-181104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850770PMC
August 2020

Comparison of methods for multivariate gene-based association tests for complex diseases using common variants.

Eur J Hum Genet 2019 05 25;27(5):811-823. Epub 2019 Jan 25.

Bioinformatics Graduate Program, Boston University, Boston, MA, USA.

Complex diseases are usually associated with multiple correlated phenotypes, and the analysis of composite scores or disease status may not fully capture the complexity (or multidimensionality). Joint analysis of multiple disease-related phenotypes in genetic tests could potentially increase power to detect association of a disease with common SNPs (or genes). Gene-based tests are designed to identify genes containing multiple risk variants that individually are weakly associated with a univariate trait. We combined three multivariate association tests (O'Brien method, TATES, and MultiPhen) with two gene-based association tests (GATES and VEGAS) and compared performance (type I error and power) of six multivariate gene-based methods using simulated data. Data (n = 2000) for genetic sequence and correlated phenotypes were simulated by varying causal variant proportions and phenotype correlations for various scenarios. These simulations showed that two multivariate association tests (TATES and MultiPhen, but not O'Brien) paired with VEGAS have inflated type I error in all scenarios, while the three multivariate association tests paired with GATES have correct type I error. MultiPhen paired with GATES has higher power than competing methods if the correlations among phenotypes are low (r < 0.57). We applied these gene-based association methods to a GWAS dataset from the Alzheimer's Disease Genetics Consortium containing three neuropathological traits related to Alzheimer disease (neuritic plaque, neurofibrillary tangles, and cerebral amyloid angiopathy) measured in 3500 autopsied brains. Gene-level significant evidence (P < 2.7 × 10) was identified in a region containing three contiguous genes (TRAPPC12, TRAPPC12-AS1, ADI1) using O'Brien and VEGAS. Gene-wide significant associations were not observed in univariate gene-based tests.
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http://dx.doi.org/10.1038/s41431-018-0327-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461986PMC
May 2019

A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease.

Alzheimers Dement 2019 03 3;15(3):441-452. Epub 2019 Jan 3.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA. Electronic address:

Introduction: The genetic architecture of Alzheimer's disease (AD) is only partially understood.

Methods: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families.

Results: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10).

Discussion: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.
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http://dx.doi.org/10.1016/j.jalz.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408965PMC
March 2019

An efficient analytic approach in genome-wide identification of methylation quantitative trait loci response to fenofibrate treatment.

BMC Proc 2018 17;12(Suppl 9):44. Epub 2018 Sep 17.

3Department of Biostatistics, Boston University School of Public Health, Boston University, 715 Albany St, Boston, MA 02118 USA.

Background: The study of DNA methylation quantitative trait loci (meQTLs) helps dissect regulatory mechanisms underlying genetic associations of human diseases. In this study, we conducted the first genome-wide examination of genetic drivers of methylation variation in response to a triglyceride-lowering treatment with fenofibrate (response-meQTL) by using an efficient analytic approach.

Methods: Subjects ( = 429) from the GAW20 real data set with genotype and both pre- (visit 2) and post- (visit 4) fenofibrate treatment methylation measurements were included. Following the quality control steps of removing certain cytosine-phosphate-guanine (CpG) probes, the post-/premethylation changes (post/pre) were log transformed and the association was performed on 208,449 CpG sites. An additive linear mixed-effects model was used to test the association between each CpG probe and single nucleotide polymorphisms (SNPs) around ±1 Mb region, with age, sex, smoke, batch effect, and principal components included as covariates. Bonferroni correction was applied to define the significance threshold ( < 5.6 × 10, given a total of 89,217,303 tests). Finally, we integrated our response-meQTL (re-meQTL) findings with the published genome-wide association study (GWAS) catalog of human diseases/traits.

Results: We identified 1087 SNPs as re-meQTLs associated with 610 CpG probes/sites located in 351 unique gene loci. Among these 1087 re-meQTL SNPs, 229 were unique and 6 were co-localized at 8 unique disease/trait loci reported in the GWAS catalog (enrichment  = 1.51 × 10). Specifically, a lipid SNP, rs10903129, located in intron regions of gene , was a re-meQTL ( = 3.12 × 10) associated with the CpG probe cg09222892, which is in the upstream region of the gene indicating a new target gene for rs10903129. In addition, we found that SNP rs12710728 has a suggestive association with cg17097782 ( = 1.77 × 10), and that this SNP is in high linkage disequilibrium (LD) (R > 0.8) with rs7443270, which was previously reported to be associated with fenofibrate response ( = 5.00 × 10).

Conclusions: By using a novel analytic approach, we efficiently identified thousands of re-meQTLs that provide a unique resource for further characterizing functional roles and gene targets of the SNPs that are most responsive to fenofibrate treatment. Our efficient analytic approach can be extended to large response quantitative trait locus studies with large sample sizes and multiple time points data.
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http://dx.doi.org/10.1186/s12919-018-0152-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157188PMC
September 2018

Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

Mol Psychiatry 2020 08 14;25(8):1859-1875. Epub 2018 Aug 14.

McDonnell Genome Institute, Washington University, St. Louis, MO, USA.

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
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http://dx.doi.org/10.1038/s41380-018-0112-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375806PMC
August 2020

Acute Right Ventricular Failure After Surgical Drainage of Pericardial Tamponade: A Case Report of Pericardial Decompression Syndrome and Review of the Literature.

J Cardiothorac Vasc Anesth 2019 Mar 3;33(3):768-771. Epub 2018 Apr 3.

Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. Electronic address:

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http://dx.doi.org/10.1053/j.jvca.2018.04.009DOI Listing
March 2019

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease.

Alzheimers Res Ther 2018 02 20;10(1):22. Epub 2018 Feb 20.

Bioinformatics Graduate Program, Boston University, Boston, MA, USA.

Background: Simultaneous consideration of two neuropathological traits related to Alzheimer's disease (AD) has not been attempted in a genome-wide association study.

Methods: We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data.

Results: Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10) and visual (P = 5.6 × 10) cortices.

Conclusions: Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.
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http://dx.doi.org/10.1186/s13195-018-0349-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819208PMC
February 2018

Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages.

Alzheimers Dement 2018 05 20;14(5):623-633. Epub 2017 Dec 20.

Department of Medicine (Biomedical Genetics), Boston University, Boston, MA, USA; Neurogenetics and Integrated Genomics, Andover Innovative Medicines (AiM) Institute, Eisai Inc, Andover, MA, USA. Electronic address:

Introduction: Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated.

Methods: We conducted genome-wide association studies for AD-related endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid Aβ and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative study.

Results: In CN subjects, study-wide significant (P < 8.3 × 10) loci were identified for total tau near SRRM4 and C14orf79 and for hippocampal volume near MTUS1. In mild cognitive impairment subjects, study-wide significant association was found with single nucleotide polymorphisms (SNPs) near ZNF804B for logical memory test of delayed recall scores. We found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls.

Discussion: Our findings for AD-related brain changes before AD provide insight about early AD-related biological processes.
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http://dx.doi.org/10.1016/j.jalz.2017.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938137PMC
May 2018

Silyl Ether as a Robust and Thermally Stable Dynamic Covalent Motif for Malleable Polymer Design.

J Am Chem Soc 2017 10 16;139(42):14881-14884. Epub 2017 Oct 16.

Department of Chemistry, University of California , Irvine, California 92697, United States.

Here we introduce silyl ether linkage as a novel dynamic covalent motif for dynamic material design. Through introduction of a neighboring amino moiety, we show that the silyl ether exchange rate can be accelerated by almost three orders of magnitude. By incorporating such silyl ether linkages into covalently cross-linked polymer networks, we demonstrate dynamic covalent network polymers displaying both malleability and reprocessability. The malleability of the networks is studied by monitoring stress relaxation at varying temperature, and their topology freezing temperatures are determined. The tunable dynamic properties coupled with the high thermal stability and reprocessability of silyl ether-based networks open doors to many potential applications for this family of materials.
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http://dx.doi.org/10.1021/jacs.7b08826DOI Listing
October 2017

Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

Alzheimers Dement 2017 Jul 7;13(7):727-738. Epub 2017 Feb 7.

Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA; Department of Neurological Sciences and Rush Alzheimer's Disease Center, Chicago, IL, USA; National Center for PTSD, Behavioral Science Division, Boston VA Healthcare System, Boston, MA, USA.

Introduction: Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.

Methods: We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.

Results: Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10).

Discussion: Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.
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http://dx.doi.org/10.1016/j.jalz.2016.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496797PMC
July 2017

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans.

Alzheimers Dement 2017 02 20;13(2):119-129. Epub 2016 Oct 20.

Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Alzheimer's Disease and CTE Center, Boston University School of Medicine, Boston, MA, USA; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.

Introduction: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power.

Methods: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs.

Results: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10), upstream of COBL, and rs16961023 (P = 4.6 × 10), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability.

Discussion: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS.
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http://dx.doi.org/10.1016/j.jalz.2016.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318231PMC
February 2017

Recovery of Muscle Strength After Intact Arthroscopic Rotator Cuff Repair According to Preoperative Rotator Cuff Tear Size.

Am J Sports Med 2016 Apr 5;44(4):972-80. Epub 2016 Feb 5.

Department of Orthopaedic Surgery, Mokdong Hospital, Ewha Womans University, Seoul, Korea.

Background: The recovery of muscle strength after arthroscopic rotator cuff repair based on the preoperative tear size has not yet been well described.

Purpose/hypothesis: The purpose of this study was to evaluate the recovery period of muscle strength by a serial assessment of isometric strength after arthroscopic rotator cuff repair based on the preoperative tear size. The hypothesis was that muscle strength in patients with small and medium tears would recover faster than that in those with large-to-massive tears.

Study Design: Cohort study; Level of evidence, 3.

Methods: A total of 164 patients who underwent arthroscopic rotator cuff repair were included. Isometric strength in forward flexion (FF), internal rotation (IR), and external rotation (ER) was evaluated preoperatively and at 6, 12, 18, and 24 months after surgery. Preoperative magnetic resonance imaging scans were assessed to evaluate the quality of the rotator cuff muscle, including fatty infiltration, occupation ratio, and tangent sign. Patient satisfaction as well as visual analog scale (VAS) for pain, American Shoulder and Elbow Surgeons (ASES), and Constant scores were assessed at every follow-up.

Results: Muscle strength demonstrated the slowest recovery in pain relief and the restoration of shoulder function. To reach the strength of the uninjured contralateral shoulder in all 3 planes of motion, recovery took 6 months in patients with small tears and 18 months in patients with medium tears. Patients with large-to-massive tears showed continuous improvement in strength up to 18 months; however, they did not reach the strength of the contralateral shoulder at final follow-up. At final follow-up, mean strength in FF, IR, and ER was 113.0%, 118.0%, and 112.6% of the contralateral shoulder in patients with small tears, respectively; 105.0%, 112.1%, and 102.6% in patients with medium tears, respectively; and 87.6%, 89.5%, and 85.2% in patients with large-to-massive tears, respectively. Muscle strength in any direction did not significantly correlate with postoperative patient satisfaction (P = .374, .515, and .692 for FF, IR, and ER, respectively), whereas it highly correlated with preoperative quality of the muscle.

Conclusion: The recovery of muscle strength after arthroscopic repair was poorly correlated with patient satisfaction. This study recommends that regardless of pain relief and improved shoulder function, patients with larger than medium tears should be encouraged to continue with rehabilitation for the maximal restoration of muscle strength beyond 1 year postoperatively.
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http://dx.doi.org/10.1177/0363546515625043DOI Listing
April 2016

Ultrasound-Guided Out-of-Plane vs. In-Plane Interscalene Catheters: A Randomized, Prospective Study.

Anesth Pain Med 2015 Dec 5;5(6):e31111. Epub 2015 Dec 5.

Department of Nursing, Thomas Jefferson University Hospital, Thomas Jefferson University, Philadelphia, USA.

Background: Continuous interscalene blocks provide excellent analgesia after shoulder surgery. Although the safety of the ultrasound-guided in-plane approach has been touted, technical and patient factors can limit this approach. We developed a caudad-to-cephalad out-of-plane approach and hypothesized that it would decrease pain ratings due to better catheter alignment with the brachial plexus compared to the in-plane technique in a randomized, controlled study.

Objectives: To compare an out-of-plane interscalene catheter technique to the in-plane technique in a randomized clinical trial.

Patients And Methods: Eighty-four patients undergoing open shoulder surgery were randomized to either the in-plane or out-of-plane ultrasound-guided continuous interscalene technique. The primary outcome was VAS pain rating at 24 hours. Secondary outcomes included pain ratings in the recovery room and at 48 hours, morphine consumption, the incidence of catheter dislodgments, procedure time, and block difficulty. Procedural data and all pain ratings were collected by blinded observers.

Results: There were no differences in the primary outcome of median VAS pain rating at 24 hours between the out-of-plane and in-plane groups (1.50; IQR, [0 - 4.38] vs. 1.25; IQR, [0 - 3.75]; P = 0.57). There were also no differences, respectively, between out-of-plane and in-plane median PACU pain ratings (1.0; IQR, [0 - 3.5] vs. 0.25; IQR, [0 - 2.5]; P = 0.08) and median 48-hour pain ratings (1.25; IQR, [1.25 - 2.63] vs. 0.50; IQR, [0 - 1.88]; P = 0.30). There were no differences in any other secondary endpoint.

Conclusions: Our out-of-plane technique did not provide superior analgesia to the in-plane technique. It did not increase the number of complications. Our technique is an acceptable alternative in situations where the in-plane technique is difficult to perform.
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http://dx.doi.org/10.5812/aapm.31111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688811PMC
December 2015

Mechanically Robust and Self-Healable Superlattice Nanocomposites by Self-Assembly of Single-Component "Sticky" Polymer-Grafted Nanoparticles.

Adv Mater 2015 Jul 27;27(26):3934-41. Epub 2015 May 27.

Department of Chemistry, 1102 Natural Sciences 2, University of California, Irvine, CA, 92697, USA.

A simple, scalable synthesis of mechanically robust and self-healable superlattice nanocomposites is achieved through self-assembly of single-component "sticky" polymer-grafted nanoparticles. The multi-valent hydrogen-bonding interactions between the nanoparticles provide strong cohesive energy, binding the nanoparticles into strong and tough materials. Furthermore, the dynamic hydrogen-bonding interactions afford the formation of highly dynamic, self-healing, and mechanochromic nanocomposite materials in the bulk.
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http://dx.doi.org/10.1002/adma.201500927DOI Listing
July 2015

Forced unfolding of single-chain polymeric nanoparticles.

J Am Chem Soc 2015 Jun 22;137(21):6880-8. Epub 2015 May 22.

†Institute for Complex Molecular Systems and Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands.

Atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) is applied to single-chain polymeric nanoparticles (SCPNs) to acquire information about the internal folding structure of SCPNs and inherent kinetic parameters of supramolecular self-assembling motifs embedded into the SCPNs. The SCPNs used here are polyacrylate-based polymers carrying 2-ureido-4-[1H]-pyrimidinone (UPy) or benzene-1,3,5-tricarboxamide (BTA) pendants that induce an intramolecular chain collapse into nanoparticles consisting of one polymer chain only via internal supramolecular cross-linking. The SCPN is stretched by an AFM cantilever to unfold mechanically, which allows measuring of force-extension profiles of the SCPNs. Consecutive peaks observed in the force profiles are attributed to rupture events of self-assembled UPy/BTA units in the SCPNs. The force profiles have been analyzed statistically for a series of polymers with different UPy/BTA incorporation densities. The results provide insights into the internal conformation of SCPNs, where the folding structure can be changed with the incorporation density of UPy/BTA. In addition, dynamic loading rate analysis allows the determination of kinetic parameters of BTA self-assembly, which has not been accessible by any other method. This study offers a rational tool for understanding the folding structure, kinetics, and pathway of two series of SCPNs.
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http://dx.doi.org/10.1021/jacs.5b02967DOI Listing
June 2015