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1. Using community-based geographical information system (GIS) to recruit older Asian Americans in an Alzheimer’s disease study

Author

Tiffany W Chow, Hyun-Sik Yang, Haeok Lee, Hoehun Ha, Sejung Yim, Veronica Lee, Eunju Hong, Van Ta Park, Li-San Wang, Gyungah Jun, and Yun-Beom Choi

Subjects
Medicine
Abstract

Objective This study aims to show the usefulness of incorporating a community-based geographical information system (GIS) in recruiting research participants for the Asian Cohort for Alzheimer’s Disease (ACAD) study for using the subgroup of Korean American (KA) older adults. The ACAD study is the first large study in the USA and Canada focusing on the recruitment of Chinese, Korean and Vietnamese older adults to address the issues of under-representation of Asian Americans in clinical research.Methods To promote clinical research participation of racial/ethnic minority older adults with and without dementia, we used GIS by collaborating with community members to delineate boundaries for geographical clusters and enclaves of church and senior networks, and KA serving ethnic clinics. In addition, we used socioeconomic data identified as recruitment factors unique to KA older adults which was analysed for developing recruitment strategies.Results GIS maps show a visualisation of the heterogeneity of the sociodemographic characteristics and the resources of faith-based organisations and KA serving local clinics. We addressed these factors that disproportionately affect participation in clinical research and successfully recruited the intended participants (N=60) in the proposed period.Discussion Using GIS maps to locate KA provided innovative inroads to successful research outreach efforts for a pilot study that may be expanded to other underserved populations across the USA in the future. We will use this tool subsequently on a large-scale clinical genetic epidemiology study.Policy implication This approach responds to the call from the National Institute on Aging to develop strategies to improve the health status of older adults in diverse populations. Our study will offer a practical guidance to health researchers and policymakers in identifying understudied and hard-to-reach specific Asian American populations for clinical studies or initiatives. This would further contribute in reducing the health and research disparity gaps among older minority populations.

Published
2023
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2. Correction: A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration.

Author

Theru A Sivakumaran, Robert P Igo, Jeffrey M Kidd, Andy Itsara, Laura J Kopplin, Wei Chen, Stephanie A Hagstrom, Neal S Peachey, Peter J Francis, Michael L Klein, Emily Y Chew, Vedam L Ramprasad, Wan-Ting Tay, Paul Mitchell, Mark Seielstad, Dwight E Stambolian, Albert O Edwards, Kristine E Lee, Dmitry V Leontiev, Gyungah Jun, Yang Wang, Liping Tian, Feiyou Qiu, Alice K Henning, Thomas LaFramboise, Parveen Sen, Manoharan Aarthi, Ronnie George, Rajiv Raman, Manmath Kumar Das, Lingam Vijaya, Govindasamy Kumaramanickavel, Tien Y Wong, Anand Swaroop, Goncalo R Abecasis, Ronald Klein, Barbara E K Klein, Deborah A Nickerson, Evan E Eichler, and Sudha K Iyengar

Subjects
Medicine, Science
Abstract

[This corrects the article DOI: 10.1371/journal.pone.0025598.].

Published
2018
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3. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

Author

Valentina Escott-Price, Céline Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L DeStefano, Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Adam C Naj, Rebecca Sims, Gyungah Jun, Joshua C Bis, Gary W Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A Thornton-Wells, Nicola Denning, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Maria Vronskaya, United Kingdom Brain Expression Consortium, Andrew D Johnson, Agustin Ruiz, Marie-Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiévet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B Larson, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renee F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Jean-François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Jonathan L Haines, Mark Lathrop, Margaret A Pericak-Vance, Lenore J Launer, Christine Van Broeckhoven, Lindsay A Farrer, Cornelia M van Duijn, Alfredo Ramirez, Sudha Seshadri, Gerard D Schellenberg, Philippe Amouyel, Julie Williams, and Cardiovascular Health Study (CHS)

Subjects
Medicine, Science
Abstract

BACKGROUND:Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS:In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE:The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

Published
2014
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4. Correction: Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians.

Author

Akinori Miyashita, Asako Koike, Gyungah Jun, Li-San Wang, Satoshi Takahashi, Etsuro Matsubara, Takeshi Kawarabayashi, Mikio Shoji, Naoki Tomita, Hiroyuki Arai, Takashi Asada, Yasuo Harigaya, Masaki Ikeda, Masakuni Amari, Haruo Hanyu, Susumu Higuchi, Takeshi Ikeuchi, Masatoyo Nishizawa, Masaichi Suga, Yasuhiro Kawase, Hiroyasu Akatsu, Kenji Kosaka, Takayuki Yamamoto, Masaki Imagawa, Tsuyoshi Hamaguchi, Masahito Yamada, Takashi Morihara, Masatoshi Takeda, Takeo Takao, Kenji Nakata, Yoshikatsu Fujisawa, Ken Sasaki, Ken Watanabe, Kenji Nakashima, Katsuya Urakami, Terumi Ooya, Mitsuo Takahashi, Takefumi Yuzuriha, Kayoko Serikawa, Seishi Yoshimoto, Ryuji Nakagawa, Jong-Won Kim, Chang-Seok Ki, Hong-Hee Won, Duk L. Na, Sang Won Seo, Inhee Mook-Jung, Peter St. George-Hyslop, Richard Mayeux, Jonathan L. Haines, Margaret A. Pericak-Vance, Makiko Yoshida, Nao Nishida, Katsushi Tokunaga, Ken Yamamoto, Shoji Tsuji, Ichiro Kanazawa, Yasuo Ihara, Gerard D. Schellenberg, Lindsay A. Farrer, and Ryozo Kuwano

Subjects
Medicine, Science
Published
2013
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5. SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians.

Author

Akinori Miyashita, Asako Koike, Gyungah Jun, Li-San Wang, Satoshi Takahashi, Etsuro Matsubara, Takeshi Kawarabayashi, Mikio Shoji, Naoki Tomita, Hiroyuki Arai, Takashi Asada, Yasuo Harigaya, Masaki Ikeda, Masakuni Amari, Haruo Hanyu, Susumu Higuchi, Takeshi Ikeuchi, Masatoyo Nishizawa, Masaichi Suga, Yasuhiro Kawase, Hiroyasu Akatsu, Kenji Kosaka, Takayuki Yamamoto, Masaki Imagawa, Tsuyoshi Hamaguchi, Masahito Yamada, Takashi Morihara, Masatoshi Takeda, Takeo Takao, Kenji Nakata, Yoshikatsu Fujisawa, Ken Sasaki, Ken Watanabe, Kenji Nakashima, Katsuya Urakami, Terumi Ooya, Mitsuo Takahashi, Takefumi Yuzuriha, Kayoko Serikawa, Seishi Yoshimoto, Ryuji Nakagawa, Jong-Won Kim, Chang-Seok Ki, Hong-Hee Won, Duk L Na, Sang Won Seo, Inhee Mook-Jung, Alzheimer Disease Genetics Consortium, Peter St George-Hyslop, Richard Mayeux, Jonathan L Haines, Margaret A Pericak-Vance, Makiko Yoshida, Nao Nishida, Katsushi Tokunaga, Ken Yamamoto, Shoji Tsuji, Ichiro Kanazawa, Yasuo Ihara, Gerard D Schellenberg, Lindsay A Farrer, and Ryozo Kuwano

Subjects
Medicine, Science
Abstract

To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values

Published
2013
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6. δ-Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes.

Author

Gyungah Jun, Juliet A Moncaster, Carolina Koutras, Sudha Seshadri, Jacqueline Buros, Ann C McKee, Georges Levesque, Philip A Wolf, Peter St George-Hyslop, Lee E Goldstein, and Lindsay A Farrer

Subjects
Medicine, Science
Abstract

Multiple lines of evidence suggest that specific subtypes of age-related cataract (ARC) and Alzheimer disease (AD) are related etiologically. To identify shared genetic factors for ARC and AD, we estimated co-heritability of quantitative measures of cataract subtypes with AD-related brain MRI traits among 1,249 members of the Framingham Eye Study who had a brain MRI scan approximately ten years after the eye exam. Cortical cataract (CC) was found to be co-heritable with future development of AD and with several MRI traits, especially temporal horn volume (THV, ρ = 0.24, P

Published
2012
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7. Influence of ROBO1 and RORA on risk of age-related macular degeneration reveals genetically distinct phenotypes in disease pathophysiology.

Author

Gyungah Jun, Michael Nicolaou, Margaux A Morrison, Jacqueline Buros, Denise J Morgan, Monte J Radeke, Yoshihiro Yonekawa, Evangelia E Tsironi, Maria G Kotoula, Fani Zacharaki, Nissa Mollema, Yang Yuan, Joan W Miller, Neena B Haider, Gregory S Hageman, Ivana K Kim, Debra A Schaumberg, Lindsay A Farrer, and Margaret M DeAngelis

Subjects
Medicine, Science
Abstract

ROBO1 is a strong candidate gene for age-related macular degeneration (AMD) based upon its location under a linkage peak on chromosome 3p12, its expression pattern, and its purported function in a pathway that includes RORA, a gene previously associated with risk for neovascular AMD. Previously, we observed that expression of ROBO1 and RORA is down-regulated among wet AMD cases, as compared to their unaffected siblings. Thus, we hypothesized that contribution of association signals in ROBO1, and interaction between these two genes may be important for both wet and dry AMD. We evaluated association of 19 single nucleotide polymorphisms (SNPs) in ROBO1 with wet and dry stages of AMD in a sibling cohort and a Greek case-control cohort containing 491 wet AMD cases, 174 dry AMD cases and 411 controls. Association signals and interaction results were replicated in an independent prospective cohort (1070 controls, 164 wet AMD cases, 293 dry AMD cases). The most significantly associated ROBO1 SNPs were rs1387665 under an additive model (meta P = 0.028) for wet AMD and rs9309833 under a recessive model (meta P = 6 × 10(-4)) for dry AMD. Further analyses revealed interaction between ROBO1 rs9309833 and RORA rs8034864 for both wet and dry AMD (interaction P

Published
2011
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8. A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration.

Author

Theru A Sivakumaran, Robert P Igo, Jeffrey M Kidd, Andy Itsara, Laura J Kopplin, Wei Chen, Stephanie A Hagstrom, Neal S Peachey, Peter J Francis, Michael L Klein, Emily Y Chew, Vedam L Ramprasad, Wan-Ting Tay, Paul Mitchell, Mark Seielstad, Dwight E Stambolian, Albert O Edwards, Kristine E Lee, Dmitry V Leontiev, Gyungah Jun, Yang Wang, Liping Tian, Feiyou Qiu, Alice K Henning, Thomas LaFramboise, Parveen Sen, Manoharan Aarthi, Ronnie George, Rajiv Raman, Manmath Kumar Das, Lingam Vijaya, Govindasamy Kumaramanickavel, Tien Y Wong, Anand Swaroop, Goncalo R Abecasis, Ronald Klein, Barbara E K Klein, Deborah A Nickerson, Evan E Eichler, and Sudha K Iyengar

Subjects
Medicine, Science
Abstract

Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10(-109)); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10(-9)) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.

Published
2011
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9. EPHA2 is associated with age-related cortical cataract in mice and humans.

Author

Gyungah Jun, Hong Guo, Barbara E K Klein, Ronald Klein, Jie Jin Wang, Paul Mitchell, Hui Miao, Kristine E Lee, Tripti Joshi, Matthias Buck, Preeti Chugha, David Bardenstein, Alison P Klein, Joan E Bailey-Wilson, Xiaohua Gong, Tim D Spector, Toby Andrew, Christopher J Hammond, Robert C Elston, Sudha K Iyengar, and Bingcheng Wang

Subjects
Genetics, QH426-470
Abstract

Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of age-related cataract. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. We report that homozygous deletion of Epha2 in two independent strains of mice developed progressive cortical cataract. Retroillumination revealed development of cortical vacuoles at one month of age; visible cataract appeared around three months, which progressed to mature cataract by six months. EPHA2 protein expression in the lens is spatially and temporally regulated. It is low in anterior epithelial cells, upregulated as the cells enter differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. Deletion of Epha2 caused a significant increase in the expression of HSP25 (murine homologue of human HSP27) before the onset of cataract. The overexpressed HSP25 was in an underphosphorylated form, indicating excessive cellular stress and protein misfolding. The orthologous human EPHA2 gene on chromosome 1p36 was tested in three independent worldwide Caucasian populations for allelic association with cortical cataract. Common variants in EPHA2 were found that showed significant association with cortical cataract, and rs6678616 was the most significant in meta-analyses. In addition, we sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln, in the protein kinase domain that significantly alters EPHA2 functions in cellular and biochemical assays. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with age.

Published
2009
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10. Plasma p‐tau 181 shows stronger network association to Alzheimer's disease dementia than neurofilament light and total tau

Author

Robert S. Stern, Neil W. Kowall, Thomas K. Karikari, Brett Martin, Gyungah Jun, Thor D. Stein, Bailee Brekke, Michael A. Sugarman, Irene Simkina, Eric G. Steinberg, Wei Qiao Qiu, Madeline Ally, Nicholas J. Ashton, Rhoda Au, Katherine W. Turk, Kaj Blennow, Joseph Palmisano, Andrew E. Budson, Jesse Mez, Yorghos Tripodis, Ronald J. Killiany, Maureen K. O’Connor, Henrik Zetterberg, Lee E. Goldstein, Brandon Frank, Ann C. McKee, and Michael L. Alosco

Subjects
Oncology, medicine.medical_specialty, medicine.diagnostic_test, Epidemiology, business.industry, Health Policy, Neurofilament light, Neuropsychology, Total tau, Disease, Neuropsychological test, Plasma biomarkers, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, mental disorders, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, Association (psychology), business
Abstract

Introduction We examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL). Methods Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables. Results Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM. Discussion These results support plasma p-tau181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.

Published
2021

11. A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages

Author

Jee Hye Choi, Sangmyung Rhee, Sung Haeng Lee, Simon Lovestone, Lee Sael, Ah Ra Do, Jungsoo Gim, Suparna Ghosh, Sanghun Lee, Kyu Yeong Choi, SangYun Kim, Seula Keum, Juhong Park, Lindsay A. Farrer, Jang Jae Lee, Andrew J. Saykin, Gyun Jee Song, Byeong C. Kim, Kwangsik Nho, Jun Young Park, Eunae Kim, Kun Ho Lee, Immanuel Dhanasingh, Seung Hwan Moon, Hoowon Kim, Kyungtaek Park, Donghe Li, Jinyeon Jo, Tamil Iniyan Gunasekaran, Dong Soo Lee, Sungho Won, Sarang Kang, and Gyungah Jun

Subjects
Oncology, medicine.medical_specialty, Nerve Tissue Proteins, Neurosciences. Biological psychiatry. Neuropsychiatry, Disease, Article, Pathogenesis, Cellular and Molecular Neuroscience, Atrophy, Ubiquitin, Neuroimaging, Alzheimer Disease, Internal medicine, Genetics, Humans, Medicine, Missense mutation, Cognitive Dysfunction, Ubiquitins, Biological Psychiatry, Genetic association, Amyloid beta-Peptides, biology, business.industry, Brain, medicine.disease, Magnetic Resonance Imaging, Psychiatry and Mental health, biology.protein, Signal transduction, business, Biomarkers, Genome-Wide Association Study, RC321-571
Abstract

Established genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.

Published
2021

12. Antemortem Domain-Specific Cognitive Functions Predict Postmortem Neuropathological Traits in the Framingham Heart Study

Author

Donghe Li, Yuehting Wang, Ting F.A. Ang, Weiming Xia, Nurgul Aytan, Jesse Mez, Sherral Devine, Rhoda Au, Lindsay A. Farrer, Thor D. Stein, and Gyungah Jun

Abstract

Background: Clinical diagnosis of Alzheimer’s disease is aided by neuropsychological (NP) tests. However, correlations between antemortem domain specific cognitive functions from NP tests and neuropathological outcomes at autopsy are not well known. Methods: We conducted association tests between antemortem NP tests and postmortem neuropathological traits in 159 participants from the Framingham Heart Study (FHS). The NP tests included memory, language, executive, and visuospatial domains. Neuropathological traits contained neuropathological diagnosis of AD (AD), Braak stage, neuritic plaque score, and quantitative measures of site-specific tau phosphorylation (pTau), density of microglia and synaptic protein density from the dorsolateral prefrontal cortex area of the autopsied brains in the FHS subjects. For the most significantly associated postmortem outcome (pTau) with antemortem cognitive domains, we compared prediction models containing significant cognitive domains with those including all cognitive domains, adjusting for interval age and APOE ɛ4 status as covariates. Results: We identified significant associations for AD pathology with memory, language, and executive domains (best P with memory=1.1x10-4). At least three distinct cognitive domains were nominally associated (PConclusions: These findings confirm significant associations between antemortem domain specific cognitive tests and neuropathological traits at autopsy, especially postmortem measures of phosphorylated tau levels. Prediction models demonstrated that impairment in block design alone is sufficient to predict a high-level of pTau396 at autopsy.

Published
2022

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

Author

Preeti Gupta, Maryam Hazly Hilmy, Jie Jin Wang, Jiemin Liao, Allan Fong, Maria K. Swift, Johanna M. Colijn, Paul Mitchell, Ya Xing Wang, Anita S Y Chan, Barbara E.K. Klein, Pirro G. Hysi, Jaeyoon Chung, Emily Y. Chew, Wanting Zhao, Yang Shen, Ava Grace Tan, Hengtong Li, Eranga N. Vithana, Gyungah Jun, Wenting Liu, Tin Aung, Qiao Fan, Yuan Shi, Ekaterina Yonova-Doing, Soon-Phaik Chee, Sudha K. Iyengar, Yik Ying Teo, Periasamy Sundaresan, Chiea Chuen Khor, Zheng Li, Kathryn P. Burdon, Miao Ling Chee, Yih Chung Tham, Christopher J Hammond, Xiaoran Chai, Kerrin S. Small, Queenie S. Tan, Jacqueline Chua, Jost B. Jonas, Astrid E. Fletcher, Alexessander Couto Alves, Pieter W.M. Bonnemaijer, Ravilla D. Ravindran, Mei Chin Lee, Milly S. Tedja, Robert P. Igo, Kristine E. Lee, Tien Y Wong, Xinyi Su, Caroline C W Klaver, Xueling Sim, Ching-Yu Cheng, Chaolong Wang, Lars G. Fritsche, Epidemiology, and Ophthalmology

Subjects
0301 basic medicine, Genotype, genetic structures, QH301-705.5, Medicine (miscellaneous), Genome-wide association study, Disease, Bioinformatics, Polymorphism, Single Nucleotide, Genome-wide association studies, Cataract, Article, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Genetic variation, Humans, Medicine, Genetic Predisposition to Disease, Allele, Biology (General), Alleles, Genetic Association Studies, Genetic association, business.industry, SOXB1 Transcription Factors, Genetic Variation, medicine.disease, eye diseases, 030104 developmental biology, Age-related nuclear cataract, 030221 ophthalmology & optometry, Congenital cataracts, Lens diseases, sense organs, General Agricultural and Biological Sciences, business, Genome-Wide Association Study
Abstract

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 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 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10−19), TMPRSS5 (rs4936279, P = 2.5 × 10−10), LINC01412 (rs16823886, P = 1.3 × 10−9), GLTSCR1 (rs1005911, P = 9.8 × 10−9), and COMMD1 (rs62149908, P = 1.2 × 10−8). 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., Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.

Published
2020

14. African Ancestry GWAS of Dementia in a Large Military Cohort Identifies Significant Risk Loci

Author

Richard Sherva, Rui Zhang, Nathan Sahelijo, Gyungah Jun, Tori Anglin, Catherine Chanfreau, Kelly Cho, Jennifer R. Fonda, J. Michael Gaziano, Kelly M. Harrington, Yuk-Lam Ho, William S. Kremen, Elizabeth Litkowski, Julie Lynch, Zoe Neale, Panos Roussos, David Marra, Jesse Mez, Mark W. Miller, David H. Salat, Debby Tsuang, Erika Wolf, Qing Zeng, Matthew S. Panizzon, Victoria C. Merritt, Lindsay A. Farrer, Richard L. Hauger, and Mark W. Logue

Subjects
Cellular and Molecular Neuroscience, Psychiatry and Mental health, Molecular Biology
Abstract

We conducted the largest genome-wide association study (GWAS) of Alzheimer’s disease and related dementia (ADRD) in individuals of African-ancestry (AFR) to date using participants from the Million Veteran Program (MVP; 4,012 ADRD cases and 18,435 controls). A proxy GWAS based on survey-reported parental dementia (n=6,641 proxy cases, 45,970 controls) was also performed. The MVP AFR ADRD GWAS and proxy GWAS results were meta-analyzed and combined with the Alzheimer’s Disease Genetics Consortium’s (ADGC) AFR AD GWAS results. The MVP meta-analysis yielded genome-wide significant associations in or near APOE, ROBO1, and RP11-340A13.2. The MVP/ADGC meta-analysis yielded additional genome-wide significant variants near known risk genes TREM2, CD2AP, and ABCA7. We examined differences in expression of the implicated genes in a cohort of AD case and control brains. This study provides insight into dementia pathophysiology in historically understudied individuals of AFR and may help to address health disparities.

Published
2022

15. Blood and brain transcriptome analysis reveals APOE genotype-mediated and immune-related pathways involved in Alzheimer disease

Author

David A. Bennett, Lindsay A. Farrer, Weiming Xia, Rebecca Panitch, Gyungah Jun, Thor D. Stein, and Junming Hu

Subjects
Apolipoprotein E, Genotype, Cognitive Neuroscience, Apolipoprotein E4, Neurosciences. Biological psychiatry. Neuropsychiatry, Biology, Vascular injury, Transcriptome, Immune system, Apolipoproteins E, Differential expression, Alzheimer Disease, medicine, Humans, RC346-429, Blood-brain barrier, Co-expression network, Gene Expression Profiling, Brain, medicine.disease, Neurology, Immunology, Neurology. Diseases of the nervous system, Neurology (clinical), Alzheimer's disease, Alzheimer’s disease, APOE, RC321-571
Abstract

Background While Alzheimer disease (AD) is generally considered as a brain disorder, blood biomarkers may be useful for the diagnosis and prediction of AD brain pathology. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood-brain barrier (BBB) breakdown. Methods We evaluated the differential expression of previously established AD genes in brains from 344 pathologically confirmed AD cases and 232 controls and in blood from 112 pathologically confirmed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. Differential gene expression between AD cases and controls was analyzed in the blood and brain jointly using a multivariate approach in the total sample and within APOE genotype groups. Gene set enrichment analysis was performed within APOE genotype groups using the results from the combined blood and brain analyses to identify biologically important pathways. Gene co-expression networks in brain and blood samples were investigated using weighted correlation network analysis. Top-ranked genes from networks and pathways were further evaluated with vascular injury traits. Results We observed differentially expressed genes with P < 0.05 in both brain and blood for established AD genes INPP5D (upregulated) and HLA-DQA1 (downregulated). PIGHP1 and FRAS1 were differentially expressed at the transcriptome-wide level (P < 3.3 × 10−6) within ε2/ε3 and ε3/ε4 groups, respectively. Gene set enrichment analysis revealed 21 significant pathways (false discovery rate P < 0.05) in at least one APOE genotype group. Ten pathways were significantly enriched in the ε3/ε4 group, and six of these were unique to these subjects. Four pathways (allograft rejection, interferon gamma response, peroxisome, and TNFA signaling via NFKB) were enriched for AD upregulated genes in the ε3/ε4 group and AD downregulated genes in subjects lacking ε4. We identified a co-expressed gene network in the brain that reproduced in blood and showed higher average expression in ε4 carriers. Twenty-three genes from pathway and network analyses were significantly associated with at least one vascular injury trait. Conclusion These results suggest that the APOE genotype contributes to unique expression network profiles in both blood and brain. Several genes in these networks are associated with measures of vascular injury and potentially contribute to ε4’s effect on the BBB.

Published
2022

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

Author

Jaeyoon Chung, Gyungah Jun, Lindsay A. Farrer, and Josée Dupuis

Subjects
Multivariate statistics, Single-nucleotide polymorphism, Genome-wide association study, Disease, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Genetics, medicine, Humans, Computer Simulation, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Univariate, medicine.disease, Multivariate Analysis, Alzheimer's disease, 030217 neurology & neurosurgery, Genome-Wide Association Study, Type I and type II errors
Abstract

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

Published
2019

17. Cytokine Levels in Human Vitreous in Proliferative Diabetic Retinopathy

Author

Manju L Subramanian, Jaeyoon Chung, Weiming Xia, Gyungah Jun, Thor D. Stein, Dean F. Loporchio, Emily K Tam, Marissa G. Fiorello, Jane Cho, Nicole Siegel, and Steven Ness

Subjects
0301 basic medicine, Male, Vascular Endothelial Growth Factor A, endocrine system diseases, medicine.medical_treatment, interleukin-16, Vitrectomy, interleukin-15, neuroinflammatory markers, Pathogenesis, chemistry.chemical_compound, 0302 clinical medicine, Medicine, vitreous cytokines, Biology (General), vascular endothelial growth factor, General Medicine, Diabetic retinopathy, Middle Aged, Intercellular Adhesion Molecule-1, Vascular endothelial growth factor, Cytokine, C-Reactive Protein, Interleukin 15, Female, Fibroblast Growth Factor 2, Interleukin 16, medicine.medical_specialty, QH301-705.5, Vascular Cell Adhesion Molecule-1, Article, 03 medical and health sciences, Ophthalmology, Humans, cardiovascular diseases, Interleukin 8, Diabetic Retinopathy, quantitative immunoassay, business.industry, Interleukins, interleukin-8, basic fibroblast growth factor, medicine.disease, eye diseases, Vitreous Body, 030104 developmental biology, chemistry, 030221 ophthalmology & optometry, sense organs, business
Abstract

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 (n = 35) and non-PDR (n = 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 (p &lt, 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.

Published
2021

18. Differential effects of apolipoprotein E on the molecular and cellular phenotypes associated with Alzheimer’s disease in isogenic human iPSC‐derived neurons

Author

Wayne W. Poon, Gyungah Jun, Tsuneya Ikezu, Yang You, and Lindsay A. Farrer

Subjects
Apolipoprotein E, Epidemiology, Health Policy, Disease, Biology, Phenotype, Differential effects, Cell biology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Neurology (clinical), Geriatrics and Gerontology, Stem cell, Induced pluripotent stem cell
Published
2020

19. Mechanism for the protective effect of APOE ε2 against Alzheimer disease is linked to tau and the classical complement pathway

Author

Thor D. Stein, Kathryn L. Lunetta, Junming Hu, Lindsay A. Farrer, Richard Mayeux, Jonathan L. Haines, Gerard D. Schellenberg, Li-San Wang, Rebecca Panitch, Margaret A. Pericak-Vance, Jaeyoon Chung, Congcong Zhu, and Gyungah Jun

Subjects
Apolipoprotein E, Epidemiology, Chemistry, Mechanism (biology), Health Policy, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Classical complement pathway, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Neuroscience
Published
2020

20. Defining Alzheimer’s disease subtypes using polygenic risk scores integrated with genomic and brain transcriptomic profiles

Author

Jaeyoon Chung, Congcong Zhu, Paul K. Crane, Gyungah Jun, Thor D. Stein, Jesse Mez, Junming Hu, Lindsay A. Farrer, Rebecca Panitch, and Gary W. Beecham

Subjects
Transcriptome, Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Polygenic risk score, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology
Published
2020

21. Novel mechanism underlying the APOE ε2 protective effect for Alzheimer disease implicated by integrative genome and transcriptome analysis

Author

Lindsay A. Farrer, Congcong Zhu, Jaeyoon Chung, Gyungah Jun, Thor D. Stein, Junming Hu, and Rebecca Panitch

Subjects
Apolipoprotein E, Genetics, Epidemiology, Mechanism (biology), Health Policy, Systems biology, Biology, Omics, medicine.disease, Genome, Transcriptome, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease
Published
2020

22. Protein phosphatase 2A, complement component 4, and APOE genotype linked to Alzheimer’s disease using a systems biology approach

Author

Schellenberg Gd, Haines Jl, K. L. Lunetta, Lindsay A. Farrer, Gaoyuan Meng, Yang You, Jaeyoon Chung, Tatiana Foroud, Richard Mayeux, Tsuneya Ikezu, David A. Bennett, Li-San Wang, Rhoda Au, Margaret A. Pericak-Vance, Junming Hu, Congcong Zhu, Rebecca Panitch, Weiming Xia, Gyungah Jun, and Thor D. Stein

Subjects
Genetics, Apolipoprotein E, Complement component 4, Classical complement pathway, Genotype, medicine, Genome-wide association study, Protein phosphatase 2, Allele, Alzheimer's disease, Biology, medicine.disease
Abstract

BackgroundRecent reports suggest that the rare apolipoprotein E (APOE) Christchurch mutation and ε2 allele protect against Alzheimer’s disease (AD) pathology by reducing the burden of tau pathology. However, the mechanism(s) underlying the ε2 protective effect linking to tau is largely unknown.MethodsThe role of the ε2 allele in Alzheimer’s disease (AD) was investigated a genome-wide association study (GWAS) for AD among 2,120 ε2 carriers from the Alzheimer Disease Genetics Consortium (ADGC), and then prioritized by gene network analysis, differential gene expression analysis at tissue- and cell-levels as well as methylation profiling of CpG sites, in prefrontal cortex tissue from 761 brains of the Religious Orders Study and Memory and Aging Project (ROSMAP) and the Framingham Heart Study (FHS), Boston University Alzheimer’s Disease Center (BUADC). The levels of two catalytic subunit proteins from protein phosphatase 2A (PPP2CA and PPP2CB) were validated in prefrontal cortex area of 193 of the FHS/BUADC brains. The findings from human autopsied brains were further validated by a co-culture experiment of human isogenic APOE induced pluripotent stem cell (iPSC) derived neurons and astrocytes.ResultsOf the significantly associated loci with AD among APOE ε2 carriers (P−6), PPP2CB (P=1.1×10−7) was the key node in the APOE ε2-related gene network and contained the most significant CpG site (P=7.3×10−4) located 2,814 base pair upstream of the top-ranked GWAS variant. Among APOE ε3/ε4 subjects, the level of Aβ42 was negatively correlated with protein levels of PPP2CA (P=9.9×10−3) and PPP2CB (P=2.4×10−3), and PPP2CA level was correlated with the level of pTau231 level (P=5.3×10−3). Significant correlations were also observed for PPP2CB with complement 4B (C4B) protein levels (P=3.3×10−7) and PPP2CA with cross reactive protein (CRP) levels (P=6.4×10−4). C1q level was not associated with Aβ42, pTau231, PPP2CB, or C4B levels. We confirmed the significant correlation of PPP2CB expression with pTau231/tTau ratio (P=0.01) and C4A/B (P=2.0×10−4) expression observed in brain tissue in a co-culture experiment of iPSC derived neurons and astrocytes.ConclusionWe demonstrated for the first time a molecular link between a tau phosphatase and the classical complement pathway, especially C4, and AD-related tau pathology.

Published
2020

23. Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease

Author

Lindsay A. Farrer, David A. Bennett, Gyungah Jun, Thor D. Stein, Junming Hu, Rebecca Panitch, Kathryn L. Lunetta, Weiming Xia, Congcong Zhu, Rhoda Au, Jaeyoon Chung, Gaoyuan Meng, and Tsuneya Ikezu

Subjects
Apolipoprotein E, Genotype, Apolipoprotein E2, Molecular biology, Biology, Article, Transcriptome, Cellular and Molecular Neuroscience, Alzheimer Disease, Gene expression, medicine, Genetics, Humans, HSP70 Heat-Shock Proteins, Gene, Complement component 4, Gene Expression Profiling, C4A, Brain, Complement C4, medicine.disease, Oligodendrocyte, Complement system, Psychiatry and Mental health, medicine.anatomical_structure, Immunology, Alzheimer's disease, Neuroscience
Abstract

Mechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer’s disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135 APOE ε 2/ε 3 carriers. Complement pathway genes C4A and C4B were among the most significantly differentially expressed genes between ε 2/ε 3 AD cases and controls. We also identified an APOE ε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genes C4A, C4B, and HSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting this APOE ε 2 related co-expression network may primarily be involved with tau pathology. HSPA2 expression was oligodendrocyte specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect of APOE ε2 for AD.

Published
2020

24. Neurofilament light chain in the vitreous humor of the eye

Author

Gyungah Jun, Thor D. Stein, Madeleine Zetterberg, Viha Vig, Kaj Blennow, Manju L Subramanian, Farah Shareef, Weiming Xia, Nicole Siegel, Jaeyoon Chung, Marissa G. Fiorello, Henrik Zetterberg, and Steven Ness

Subjects
Vascular Endothelial Growth Factor A, Apolipoprotein E, Chemokine, medicine.medical_specialty, Amyloid beta, Cognitive Neuroscience, medicine.medical_treatment, Intermediate Filaments, tau Proteins, Vitrectomy, Vitreous humor, lcsh:RC346-429, lcsh:RC321-571, Proinflammatory cytokine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cerebrospinal fluid, Alzheimer Disease, Neurofilament Proteins, Ophthalmology, Humans, Medicine, Prospective Studies, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Amyloid beta-Peptides, biology, business.industry, Research, Ocular biomarkers, 3. Good health, Vitreous Body, Vascular endothelial growth factor, Cross-Sectional Studies, Neurology, chemistry, 030221 ophthalmology & optometry, biology.protein, Biomarker (medicine), Neurology (clinical), Tau, business, Alzheimer’s disease, Biomarkers, Neuro-filament light chain, 030217 neurology & neurosurgery
Abstract

BackgroundNeurofilament 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.MethodsThis 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,APOEgenotypes, MMSE scores, and ophthalmic and systemic diseases after adjustment for age, sex, education level, and other eye diseases.ResultsNfL 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 Aβ40(p = 7.7 × 10−5), Aβ42(p = 2.8 × 10−4), and t-tau (p = 5.5 × 10−7), 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 × 10−4), IL-16 (p = 2.2 × 10−4), monocyte chemoattractant protein-1 (MCP1,p = 4.1 × 10−4), and vascular proteins such as vascular endothelial growth factor receptor-1 (VEGFR1,p = 2.9 × 10−6), Vegf-C (p = 8.6 × 10−6), vascular cell adhesion molecule-1 (VCAM-1,p = 5.0 × 10−4), Tie-2 (p = 6.3 × 10−4), and intracellular adhesion molecular-1 (ICAM-1,p = 1.6 × 10−4).ConclusionNfL 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.

Published
2020

25. Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ε4 genotype

Author

Raymond Nicks, Oliver J. Standring, Jacob S. Friedberg, Sarah Svirsky, Gaoyuan Meng, Gyungah Jun, Hoon Ryu, Thor D. Stein, Rhoda Au, Jonathan D. Cherry, Victor E. Alvarez, Nurgul Aytan, and Weiming Xia

Subjects
Male, Apolipoprotein E, Apolipoprotein E4, lcsh:Medicine, Cell Count, Disease, Cohort Studies, 0302 clinical medicine, Genotype, lcsh:Science, Aged, 80 and over, 0303 health sciences, Multidisciplinary, Microglia, Microfilament Proteins, Brain, Alzheimer's disease, 3. Good health, medicine.anatomical_structure, Cytokines, Female, medicine.symptom, Antigens, Differentiation, Myelomonocytic, tau Proteins, Inflammation, Neuropathology, Models, Biological, Article, 03 medical and health sciences, Antigens, CD, medicine, Humans, Neurodegeneration, Allele, Alleles, 030304 developmental biology, Amyloid beta-Peptides, business.industry, Calcium-Binding Proteins, lcsh:R, medicine.disease, Immunology, Dementia, lcsh:Q, business, Biomarkers, 030217 neurology & neurosurgery
Abstract

Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. The apolipoprotein E (APOE) ε4 allele is the most common genetic risk factor for AD and is related to a pro-inflammatory state. To test the hypothesis that microglia and AD-implicated cytokines were differentially associated with AD pathology based on the presence of APOE ε4, we examined the dorsolateral frontal cortex from deceased participants within a community-based aging cohort (n = 154). Cellular density of Iba1, a marker of microglia, was positively associated with tau pathology only in APOE ε4 positive participants (p = 0.001). The cytokines IL-10, IL-13, IL-4, and IL-1α were negatively associated with tau pathology, independent of Aβ1–42 levels, only in APOE ε4 negative participants. Overall, the association of mostly anti-inflammatory cytokines with less tau pathology suggests a protective effect in APOE ε4 negative participants. These associations are largely absent in the presence of APOE ε4 where tau pathology was significantly associated with increased microglial cell density. Taken together, these results suggest that APOE ε4 mediates an altered inflammatory response and increased tau pathology independent of Aβ1–42 pathology.

Published
2020

26. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes

Author

Bradley T. Hyman, Gerard D. Schellenberg, Jean Paul Vonsattel, Yinghua Chen, Matthew J. Huentelman, Thomas G. Beach, Julie A. Schneider, Walter A. Kukull, M. Ilyas Kamboh, Bernardino Ghetti, Richard J. Caselli, Kathryn L. Lunetta, Yi Su, John Q. Trojanowski, Eric B. Larson, Julia Kofler, John Hardy, John Gilbert, Amanda J. Myers, Margaret A. Pericak-Vance, Thomas J. Montine, Richard Mayeux, Paul K. Crane, Joseph D. Buxbaum, Yakeel T. Quiroz, Linda Duque, Steven G. Younkin, David A. Bennett, Matthew P. Frosch, Tatiana Foroud, Lindsay A. Farrer, Joseph F. Arboleda-Velasquez, Harry E. Gwirtsman, Philip L. De Jager, Jonathan L. Haines, C. Dirk Keene, Dennis W. Dickson, Eric M. Reiman, Gyungah Jun, Li-San Wang, and Gary W. Beecham

Subjects
Apolipoprotein E, 0303 health sciences, medicine.medical_specialty, business.industry, Odds ratio, Disease, medicine.disease, Lower risk, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, mental disorders, medicine, Dementia, Alzheimer s dementia, Allele, business, 030217 neurology & neurosurgery, Alzheimers dementia, 030304 developmental biology
Abstract

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, such that APOE4 homozygotes have a particularly high risk. While the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with exceptionally low Alzheimer’s dementia odds ratios compared to APOE2/3, 3/3 and 4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of this terrible disease.

Published
2019

27. APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer’s Disease Risk in a Multiracial Sample

Author

Catriona McLean, Alzheimer's Disease Neuroimaging Initative, Ari Chong, Woo Keun Song, Sujin Seo, Pan-Woo Ko, Min Soo Byun, Ji Yeon Chung, Ho-Won Lee, Ryozo Kuwano, Gyungah Jun, Min-Kyung Song, Seong Soo A. An, So-Yoon Won, Sungho Won, Dong Young Lee, Jee Hyang Jeong, Jangho Jeong, Sangmyung Rhee, Kyung Won Park, Ji Won Han, Wooje Lee, Jang Jae Lee, Kyu Yeong Choi, Hoowon Kim, Takeshi Ikeuchi, Congcong Zhu, Ho Jae Lim, John J. Farrell, Byeong C. Kim, Jungsoo Gim, Akinori Miyashita, Young-Min Lee, Jung-Min Ha, I L Han Choo, Richard Mayeux, Eun Hyun Seo, Margaret A. Pericak-Vance, Yu Yong Choi, Seok Cheol Lee, Tamil Iniyan Gunasekaran, Gerard D. Schellenberg, Kathryn L. Lunetta, Sarang Kang, Seong Hye Choi, Seong-Min Choi, Norikazu Hara, Ki Woong Kim, Jonathan L. Haines, SangYun Kim, Kwangsik Nho, Xiaoling Zhang, Kun Ho Lee, Lindsay A. Farrer, and Jung Sup Lee

Subjects
Apolipoprotein E, medicine.medical_specialty, genetic association, lcsh:Medicine, Single-nucleotide polymorphism, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, medicine, SNP, Allele, 10. No inequality, Allele frequency, 030304 developmental biology, Genetic association, 0303 health sciences, business.industry, lcsh:R, ethnic variability, General Medicine, Odds ratio, APOE, promoter polymorphism, Endocrinology, business, Alzheimer’s disease, 030217 neurology & neurosurgery, brain atrophy
Abstract

Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer’s disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10−94, GT: OR = 15.87, p = 2.62 × 10−9) and EuroAs (TT: OR = 18.13, p = 2.69 × 10−108, GT: OR = 12.63, p = 3.44 × 10−64), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes.

Published
2019
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28. Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype

Author

Gerard D. Schellenberg, Myriam Fornage, Philip L. De Jager, Stéphanie Debette, Lindsay A. Farrer, Eden R. Martin, Richard Mayeux, Brian W. Kunkle, Adam C. Naj, David A. Bennett, Kathryn L. Lunetta, Margaret A. Pericak-Vance, Sudha Seshadri, Jaeyoon Chung, Joshua C. Bis, Gyungah Jun, Yuning Chen, Jean-Charles Lambert, Anita L. DeStefano, Kara L. Hamilton-Nelson, Céline Bellenguez, Gaël Nicolas, Yiyi Ma, Cornelia M. van Duijn, Xiaoling Zhang, Jonathan L. Haines, and Epidemiology

Subjects
Oncology, Apolipoprotein E, medicine.medical_specialty, Genotype imputation, business.industry, Odds ratio, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, medicine, 030212 general & internal medicine, Neurology (clinical), Allele, Alzheimer's disease, business, 030217 neurology & neurosurgery, Exome sequencing, Genetic association, Original Investigation
Abstract

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.

Published
2019

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

Author

Jonathan L. Haines, Kathryn L. Lunetta, Gerard D. Schellenberg, David A. Bennett, Jaeyoon Chung, Gyungah Jun, Richard Mayeux, Xiaoling Zhang, Philip L. De Jager, Lindsay A. Farrer, Brian W. Kunkle, Adam C. Naj, Margaret A. Pericak-Vance, Yiyi Ma, and Charles C. White

Subjects
0301 basic medicine, Apolipoprotein E, Oncology, mQTL, Aging, medicine.medical_specialty, Single-nucleotide polymorphism, Biology, eQTL, PICALM, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, Internal medicine, medicine, genetics, Original Paper, DNA methylation, epigenetics, Cell Biology, medicine.disease, Original Papers, 3. Good health, 030104 developmental biology, CpG site, Expression quantitative trait loci, Alzheimer disease, Alzheimer's disease, 030217 neurology & neurosurgery
Abstract

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

Published
2019

30. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report

Author

Lishuang Shen, Yinghua Chen, Kewei Chen, Silvia Rios-Romenets, Yi Su, Henrik Zetterberg, Moiz Bootwalla, Michael J. O'Hare, Arabiye Artola, Pierre N. Tariot, John B Miller, Dhanesh Amarnani, Ana Baena, Gyungah Jun, Yakeel T. Quiroz, Juliana Acosta-Uribe, Rebecca Reiman, Pradeep Thiyyagura, Marcus Naymik, Kenneth S. Kosik, Aaron P. Schultz, Daniel J. Norton, Matthew J. Huentelman, Keith A. Johnson, Santiago Delgado-Tirado, Enmanuelle Pardilla-Delgado, Francisco Lopera, Reisa A. Sperling, Leo A. Kim, Natalia Chmielewska, Eric M. Reiman, Joseph F. Arboleda-Velasquez, Edmarie Guzmán-Vélez, Xiaowu Gai, Jianling Ji, David Aguillon, Matthew A. Lalli, Justin S. Sanchez, Kahira L. Saez-Torres, Claudia Marino, Kaj Blennow, David Leyton-Cifuentes, Margarita Giraldo, and Ji Luo

Subjects
0301 basic medicine, Apolipoprotein E, Male, Aging, Amyloid, Apolipoprotein E2, Immunology, Apolipoprotein E3, Disease, Neurodegenerative, Alzheimer's Disease, Medical and Health Sciences, General Biochemistry, Genetics and Molecular Biology, Presenilin, Article, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Mutation Carrier, Alzheimer Disease, mental disorders, PSEN1, Acquired Cognitive Impairment, Presenilin-1, Medicine, 2.1 Biological and endogenous factors, Humans, Cognitive Dysfunction, Aged, business.industry, Prevention, Homozygote, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain, Neurodegenerative Diseases, General Medicine, Brain Disorders, Pedigree, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Neurological, Mutation, Dementia, Female, business
Abstract

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.

Published
2019

31. Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel

Author

James B. Brewer, Marilyn S. Albert, Bradley T. Hyman, Takiyah D. Starks, Russell H. Swerdlow, Jeffery M. Vance, Mary Sano, Gerard D. Schellenberg, Jennifer J. Manly, Walter A. Kukull, Jaeyoon Chung, Temitope Ayodele, Tatiana Foroud, Christiane Reitz, Thomas Wisniewski, Lindsay A. Farrer, Eric B. Larson, Laura B. Cantwell, David A. Bennett, Victor W. Henderson, Kara L. Hamilton-Nelson, Neill R. Graff-Radford, Hugh C. Hendrie, Denis A. Evans, Charles DeCarli, Scott A. Small, Joe D. Buxbaum, Paul K. Crane, M. Ilyas Kamboh, Robert Vassar, Suzanne Craft, M. Daniele Fallin, Richard Mayeux, Jonathan L. Haines, Melissa Jean-Francois, Izri Martinez, Thomas O. Obisesan, Li Sao Wang, John Q. Trojanowski, Jeffrey Kaye, Kathryn L. Lunetta, Frank M. LaFerla, Linda J. Van Eldik, Andrew J. Saykin, Bruce L. Miller, Lisa L. Barnes, Roger N. Rosenberg, John C. Morris, Michael A. Schmidt, Ronald C. Petersen, Eric M. Reiman, Kathleen S. Hall, Michael L. Cuccaro, Gyungah Jun, Goldie S. Byrd, Rodney C.P. Go, Oscar L. Lopez, Alison Goate, Margaret A. Pericak-Vance, Hans-Ulrich Klein, Jesse Mez, Brian W. Kunkle, Adam C. Naj, Thomas J. Grabowski, Eden R. Martin, Allan I. Levey, Larry D. Adams, Henry L. Paulson, James B. Leverenz, Stephen M. Strittmatter, Nilufer Ertekin-Taner, Todd E. Golde, Sanjay Asthana, Neil W. Kowall, Mark W. Logue, Amanda B. Kuzma, Helena C. Chui, and Phil De Jager

Subjects
Male, Apolipoprotein E, Genome-wide association study, Locus (genetics), 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Humans, Medicine, Genetic Predisposition to Disease, 030212 general & internal medicine, Aged, Genetic association, Genetics, business.industry, TREM2, Correction, Middle Aged, medicine.disease, Black or African American, Genetic Loci, Meta-analysis, Etiology, Female, Neurology (clinical), Alzheimer's disease, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

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 geneEDEM1(3p26;P = 8.9 × 10−7), near the immune response geneALCAM(3q13;P = 9.3 × 10−7), withinGPC6(13q31;P = 4.1 × 10−7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and withinVRK3(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 nearIGF1Rat 15q26 (P = 1.7 × 10−9) and 6 additional loci with suggestive significance (P ≤ 5 × 10−7) such asAPI5 at 11p12 (P = 8.8 × 10−8) andRBFOX1at 16p13 (P = 5.4 × 10−7) were identified. Gene expression data from brain tissue demonstrate association ofALCAM, ARAP1, GPC6, andRBFOX1with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, onlyAPOE,ABCA7,TREM2,BIN1,CD2AP,FERMT2, andWWOXwere 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.

Published
2021

32. Aldose Reductase Polymorphisms, Fasting Blood Glucose, and Age-Related Cortical Cataract

Author

Paul Mitchell, Jie Jin Wang, Sudha K. Iyengar, Tien Yin Wong, Wanting Zhao, Kristine E. Lee, Annette Kifley, Robert G. Cumming, Ching-Yu Cheng, Gyungah Jun, Elizabeth G. Holliday, Barbara E.K. Klein, and Ava Grace Tan

Subjects
Blood Glucose, Male, medicine.medical_specialty, genetic structures, Genotyping Techniques, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Cataract, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Aldehyde Reductase, Ophthalmology, Epidemiology, Age-related cortical cataract, medicine, Prevalence, Humans, Aged, Aged, 80 and over, business.industry, Odds ratio, Middle Aged, eye diseases, Confidence interval, Minor allele frequency, Genetic epidemiology, Hyperglycemia, 030221 ophthalmology & optometry, Female, Gene-Environment Interaction, New South Wales, business
Abstract

Purpose To determine whether there is an association between polymorphisms of the AKR1B1 gene and cortical cataract in the presence of hyperglycemia. Methods In the second cross section of the Blue Mountains Eye Study (BMES), 3508 participants (2334 at 5-year follow-up and 1174 newly recruited participants) were examined during 1997 to 2000. Cataract was graded from lens photographs using the Wisconsin Cataract Grading System. Fasting blood glucose (FBG) was measured. Continuous imputed dosages of minor alleles of 17 AKR1B1 single nucleotide polymorphisms (SNPs) were assessed for associations with prevalent cortical cataract. Gene-environment interactions between SNPs and FBG were examined. Odds ratios (OR) and 95% confidence intervals (CI) for prevalent cortical cataract were estimated using logistic regression adjusting for age, sex, smoking, hypertension, education, and myopia. A P value of 0.005 was considered statistically significant after correction for 10 independent tests. Replication of significant associations found in the BMES sample was conducted in the Singapore Epidemiology of Eye Diseases (SEED) study (n = 10,033). Results No polymorphism was associated with prevalent cortical cataract. A significant interaction was observed between rs9640883 and FBG (Pinteraction = 0.004), with increased cortical cataract prevalence associated with rs9640883 minor allele dosage in those with FBG >6.0 mM (strata-specific OR 1.72, 95% CI 1.09-2.72). No similar association was found in participants with normal FBG (OR 0.85, 95% CI 0.69-1.04). This interaction was not evident in the SEED study. Conclusions The identified interaction between rs9640883 and FBG in relation to cortical cataract was not replicated but may warrant further investigation.

Published
2018

33. P2‐113: ALZHEIMER'S DISEASE BIOMARKERS IN VITREOUS OF PATIENTS UNDERGOING VITRECTOMY ARE ASSOCIATED WITH COGNITIVE FUNCTION TESTING AND APOE GENOTYPES

Author

Marissa G. Fiorello, Gyungah Jun, Kate McConnell, Thor D. Stein, Jaeyoon Chung, Nurgul Aytan, and Manju L Subramanian

Subjects
Oncology, Apolipoprotein E, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, medicine.medical_treatment, Alzheimer's disease biomarkers, Cognition, Vitrectomy, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, Genotype, medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2018

34. Additional file 1: Table S1. of Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease

Author

Jaeyoon Chung, Xiaoling Zhang, Allen, Mariet, Wang, Xue, Yiyi Ma, Beecham, Gary, Montine, Thomas, Younkin, Steven, Dickson, Dennis, Golde, Todd, Price, Nathan, Ertekin-Taner, Nilüfer, Lunetta, Kathryn, Mez, Jesse, Mayeux, Richard, Haines, Jonathan, Pericak-Vance, Margaret, Schellenberg, Gerard, Gyungah Jun, and Farrer, Lindsay

Abstract

Sample characteristics. Table S2. Association P values of Alzheimer disease loci previously established by GWAS in univariate and pleiotropy association tests of neuropathological features. Table S3. Association of cis-eQTL for HDAC9 in the Mayo Clinic brain expression genome-wide association study (eGWAS). rs79524815 was not available in the Mayo Clinic brain eGWAS, so proxy SNPs that are in LD (D′ > 0.90) with rs79524815 were used for the eQTL test with HDAC9 expression. Table S4. Association of expression of SNPs for TRAPPC12-AS1 and ADI1 with neuropathological traits and gene expression in the GTEx portal database. Table S5. Association results from the trivariate pleiotropy model of neuritic plaque (NP), neurofibrillary tangles (NFT), and cerebral amyloid angiopathy (CAA) for study-wide significant SNPs in the bivariate pleiotropy model. Table S6. Results of differential gene expression analysis by brain region among AD cases and controls for AD loci previously established by GWAS in RNA-Seq and microarray analysis. Figure S1. Quantile-quantile plots of observed (y-axis) vs. expected (x-axis) P values of all SNPs (black dots) and after excluding SNPs in APOE region (blue dots) for the pleiotropy analysis of (a) NP and NFT, (b) NP and CAA, and (c) NFT and CAA using the O’Brien method [10]. Figure S2. Manhattan plots showing genome-wide pleiotropy analyses of (a) NP and NFT, (b) NP and CAA, and (c) NFT and CAA using the O’Brien method [10]. Red dashed line represents the genome-wide significance threshold of P < 5.0 × 10−−8. Loci achieving genome-wide significance are highlighted in red, and known AD genes that attained at least a moderate significance level (P < 10−−4) are highlighted in gold. Figure S3. Regional association plots of genes, including TRAPPC12, TRAPPC12-AS1, and ADI1, on chromosome 2 from the joint model of NFT and CAA. Figure S4. Genome-wide trivariate pleiotropy analysis of NP, NFT, and CAA. (a) Quantile-quantile plot. (b) Manhattan plot. (DOCX 1028 kb)

Published
2018
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35. Correction: A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration

Author

Manoharan Aarthi, Theru A. Sivakumaran, Manmath Kumar Das, Stephanie A. Hagstrom, Liping Tian, Rajiv Raman, Gonçalo R. Abecasis, Vedam L. Ramprasad, Deborah A. Nickerson, Mark Seielstad, Emily Y. Chew, Parveen Sen, Wei Chen, Michael L. Klein, Lingam Vijaya, Jeffrey M. Kidd, Paul Mitchell, Evan E. Eichler, Yang Wang, Dwight Stambolian, Neal S. Peachey, Peter J. Francis, Ronnie George, Barbara E.K. Klein, Feiyou Qiu, Wan Ting Tay, A. K. Henning, Gyungah Jun, Dmitry V. Leontiev, Laura J. Kopplin, Tien Yin Wong, Albert O. Edwards, Robert P. Igo, Kristine E. Lee, Thomas LaFramboise, Anand Swaroop, Sudha K. Iyengar, Andy Itsara, Govindasamy Kumaramanickavel, and Ronald Klein

Subjects
Multidisciplinary, General Science & Technology, Science, Philosophy, Age related, Medicine, Theology
Abstract

Author(s): Sivakumaran, Theru A; Igo, Robert P; Kidd, Jeffrey M; Itsara, Andy; Kopplin, Laura J; Chen, Wei; Hagstrom, Stephanie A; Peachey, Neal S; Francis, Peter J; Klein, Michael L; Chew, Emily Y; Ramprasad, Vedam L; Tay, Wan-Ting; Mitchell, Paul; Seielstad, Mark; Stambolian, Dwight E; Edwards, Albert O; Lee, Kristine E; Leontiev, Dmitry V; Jun, Gyungah; Wang, Yang; Tian, Liping; Qiu, Feiyou; Henning, Alice K; LaFramboise, Thomas; Sen, Parveen; Aarthi, Manoharan; George, Ronnie; Raman, Rajiv; Das, Manmath Kumar; Vijaya, Lingam; Kumaramanickavel, Govindasamy; Wong, Tien Y; Swaroop, Anand; Abecasis, Goncalo R; Klein, Ronald; Klein, Barbara EK; Nickerson, Deborah A; Eichler, Evan E; Iyengar, Sudha K | Abstract: [This corrects the article DOI: 10.1371/journal.pone.0025598.].

Published
2018

36. Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project

Author

William J Salerno, Christiane Reitz, Josée Dupuis, Richard Mayeux, Sudha Seshadri, Badri N. Vardarajan, Gerard D. Schellenberg, Lindsay A. Farrer, Elizabeth E. Blue, Ellen M. Wijsman, Dolly Reyes, Harkirat Sohi, Kathryn L. Lunetta, Yiyi Ma, Otto Valadares, Eden R. Martin, Sandra Barral, Anita L. DeStefano, Carlos Cruchaga, Eric Boerwinkle, Joshua C. Bis, Li-San Wang, Gyungah Jun, Alison Goate, Mariusz Butkiewicz, Jenny Lee, Patrick A. Navas, Margaret A. Pericak-Vance, Michael O. Dorschner, Gary W. Beecham, William S. Bush, Jennifer E. Below, Timothy A. Thornton, Brian W. Kunkle, Alejandro Q. Nato, Adam C. Naj, Jim Jaworski, Amanda B. Kuzma, Debby W. Tsuang, Hiep Nguyen, Cornelia M. van Duijn, Jonathan L. Haines, and Epidemiology

Subjects
Male, 0301 basic medicine, Apolipoprotein E, Cognitive Neuroscience, Nerve Tissue Proteins, Disease, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, Novel gene, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Genetic variation, Prevalence, medicine, PSEN1, Humans, Dementia, Gene, Aged, Aged, 80 and over, Genetics, TREM2, Genetic Variation, Sequence Analysis, DNA, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, Case-Control Studies, Female, Geriatrics and Gerontology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Background/Aims: The Alzheimer’s Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer’s disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as “pathogenic” in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. Results/Conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

Published
2018

37. P1-142: A GENOME-WIDE ASSOCIATION STUDY IMPLICATES EHPA6 FOR ALZHEIMER DISEASE IN FAMILY-BASED ANALYSIS

Author

Gyungah Jun, John J. Farrell, Donghe Li, Sungho Won, and Lindsay A. Farrer

Subjects
Genetics, Epidemiology, Health Policy, Genome-wide association study, Biology, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Family based
Published
2019

38. P4-259: EXCEPTIONALLY LOW RISK OF ALZHEIMER'S DEMENTIA IN APOE2 HOMOZYGOTES

Author

Yakeel T. Quiroz, Gerard D. Schellenberg, Matthew J. Huentelman, Richard Mayeux, Lindsay A. Farrer, Eric M. Reiman, Gyungah Jun, Jonathan L. Haines, Joseph F. Arboleda-Velasquez, Thomas J. Montine, Thomas G. Beach, and Gary W. Beecham

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, medicine.medical_specialty, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, medicine, Alzheimer s dementia, Neurology (clinical), Geriatrics and Gerontology, Psychiatry, business
Published
2019

39. P3-436: ASSOCIATION OF HLA SUBTYPES WITH NEUROPATHOLOGICALLY DEFINED ALZHEIMER DISEASE IS MODULATED BY APOE GENOTYPE

Author

Gyungah Jun, John J. Farrell, Michael Nicolaou, Rebecca Panitch, Congcong Zhu, and Lindsay A. Farrer

Subjects
Apolipoprotein E, Epidemiology, business.industry, Health Policy, Human leukocyte antigen, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Genotype, Immunology, medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Association (psychology), business
Published
2019

40. Convergent genetic and expression data implicate immunity in Alzheimer's disease

Author

John R. Gilbert, Simon Lovestone, Diana Zelenika, Walter A. Kukull, Peter Passmore, Chiao-Feng Lin, Nathalie Fievet, Brian W. Kunkle, Dominique Campion, Philip L. De Jager, Adam C. Naj, Kara L. Hamilton-Nelson, Lina Keller, Jean-Charles Lambert, Denise Harold, Paul K. Crane, John Powell, Kathryn L. Lunetta, Paolo Caffarra, Lei Yu, Anthony Bayer, Tricia A. Thornton-Wells, Christiane Reitz, Eric B. Larson, Florentino Sanchez Garcia, Lindsay A. Farrer, Charlene Thomas, Ekaterina Rogaeva, Victoria Alavarez, Alfredo Ramirez, Pascale Barberger-Gateau, Dan Rujescu, Paul Hollingworth, Margaret A. Pericak-Vance, Daniela Galimberti, J. Kornhuber, Alexey Vedernikov, Philippe Amouyel, Peter Holmans, Gianfranco Spalletta, Carole Dufouil, Wolfgang Maier, Patrick G. Kehoe, Florence Pasquier, Lesley Jones, Harald Hampel, Stephen Todd, Valur Emilsson, Pau Pastor, Manuel Mayhaus, Claudine Berr, Seth Love, Michelangelo Mancuso, Mikko Hiltunen, Simon Mead, Hilkka Soininen, Vincent Deramecourt, Bernadette McGuinness, Magda Tsolaki, Jean-François Dartigues, Jordi Clarimón, Marie-Thérèse Bihoreau, Laura Fratiglioni, Duane Beekly, Sabrina Pichler, Caroline Graff, Albert V. Smith, Nick C. Fox, Amy Gerrish, Karen Ritchie, Carlos Cruchaga, John Hardy, Benedetta Nacmias, Maria Candida Deniz Naranjo, Christine Van Broeckhoven, Laura B. Cantwell, Minerva M. Carrasquillo, Richard Mayeux, Karolien Bettens, Vincent Chouraki, Clive Holmes, Thomas H. Mosley, David C. Rubinsztein, Gyungah Jun, Anita L. DeStefano, Lenore J. Launer, Alexander Richards, Jerome I. Rotter, Lars Lannfelt, Annette L. Fitzpatrick, Fanggeng Zou, Joseph D. Buxbaum, Cristina Razquin, Mercè Boada, Najaf Amin, Palmi V. Jonsson, Martin Dichgans, Thomas J. Montine, Yoichiro Kamatani, Debby W. Tsuang, Alexis Brice, Hakon Hakonarson, John Collinge, Albert Hofman, Eden R. Martin, Oscar L. Lopez, Olivier Hanon, Melanie L. Dunstan, Kevin Morgan, Nicola Jones, Cornelia M. van Duijn, Valentina Escott-Price, Vilmundur Gudnason, Susanne Moebus, Peter St George-Hyslop, Michael Conlon O'Donovan, Michael Gill, Tim Becker, Markus M. Nöthen, Sandro Sorbi, Céline Bellenguez, Mike A. Nalls, Martin Ingelsson, Otto Valladares, Kristel Sleegers, Sudha Seshadri, Gerard D. Schellenberg, María J. Bullido, Patrizia Mecocci, Eric Boerwinkle, Michael John Owen, Helena Schmidt, Kristelle Brown, Julie Williams, Renée F.A.G. de Bruijn, Jonathan L. Haines, Mark Lathrop, Maria Del Zompo, Denis A. Evans, Rebecca Sims, Badri N. Vardarajan, John S. K. Kauwe, Luc Letteneur, Agustín Ruiz, David Craig, Steven G. Younkin, Bruce M. Psaty, Ignacio Mateo, Tatiana Foroud, David Wallon, P. Bosco, Alberti Lleò, Amanda J. Myers, Alberto Pilotto, Petra Proitsi, Reinhold Schmidt, Matthew J. Huentelman, David A. Bennett, Onofre Combarros, Kelley Faber, Gudny Eiriksdottir, M. Arfan Ikram, Lluís Tárraga, Francesco Panza, Carla A. Ibrahim-Verbaas, Joshua C. Bis, Li-San Wang, Matthias Riemenschneider, Gary W. Beecham, Alison Goate, Seung Hoan Choi, John Gallacher, Robert Clarke, Didier Hannequin, Deborah Blacker, Frank Jessen, Christophe Tzourio, Tamara B. Harris, Benjamin Grenier-Boley, Paola Bossù, Janet A. Johnston, M. Ilyas Kamboh, Giancarlo Russo, Timothy Stone, Carol Brayne, Eliecer Coto, French National Foundation on Alzheimer’s Disease and Related Disorders, Institut Pasteur, National Institutes of Health (US), Centre National de Genotypage (France), Fédération pour la Recherche sur le Cerveau (France), Erasmus University Rotterdam, Medical Research Council (UK), International Genomics of Alzheimer's Disease Consortium (IGAP), Neurology, and Epidemiology

Subjects
Pathway analysis, Epidemiology, ALIGATOR, Alzheimer's disease, Cholesterol metabolism, Dementia, Endocytosis, Immune response, Neurodegeneration, Ubiquitination, Weighted gene co-expression network analysis, Medizin, Genome-wide association study, genetics [Alzheimer Disease], Gene expression, Genetics, education.field_of_study, Health Policy, Brain, Single Nucleotide, 3. Good health, Psychiatry and Mental Health, Algorithms, Alzheimer Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Developmental Neuroscience, Neurology (clinical), Geriatrics and Gerontology, Cellular and Molecular Neuroscience, Alzheimer’s disease, metabolism [Alzheimer Disease], Population, Genomics, Biology, Aligator, Article, Biological pathway, SDG 3 - Good Health and Well-being, medicine, ddc:610, Polymorphism, education, medicine.disease, Protein ubiquitination, metabolism [Brain], Human medicine
Abstract

© 2015, Elsevier Inc. All rights reserved. Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics., Medical Research Council, Alzheimer’s Research UK, and theWelsh Assembly Government. ADGC and CHARGE were supported by the National Institutes of Health, National Institute on Aging (NIH-NIA). CHARGE was also supported by Erasmus Medical Center and Erasmus University. IGAP was funded by the French National Foundation on Alzheimer’s Disease and Related Disorders, the Centre National de Genotypage and the Institut Pasteur de Lille, Inserm, FRC (Fondation pour la Recherche sur le Cerveau), and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).

Published
2015

41. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

John Hardy, Nick C. Fox, Lena Lilius, Christine Van Broeckhoven, Mindy J. Katz, Carlos Cruchaga, Joshua W. Miller, Carol Brayne, Letizia Concari, Christopher Shaw, Minerva M. Carrasquillo, Richard Mayeux, Anne Boland, Charles DeCarli, Helena C. Chui, Laura B. Cantwell, Yoland Aladro Benito, Chuang Kuo Wu, Elaine R. Peskind, Andrew McDavid, M. Ilyas Kamboh, Amanda Smith, Pascual Sánchez-Juan, Jean-François Deleuze, Jayanadra J. Himali, Thomas H. Mosley, Thomas J. Montine, Chuanhai Cao, Andreas J. Forstner, Thomas G. Beach, Robert Barber, Miquel Aguilar, Liming Qu, Jerome I. Rotter, Matthew J. Huentelman, Christiane Reitz, Christopher J. O'Donnell, Steven G. Younkin, Bradley T. Hyman, Bruce L. Miller, Rachelle S. Doody, Eric B. Larson, Ronald L. Hamilton, Todd E. Golde, Steven E. Arnold, Melissa E. Garcia, Rachel Raybould, Lena Kilander, Mark A. Sager, Kevin Morgan, Kathryn L. Lunetta, William Perry, Joseph D. Buxbaum, Craig S. Atwood, Thomas D. Bird, Michael Conlon O'Donovan, Robert Olaso, Juan Fortea, Susanne Moebus, Lisa L. Barnes, Rachel Marshall, Huntington Potter, Mercè Boada, Shahzad Ahmad, Paolo Caffarra, Daniel C. Marson, Jonathan L. Haines, Perrie M. Adams, John M Olichney, Lars Lannfelt, Stefanie Heilmann-Heimbach, Markus M. Nöthen, Shubhabrata Mukherjee, John Malamon, Xue Wang, Christopher S. Carlson, Karen Ritchie, Roger N. Rosenberg, Paul K. Crane, Alexa S. Beiser, Céline Bellenguez, Robert C. Green, Maria Urbano, Petra Proitsi, John Powell, Elisa Majounie, Ammar Al-Chalabi, Hakon Hakonarson, Yogen Patel, Martin Scherer, Julie Williams, Richard B. Lipton, Vincent Dermecourt, Adam L. Boxer, Gerard D. Schellenberg, David G. Clark, Anita L. DeStefano, Joel H. Kramer, Victoria Alvarez, Nandini Badarinarayan, Oscar L. Lopez, Chris Corcoran, Ubaldo Bonuccelli, Donald R. Royall, James Bowen, Monica Diez Fairen, Tricia A. Thornton-Wells, Nilufer Ertekin-Taner, Florence Pasquier, Martin Ingelsson, Yi Zhao, John R. Gilbert, Valentina Escott-Price, Amanda B. Kuzma, Fabienne Garzia, Reinhard Heun, Otto Valladares, Andrew J. Saykin, Sara Ortega-Cubero, Liana G. Apostolova, Henry L. Paulson, John K Kauwe, Imelda Barber, Carolina Ceballos Diaz, Douglas Galasko, M. Arfan Ikram, Lluís Tárraga, Carlo Caltagirone, Joan S. Reisch, Wolfgang Maier, Bruno Vellas, Rebecca Sims, Angela Hodges, Matthew P. Frosch, Isabel Henández, Annakaisa Haapasalo, Thor Aspelund, Håkan Thonberg, Aimee Pierce, Roger L. Albin, Wayne W. Poon, Rebecca Sussams, Amy Braddel, Ranjan Duara, Albert V. Smith, Kirk C. Wilhelmsen, Gianfranco Spalletta, Simon Lovestone, Peter Passmore, Ana Frank-García, Cynthia M. Carlsson, Jade Chapman, Nathan D. Price, Philip L. De Jager, John M. Ringman, Seung Hoan Choi, Nicola Denning, Michael John Owen, Clinton T. Baldwin, Amalia C. Bruni, Denis A. Evans, Rudolph E. Tanzi, Dominique Campion, Laura Fratiglioni, Alberto Lleó, Per Hoffmann, Carole Dufouil, Charlotte Forsell, Alun Meggy, Charlene Thomas, Robert S. Stern, James B. Leverenz, Tatiana Foroud, William W. Seeley, James J. Lah, Brian A. Lawlor, Kenneth B. Fallon, Matthias Riemenschneider, Ryan M. Huebinger, Regina M. Carney, Clinton B. Wright, Didier Hannequin, Deborah Blacker, Anne Kinhult-Ståhlbom, Ekaterina Rogaeva, Andrew P. Lieberman, Bernardino Ghetti, Linda J. Van Eldik, Bernadette McGuinness, Thomas Fairchild, Margaret A. Pericak-Vance, Ashok Raj, Reinhold Schmidt, Ronald C. Petersen, Harald Hampel, María J. Bullido, Steven L. Carroll, Maria Candida Deniz Naranjo, Kathleen A. Welsh-Bohmer, Myriam Fornage, Joseph F. Quinn, Caroline Graff, Claudia L. Satizabal, Patrice L. Whitehead, David Wallon, Christopher Medway, Lindsay A. Farrer, Vilmundur Gudnason, Peter St George-Hyslop, Pau Pastor, Frank Jessen, Erin L. Abner, Johanna Jakobsdottir, Hieab H.H. Adams, Roberta Cecchetti, Walter A. Kukull, Thomas S. Wingo, Michelle K. Lupton, Valur Emilsson, Susan M. McCurry, Simon Mead, Hilkka Soininen, Sandra Weintraub, Amy Gerrish, Lindy E. Harrell, Lina Keller, Jean-Charles Lambert, Denise Harold, Stephen Todd, Wei Gu, Maura Gallo, Najaf Amin, Lenore J. Launer, Eleonora Sacchinelli, Mikko Hiltunen, Cécile Dulary, Eliecer Coto, Xueqiu Jian, Nathalie Fievet, Patrizia Mecocci, Sarah Taylor, Eric Boerwinkle, Maria Serpente, Ronald G. Munger, Ina Giegling, Carlo Masullo, Aoibhinn Lynch, Eliezer Masliah, Anne M. Koivisto, Chang En Yu, Qiong Yang, Benedetta Nacmias, Wayne C. McCormick, Kristelle Brown, Alessio Squassina, Deborah C. Mash, Brian W. Kunkle, Makrina Daniilidou, Alison Goate, David Carrell, Kara L. Hamilton-Nelson, Sandra Barral, Vincent Chouraki, Kristel Sleegers, Frank J. Wolters, Joseph E. Parisi, Iwona Kłoszewska, Ronald C. Kim, Sonia Moreno-Grau, Marina Arcaro, Carmen Muñoz Fernadez, Vernon S. Pankratz, Duane Beekly, Sabrina Pichler, Gislain Septier, Delphine Bacq, Amanda J. Myers, Adam C. Naj, Frank Martiniuk, Sudha Seshadri, Badri N. Vardarajan, Joshua A. Sonnen, M.-Marsel Mesulam, Howard J. Rosen, James T. Becker, Chiara Fenoglio, Ge Li, Alberto Pilotto, Mary Sano, Olivier Hanon, Honghuang Lin, Jean Paul G. Vonsattel, W. T. Longstreth, Daniela Galimberti, David C. Rubinsztein, RoseMarie Brundin, Vilmantas Giedraitis, Christine M. Hulette, Peter Holmans, Martin Dichgans, Maria Vronskaya, Céline Derbois, Michelangelo Mancuso, Constantine G. Lyketsos, Christophe Tzourio, Jacques Epelbaum, Raffaele Maletta, Mariet Allen, Hong-Dong Li, James R. Burke, Rik Vandenberghe, David G. Mann, Bruce M. Psaty, Lawrence S. Honig, Beth A. Dombroski, Erik D. Roberson, Cornelia M. van Duijn, Benjamin Grenier-Boley, Seppo Helisalmi, Jean-François Dartigues, Russell H. Swerdlow, Paola Bossù, Ashley R. Winslow, Elio Scarpini, Lesley Jones, Sebastien Engelborghs, John Q. Trojanowski, Jeffrey Kaye, Jenny Lord, Chiara Cupidi, Janet A. Johnston, Dan Rujescu, Feroze Golamaully, Anne Braae, Rafael Blesa, L. Adrienne Cupples, Dennis W. Dickson, Gail P. Jarvik, David W. Fardo, David H. Cribbs, Michael Gill, Jose Bras, Allan I. Levey, Jennifer Williamson, Rhodri Thomas, John C. Morris, Lei Yu, Debby W. Tsuang, Annette M. Hartmann, John H. Growdon, John Collinge, Claudine Berr, Fernando Rivadeneira, Oliver Peters, Albert Hofman, Frank M. LaFerla, Vivianna M. Van Deerlin, James Uphill, David A. Bennett, Onofre Combarros, Gudny Eiriksdottir, Jeremy D. Burgess, Melanie L. Dunstan, Elizabeth Crocco, Keeley J. Brookes, Robert R. Graham, Lon S. Schneider, Eden R. Martin, Matt Hill, Neill R. Graff-Radford, Joseph T. Hughes, Vincenzo Solfrizzi, Taniesha Morgan, Antonio Ciaramella, Bruno Dubois, Juan C. Troncoso, Paolo Bosco, Jordi Clarimón, Daniel H. Geschwind, Virginia Boccardi, Barry Reisberg, Timothy W. Behrens, Annette L. Fitzpatrick, Salvatore Spina, Alexis Brice, Eileen H. Bigio, Marla Gearing, Jeffrey M. Burns, Carol A. Miller, Marilyn S. Albert, Sven J. van der Lee, Sandro Sorbi, C. Dirk Keene, Daniel Levy, Antonio Daniele, Eric M. Reiman, Paramita Chakrabarty, Oscar Sotolongo-Grau, Helena Schmidt, Francesco Panza, Murray A. Raskind, Rita Guerreiro, Gyungah Jun, Anna Karydas, Markus Leber, Harry V. Vinters, Cory C. Funk, Charles C. White, Jill R. Murrell, Sid E. O'Bryant, Nigel J. Cairns, Josée Dupuis, Ann C. McKee, Julie A. Schneider, Megan L. Grove, Malcolm B. Dick, Bradley F. Boeve, Jennifer A. Brody, Sanjay Asthana, Agustín Ruiz, Stefan Herms, Yuning Chen, David Craig, Neil W. Kowall, Maria Donata Orfei, JoAnn T. Tschanz, Florentino Sanchez Garcia, Manuel Mayhaus, Alfredo Ramirez, James Turton, André G. Uitterlinden, Davide Seripa, Lee-Way Jin, Kelley Faber, Maria C. Norton, Shuo Li, Steven H. Ferris, Steffi G. Riedel-Heller, Joshua C. Bis, Li-San Wang, Johannes Kornhuber, Peter Paul De Deyn, Martin R. Farlow, Randall L. Woltjer, Gary W. Beecham, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Icelandic Heart Association [Kopavogur, Iceland] (IHA), John P. Hussman Institute for Human Genomics [Miami, FL, USA], University of Miami [Coral Gables], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Medicine, University of Washington [Seattle], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], Department of Molecular Genetics, Institut Català de Neurociències Aplicades [Barcelona, Spain], Well Advanced Solutions, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], The University of Texas Health Science Center at Houston (UTHealth), Columbia University [New York], University of Eastern Finland, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emmy Noether Project (SFB 833), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Boston University [Boston] (BU), Department of Genomics, Institute for Systems Biology [Seattle, WA, USA], Universitätsklinikum Bonn (UKB), Centre of Excellence for Robotic Vision [Canberra], Australian Research Council [Canberra] (ARC), Neuroscience and Mental Health Research Institute [Cardiff, UK] (School of Medicine), Boston University School of Medicine (BUSM), Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania [Philadelphia], Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Department of Epidemiology and Biostatistics, ERASMUS, Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain], Department of Neurodegenerative Diseases, University of Mississippi Medical Center (UMMC), Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Penn Neurodegeneration Genomics Center), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatics, GlaxoSmithKline, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], University of Nottingham, UK (UON), University of Texas Health Science Center, Department of Neurobiology, Caring Sciences and Society (NVS), University of Bari Aldo Moro (UNIBA), Ageing Group, Centre for Public Health, Queen's University [Belfast] (QUB), Mayo Clinic [Jacksonville], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Università degli Studi di Perugia (UNIPG), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), CHU Rouen, Normandie Université (NU), Universidad Autonoma de Madrid (UAM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Florida [Gainesville] (UF), University of Parma = Università degli studi di Parma [Parme, Italie], Center for Cognitive Disorders AUSL [Parma, Italy], School of Public Health [Boston], Uppsala University, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Xi'an Jiaotong University (Xjtu), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Institute of Gerontology and Geriatrics, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Geriatric Medicine and Metabolic Diseases, Departments of Nuclear Medicine, University Medical Centre Hamburg-Eppendorf [Hamburg, Germany], University of Texas Southwestern Medical Center [Dallas], University of Cologne, Laboratoire d'Etudes et de Recherche en Informatique d'Angers (LERIA), Université d'Angers (UA), Johns Hopkins University (JHU), Universität Leipzig [Leipzig], University of Iceland [Reykjavik], Metacohorts Consortium, Harvard School of Public Health, Catholic University of Rome, Medical University Graz, Baylor College of Medicine (BCM), Baylor University, University of North Texas Health Science Center [Fort Worth], Santa Lucia Foundation (IRCCS), Nextel S.A. [Bilbao], Massachusetts General Hospital [Boston], Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Joint Institute for the Study of the Atmosphere and Ocean (JISAO), Beijing University of Technology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Saul B. Korey Department of Neurology, Albert Einstein College of Medicine [New York]-Yeshiva University, Utah State University (USU), Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain], Hospital Universitario Mutua de Terrassa, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Medical University of Łódź (MUL), University of Leicester, MRC Prion Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome], Università degli Studi di Roma Tor Vergata [Roma], Saarland University Hospital, Universitat Autònoma de Barcelona (UAB), Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Universidade do Porto, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Experimental and Clinical Pharmacology, St. James Hospital and Trinity College [Dublin, Ireland], School of Medicine [Dublin], Trinity College Dublin, University of Sheffield [Sheffield], Lancaster University, University of Michigan [Ann Arbor], University of Michigan System, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Wisconsin-Madison, Rush Alzheimer Disease Center [Chicago, IL, États-Unis], Rush University Medical Center [Chicago], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), School of Engineering [Cardiff], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Northwestern University Feinberg School of Medicine, Mayo Clinic [Rochester], Swedish Medical Center [Seattle, WA, USA], University of California [San Francisco] (UCSF), University of California, Duke University [Durham], University of Kansas Medical Center [Lawrence], Laboratory of Molecular Neuropsychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Washington University in Saint Louis (WUSTL), University of South Florida [Tampa] (USF), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Medical University of South Carolina [Charleston] (MUSC), University of Southern California (USC), Los Alamos National Laboratory (LANL), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), University of California [Irvine] (UCI), Mount Sinai Medical Center, Indiana State University, University of Alabama at Birmingham [ Birmingham] (UAB), University of Kentucky, New York University [New York] (NYU), NYU System (NYU), Department of Medical and Molecular Genetics, Department of Epidemiology and biostatistics, VU University Medical Center [Amsterdam], Emory University [Atlanta, GA], Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Department of Medical Genetics, HMNC Brain Health, Alzheimer Disease Research Laboratory, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance (LISTIC), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Psychiatry, School of Medicine-Johns Hopkins University and Johns Hopkins Bayview Medical Center, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Department of neurosciences, University of California [San Diego] (UC San Diego), Department of Physics and Astronomy [Fort Worth], Texas Christian University (TCU), Department of Computer Science [University of California, Davis], Indiana University System, Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), Department of Laboratory Medicine and Pathology, Mayo Clinic, Institute for Memory Impairments and Neurological Disorders [Irvine], University of Colorado Anschutz [Aurora], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Keck School of Medicine [Los Angeles], Indiana University [South Bend], Massachusetts General Hospital, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génomique d'Evry (IG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Antwerp (UA), Institute Born-Bunge, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], University of Kuopio, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Laboratoire d'Analyse Génomique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Inserm-U1167, Dpt Gériatrie [CHU Broca], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Epidemiology, University of Washington, School of Medicine [Los Angeles], Albert Einstein College of Medicine [New York], IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department of Internal Medicine, University of Central Asturias [Oviedo, Spain], Human Genome Sequencing Center, Baylor College of Medicine, Baylor University-Baylor University, Department of Epidemiology, Erasmus Medical Centre, Translational Genomics Research Institute [Phoenix, AZ, USA], University of Arizona, Banner Alzheimer's Institute [Phoenix, AZ, États-Unis], University of Texas Health Science Center at San Antonio [San Antonio], Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Centre for Research in Neurodegenerative Diseases, VA Puget Sound Health Care System/GRECC [Seattle, WA, USA], University of Pisa - Università di Pisa, Pfizer Worldwide Research and Development [Cambridge, MA, USA], Università cattolica del Sacro Cuore [Piacenza e Cremona] (Unicatt), Texas Tech University Health Sciences Center, Texas Tech University [Lubbock] (TTU), Saarland University [Saarbrücken], University of Bonn, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Cambridge Institute for Medical Research (CIMR), Department of Molecular Neurosciences, Institute of Neurology, UCL, Institute of Psychiatry, Institute of psychiatry, University of British Columbia (UBC), the Clinical Neuroscience Research Group, University of Manchester [Manchester]-Greater Manchester Neurosciences Centre, Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Pa, University of Barcelona, University of Southampton, Department of Psychiatry [Oxford] (POWIC), University of Oxford [Oxford]-The Warneford Hospital, School of Psychology [Cardiff University], Department of Medical Sciences, UCL, Institute of Neurology [London], Washington University School of Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), School of Medecine, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], School of Life Sciences, Department of Neuroscience, Mayo Clinic Jacksonville, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Clínica Universidad de Navarra [Pamplona], Neurodegenerative Brain Diseases Group, VIB, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Brigham Young University (BYU), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, The Gertrude H Sergivesky Center, Columbia University College of Physicians and Surgeons, Genetic Epidemiology Unit, Section of Clinical and Molecular Neurogenetics, Universität zu Lübeck [Lübeck], University of Pennsylvania - Department of Pathology & Laboratory Medecine, Framingham Heart Study [Framingham, MA, USA], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), European Project: 29845,LSH-ACC-MENTOR, University of Pennsylvania-University of Pennsylvania, Universität Bonn = University of Bonn-Institute of Human Genetics [Bonn, Germany], Universität Leipzig-Universität Leipzig, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli Studi di Perugia = University of Perugia (UNIPG), Universidad Autónoma de Madrid (UAM), Università degli studi di Parma = University of Parma (UNIPR), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universität Leipzig, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Yeshiva University- Albert Einstein College of Medicine [New York], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Università degli Studi di Milano = University of Milan (UNIMI), Saarland University Hospital (UKS), Università degli Studi di Firenze = University of Florence (UniFI), Universidade do Porto = University of Porto, University of California (UC)-University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Kansas Medical Center [Kansas City, KS, USA], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of California [Irvine] (UC Irvine), University of Kentucky (UK), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Universität Bonn = University of Bonn, University of Oxford-The Warneford Hospital, Medical Research Council-Cardiff University, Universität zu Lübeck = University of Lübeck [Lübeck], Epidemiology, Neurology, Gastroenterology & Hepatology, Internal Medicine, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, IRCCS 'Casa Sollievo della Sofferenza', Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (Ciberned), University of Florida [Gainesville], University of Parma, Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Yeshiva University- Albert Einstein College of Medicine, Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), Autonomous University of Barcelona (UAB), Università degli Studi di Firenze [Firenze], Universidade do Porto [Porto], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Washington University in St Louis, University of South Florida (USF), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, McGill University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique, Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Albert Einstein College of Medicine, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Università Cattolica del S. Cuore - Catholic University of the Sacred Hearth, University of Florence (UNIFI), CIBER de Enfermedades Neurodegenerativas (CIBERNED), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Department of Psychiatry, van der Lee, Sven J [0000-0003-1606-8643], Naj, Adam C [0000-0002-9621-2942], Badarinarayan, Nandini [0000-0002-6944-748X], Chouraki, Vincent [0000-0002-4698-1794], Graham, Robert R [0000-0001-7151-4277], Hoffmann, Per [0000-0002-6573-983X], Smith, Albert V [0000-0003-1942-5845], Satizabal, Claudia L [0000-0002-1115-4430], Brody, Jennifer A [0000-0001-8509-148X], Wolters, Frank J [0000-0003-2226-4050], Lupton, Michelle K [0000-0002-7274-7299], Lin, Honghuang [0000-0003-3043-3942], Adams, Hieab H [0000-0003-3687-2508], Giedraitis, Vilmantas [0000-0003-3423-2021], Pasquier, Florence [0000-0001-9880-9788], Chen, Yuning [0000-0002-7358-7055], Bossù, Paola [0000-0002-1432-0078], Ghetti, Bernardino [0000-0002-1842-8019], Yang, Qiong [0000-0002-3658-1375], Aspelund, Thor [0000-0002-7998-5433], Bullido, María J [0000-0002-6477-1117], Rivadeneira, Fernando [0000-0001-9435-9441], Rubinsztein, David C [0000-0001-5002-5263], Al-Chalabi, Ammar [0000-0002-4924-7712], Tsolaki, Magda [0000-0002-2072-8010], De Jager, Philip L [0000-0002-8057-2505], Dickson, Dennis W [0000-0001-7189-7917], Van Broeckhoven, Christine [0000-0003-0183-7665], Ikram, M Arfan [0000-0003-0372-8585], Amouyel, Philippe [0000-0001-9088-234X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Berr, Claudine, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, and Mentoring of LifeSciHealth-Multipliers in the Accession Candidate Countries - LSH-ACC-MENTOR - 29845 - OLD

Subjects
0301 basic medicine, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Medizin, Sequence Homology, Genome-wide association study, genetics [Alzheimer Disease], metabolism [Microglia], Linkage Disequilibrium, 0302 clinical medicine, genetics [Protein Interaction Maps], genetics [Membrane Glycoproteins], Gene Frequency, Immunologic, genetics [Adaptor Proteins, Signal Transducing], Receptors, genetics [Exome], Odds Ratio, Innate, genetics [Receptors, Immunologic], Exome, Protein Interaction Maps, genetics [Genetic Predisposition to Disease], Receptors, Immunologic, ABI3 protein, human, Genetics, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Membrane Glycoproteins, Microglia, Phospholipase C gamma, Sequence Homology, Amino Acid, Polymorphism, Single Nucleotide, Adaptor Proteins, Single Nucleotide, 3. Good health, [SDV] Life Sciences [q-bio], Amino Acid, Settore MED/26 - NEUROLOGIA, genetics [Phospholipase C gamma], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, Common disease-common variant, Biology, Article, 03 medical and health sciences, ddc:570, medicine, Journal Article, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Polymorphism, Allele frequency, TREM2 protein, human, TREM2, Case-control study, Signal Transducing, Immunity, medicine.disease, R1, Minor allele frequency, genetics [Immunity, Innate], 030104 developmental biology, Human medicine, 030217 neurology & neurosurgery
Abstract

International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Published
2017

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

Author

Nilufer Ertekin-Taner, Gerard D. Schellenberg, Jaeyoon Chung, Steven G. Younkin, Todd E. Golde, Xiaoling Zhang, Thomas J. Montine, Dennis W. Dickson, Yiyi Ma, Margaret A. Pericak-Vance, Kathryn L. Lunetta, Nathan D. Price, Jonathan L. Haines, Richard Mayeux, Gyungah Jun, Mariet Allen, Lindsay A. Farrer, Jesse Mez, Gary W. Beecham, and Xue Wang

Subjects
0301 basic medicine, Male, Genome-wide association study, ECRG4, Cognitive Neuroscience, Single-nucleotide polymorphism, Plaque, Amyloid, Biology, Polymorphism, Single Nucleotide, lcsh:RC346-429, Histone Deacetylases, lcsh:RC321-571, Pleiotropy analysis, 03 medical and health sciences, Meta-Analysis as Topic, Alzheimer Disease, medicine, SNP, Humans, Senile plaques, Gene, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Genetics, Tumor Suppressor Proteins, Research, Neurofibrillary tangle, Genetic Pleiotropy, Neurofibrillary Tangles, medicine.disease, 3. Good health, Neoplasm Proteins, Repressor Proteins, Cerebral Amyloid Angiopathy, 030104 developmental biology, Neurology, Expression quantitative trait loci, HDAC9, Female, Neurology (clinical), Cerebral amyloid angiopathy, Neuropathological traits, Alzheimer’s disease
Abstract

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 × 10−8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10−8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10−6) 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 × 10−3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10−3) and visual (P = 5.6 × 10−4) 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. Electronic supplementary material The online version of this article (10.1186/s13195-018-0349-z) contains supplementary material, which is available to authorized users.

Published
2017

43. [P1–242]: GENOME‐WIDE ASSOCIATION STUDY OF ALZHEIMER DISEASE ENDOPHENOTYPES AT PRECLINICAL AND MCI STAGES

Author

Richard Sherva, Yiyi Ma, Xiaoling Zhang, Lindsay A. Farrer, Toru Maruyama, Jesse Mez, Haruko Takeyama, Gyungah Jun, Minsup Kim, Kathryn L. Lunetta, Jaeyoon Chung, and Xulong Wang

Subjects
Epidemiology, business.industry, Health Policy, Genome-wide association study, Computational biology, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Endophenotype, Medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, business
Published
2017

44. [O1–11–01]: BIVARIATE GENOME‐WIDE ASSOCIATION STUDY OF NEUROPATHOLOGIC FEATURES OF ALZHEIMER's DISEASE

Author

Lindsay A. Farrer, Gyungah Jun, Gary W. Beecham, Gerard D. Schellenberg, Jesse Mez, Jonathan L. Haines, Xiaoling Zhang, Kathryn L. Lunetta, Margaret A. Pericak-Vance, Qiong Yang, Yiyi Ma, and Jaeyoon Chung

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genome-wide association study, Neurology (clinical), Bivariate analysis, Disease, Geriatrics and Gerontology, Biology
Published
2017

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

Author

Richard Sherva, Gyungah Jun, Kathryn L. Lunetta, Toru Maruyama, Jaeyoon Chung, Lindsay A. Farrer, Yiyi Ma, Haruko Takeyama, Xiaoling Zhang, Jesse Mez, and Xulong Wang

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Epidemiology, Endophenotypes, Genome-wide association study, Single-nucleotide polymorphism, Nerve Tissue Proteins, tau Proteins, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Neuroimaging, Alzheimer Disease, Internal medicine, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, Phosphorylation, Genetic association, Amyloid beta-Peptides, business.industry, Health Policy, Cognition, medicine.disease, Magnetic Resonance Imaging, Psychiatry and Mental health, 030104 developmental biology, Early Diagnosis, Endophenotype, Biomarker (medicine), Female, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Biomarkers, Genome-Wide Association Study
Abstract

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 42 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 −9 ) 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.

Published
2017

46. PLXNA4is associated with Alzheimer disease and modulates tau phosphorylation

Author

Gyungah Jun, Gerard D. Schellenberg, Tsuneya Ikezu, Joseph D. Buxbaum, Tatiana Foroud, Jaeyoon Chung, Carmela R. Abraham, Jong-Won Kim, S.T. Kim, Elodie Drapeau, Jong-Ho Park, Hirohide Asai, Ryozo Kuwano, Kathryn L. Lunetta, Ci-Di Chen, Lindsay A. Farrer, Richard Mayeux, Vahram Haroutunian, Jonathan L. Haines, Margaret A. Pericak-Vance, and Ella Zeldich

Subjects
medicine.medical_specialty, Pathology, Clinical Dementia Rating, HEK 293 cells, Single-nucleotide polymorphism, Transfection, Human brain, Biology, medicine.disease, Pathogenesis, Minor allele frequency, Endocrinology, medicine.anatomical_structure, Neurology, Internal medicine, medicine, Neurology (clinical), Alzheimer's disease
Abstract

Objective Much of the genetic basis for Alzheimer disease (AD) is unexplained. We sought to identify novel AD loci using a unique family-based approach that can detect robust associations with infrequent variants (minor allele frequency

Published
2014

47. Seven new loci associated with age-related macular degeneration

Author

Paul Mitchell, Lindsay A. Farrer, Ming Zhang, Mohammad Othman, Michiaki Kubo, André G. Uitterlinden, Anton Orlin, Kyu Hyung Park, Simon P. Harding, Yusuke Nakamura, Eric H Souied, William K. Scott, Gregory S. Hageman, Anita Agarwal, G. Rudolph, Henry Ferreyra, Yutaka Kiyohara, Humma Shahid, Yukinori Okada, Gregory Hannum, Hendrik P. N. Scholl, Christian Gieger, Clara Lee, H.-Erich Wichmann, Andrew R. Webster, Margaret A. Pericak-Vance, Brian L. Yaspan, Bernhard H. F. Weber, Gyungah Jun, Gabriëlle H.S. Buitendijk, Ching-Yu Cheng, Igor Kozak, Ana Maria Armbrecht, Gaetano R. Barile, Valentina Cipriani, Stephanie A. Hagstrom, Paul N. Baird, Margaret M. DeAngelis, Ronald Klein, Itay Chowers, Matthew Brooks, Mark J. Daly, Kimberly A Chin, Wei Chen, Thierry Léveillard, Cornelia M. van Duijn, Barbara E.K. Klein, Tien Yin Wong, Olivier Poch, Yi Yu, Peter Lichtner, Michael L. Klein, Lars G. Fritsche, Daniel E. Weeks, Radu Cojocaru, Gayle J.T. Pauer, Jaclyn L. Kovach, John R. Heckenlively, Jonathan L. Haines, Andrew J. Lotery, Nicholas Katsanis, Caroline C W Klaver, Stephan Ripke, Unnur Thorsteinsdottir, M. Carolina Ortube, Rando Allikmets, Nirubol Tosakulwong, Barbara Truitt, Robert P. Igo, Johanna M. Seddon, Kristine E. Lee, Emily Y. Chew, Kang Zhang, Debra A. Schaumberg, David Clayton, Frank G. Holz, Robyn Reynolds, Matthew Schu, Neal S. Peachey, Neel Gupta, Tatsuro Ishibashi, William Cade, Melinda Cain, Gwen M. Sturgill-Short, Jane C. Khan, Asbjorg Geirsdottir, Atsushi Takahashi, Thomas Meitinger, Belinda K. Cornes, Xueling Sim, Raymond Ripp, Evangelos Evangelou, Saddek Mohand-Said, Albert O. Edwards, Theru A. Sivakumaran, John P. A. Ioannidis, Kari Branham, Peronne Joseph, Jie Jin Wang, Chelsea E. Myers, Thomas W. Winkler, Johannes R. Vingerling, Robyn H. Guymer, Anthony T. Moore, Christos Haritoglou, Peter A. Campochiaro, Ronnie George, Chi-Chao Chan, Sudha K. Iyengar, Lucia Sobrin, Eranga N. Vithana, Haraldur Sigurdsson, James S. Friedman, Guy Hughes, Baljean Dhillon, Lingam Vijaya, Alan F. Wright, José-Alain Sahel, Rinki Ratna Priya, Tin Aung, R. Theodore Smith, Isabelle Audo, Satoshi Arakawa, Alexander J. Brucker, Gonçalo R. Abecasis, Evangelia E. Tsironi, Anand Swaroop, Mark Lathrop, Mustapha Benchaboune, Diana Zelenika, Joanna E. Merriam, Iris M. Heid, Denise J. Morgan, Michael B. Gorin, Donald J. Zack, Ling Zhao, Hreinn Stefansson, Andrea J. Richardson, Yvette P. Conley, Kari Stefansson, Giuliana Silvestri, Yoichiro Kamatani, Ivana K. Kim, Gudmar Thorleifsson, Stephen G. Schwartz, Alan C. Bird, Claudia N. Keilhauer, Euijung Ryu, Margaux A. Morrison, Chris Pappas, Dwight Stambolian, John R.W. Yates, Paul N. Bishop, Jesen Fagerness, Adam C. Naj, Peter J. Francis, Ophthalmology, Internal Medicine, Epidemiology, and Obstetrics & Gynecology

Subjects
Male, Genome-wide association study, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, Macular Degeneration, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Risk Factors, Polymorphism (computer science), Genotype, Genetics, medicine, Humans, SNP, Genetic Predisposition to Disease, 030304 developmental biology, 0303 health sciences, Haplotype, Case-control study, Macular degeneration, medicine.disease, eye diseases, 3. Good health, Genetic Loci, Case-Control Studies, Factor H, 030221 ophthalmology & optometry, Female, Biomarkers, Genome-Wide Association Study
Abstract

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P

Published
2013

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

Author

Alexandra P. Bourlas, Lindsay A. Farrer, Denis A. Evans, Gerard D. Schellenberg, Alison Goate, Eric B. Larson, Paul K. Crane, Tatiana Foroud, Kathleen S. Hall, Mark W. Logue, David A. Bennett, Lisa L. Barnes, Walter A. Kukull, Jennifer J. Manly, Richard Sherva, Neill R. Graff-Radford, Goldie S. Byrd, Nilufer Ertekin-Taner, Richard Mayeux, M. Daniele Fallin, Jonathan L. Haines, M. Ilyas Kamboh, Kathryn L. Lunetta, Jesse Mez, Gyungah Jun, Jaeyoon Chung, Joshua Kriegel, Margaret A. Pericak-Vance, and Joseph D. Buxbaum

Subjects
0301 basic medicine, Oncology, Apolipoprotein E, Male, medicine.medical_specialty, Epidemiology, Organic Anion Transporters, Sodium-Dependent, Single-nucleotide polymorphism, Genome-wide association study, Disease, Polymorphism, Single Nucleotide, Article, Diabetes Complications, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Apolipoproteins E, Developmental Neuroscience, Alzheimer Disease, Internal medicine, Diabetes mellitus, medicine, Prevalence, Humans, Genetic Predisposition to Disease, Genetic risk, Association (psychology), Aged, Genetics, Aged, 80 and over, Symporters, business.industry, Health Policy, Microfilament Proteins, Smoking, medicine.disease, Black or African American, Psychiatry and Mental health, 030104 developmental biology, Genetic Loci, Educational Status, Smoking status, ATP-Binding Cassette Transporters, Female, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

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 −8 ), upstream of COBL , and rs16961023 ( P = 4.6 × 10 −8 ), 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.

Published
2016

49. P1‐122: Multivariate Phenotypes Association Study of Neuropathological Features of Alzheimer's Disease and Related Dementias

Author

Gyungah Jun, Jaeyoon Chung, Gerard D. Schellenberg, Jesse Mez, Jonathan L. Haines, Kathryn L. Lunetta, Richard Mayeux, Lindsay A. Farrer, Gary W. Beecham, Margaret A. Pericak-Vance, and Yiyi Ma

Subjects
Multivariate statistics, Epidemiology, business.industry, Health Policy, Disease, Bioinformatics, Phenotype, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, Association (psychology)
Published
2016

50. P2‐085: Further Stratification of APOE E4‐Negative Subjects Identifies Novel Genes for Alzheimer's Disease

Author

Lindsay A. Farrer, Gyungah Jun, Jaeyoon Chung, Jonathan L. Haines, Gerard D. Schellenberg, Kathryn L. Lunetta, Margaret A. Pericak-Vance, and Richard Mayeux

Subjects
Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, Stratification (mathematics), Novel gene, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2016

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