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1. Manifestations of Alzheimer’s disease genetic risk in the blood are evident in a multiomic analysis in healthy adults aged 18 to 90

Author

Laura Heath, John C. Earls, Andrew T. Magis, Sergey A. Kornilov, Jennifer C. Lovejoy, Cory C. Funk, Noa Rappaport, Benjamin A. Logsdon, Lara M. Mangravite, Brian W. Kunkle, Eden R. Martin, Adam C. Naj, Nilüfer Ertekin-Taner, Todd E. Golde, Leroy Hood, Nathan D. Price, and Alzheimer’s Disease Genetics Consortium

Subjects
Medicine, Science
Abstract

Abstract Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed. We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. We did not observe associations between the PGRS and any analyte. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case–control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

Published
2022
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2. ODACH: a one-shot distributed algorithm for Cox model with heterogeneous multi-center data

Author

Chongliang Luo, Rui Duan, Adam C. Naj, Henry R. Kranzler, Jiang Bian, and Yong Chen

Subjects
Medicine, Science
Abstract

Abstract We developed a One-shot Distributed Algorithm for Cox proportional-hazards model to analyze Heterogeneous multi-center time-to-event data (ODACH) circumventing the need for sharing patient-level information across sites. This algorithm implements a surrogate likelihood function to approximate the Cox log-partial likelihood function that is stratified by site using patient-level data from a lead site and aggregated information from other sites, allowing the baseline hazard functions and the distribution of covariates to vary across sites. Simulation studies and application to a real-world opioid use disorder study showed that ODACH provides estimates close to the pooled estimator, which analyzes patient-level data directly from all sites via a stratified Cox model. Compared to the estimator from meta-analysis, the inverse variance-weighted average of the site-specific estimates, ODACH estimator demonstrates less susceptibility to bias, especially when the event is rare. ODACH is thus a valuable privacy-preserving and communication-efficient method for analyzing multi-center time-to-event data.

Published
2022
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3. Manifestations of Alzheimer’s Disease Genetic Risk in the Blood: A Cross-Sectional Multi-Omic Analysis in Healthy Adults Aged 18-90+

Author

Sergey A. Kornilov, Nilufer Ertekin-Taner, Lara M. Mangravite, John C. Earls, Benjamin A. Logsdon, Nathan D. Price, Laura Heath, Todd E. Golde, Andrew T. Magis, Cory C. Funk, Noa Rappaport, Adam C. Naj, Jennifer C. Lovejoy, Brian W. Kunkle, Leroy Hood, and Eden Martin

Subjects
medicine.medical_specialty, business.industry, Internal medicine, medicine, Disease, Genetic risk, Omics, business
Abstract

Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease.Methods: We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants, adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed.Results: We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable.Conclusions: Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

Published
2021

4. Manifestations of genetic risk for Alzheimer’s Disease in the blood: a cross-sectional multi-omic analysis in healthy adults aged 18-90+

Author

Todd E. Golde, Nathan D. Price, Cory C. Funk, Brian W. Kunkle, Adam C. Naj, Laura Heath, Noa Rappaport, Nilufer Ertekin-Taner, Sergey A. Kornilov, Lara M. Mangravite, Andrew T. Magis, Leroy Hood, Benjamin A. Logsdon, John C. Earls, Jennifer C. Lovejoy, and Eden R. Martin

Subjects
Genetics, business.industry, Cohort, Multiple comparisons problem, Medicine, Genome-wide association study, Single-nucleotide polymorphism, INPP5D, Disease, Omics, business, PICALM
Abstract

Deeply phenotyped cohort data can elucidate differences associated with genetic risk for common complex diseases across an age spectrum. Previous work has identified genetic variants associated with Alzheimer’s disease (AD) risk from large-scale genome-wide association study meta-analyses. To explore effects of known AD-risk variants, we performed a phenome-wide association study on ~2000 clinical, proteomic, and metabolic blood-based analytes obtained from 2,831 cognitively normal adult clients of a consumer-based scientific wellness company. Results uncovered statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or nearNYAP1, ABCA7, INPP5D, andAPOE). These effects were detectable from early adulthood. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with thePICALMvariant. Sex-stratified GWAS results from an independent AD case-control meta-analysis supported sexspecific disease effects of thePICALMvariant, highlighting the importance of sex as a biological variable. These analyses support evidence from previous functional genomics studies in the identification of a causal variant within thePILRAgene. Taken together, this study highlights clues to the earliest effects of AD genetic risk variants in individuals where disease symptoms have not (yet) arisen.

Published
2021

5. Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis

Author

Colin Quinn, Corey T. McMillan, Adam C. Naj, David J. Irwin, Andrea Swenson, John Ravits, Leo McCluskey, John Q. Trojanowski, Jeffrey Statland, Evadnie Rampersaud, J. Paul Taylor, Philip A. Cook, Rosa Rademakers, Michael Benatar, Joanne Wuu, James C. Gee, Ted M. Burns, Gang Wu, Yuen T. So, James Caress, Edward B. Lee, David Walk, Wenan Chen, Katerina Placek, Erik P. Pioro, Laura Hennessy, Lauren Elman, Murray Grossman, J. S. Katz, Volkan Granit, Samuel Maiser, Jin Sha, Carlayne E. Jackson, Vivianna M. Van Deerlin, and The CReATe Consortium

Subjects
0301 basic medicine, cognition, Medicine (General), amyotrophic lateral sclerosis, Hippocampus, QH426-470, frontotemporal dementia, Article, Premotor cortex, Machine Learning, 03 medical and health sciences, R5-920, 0302 clinical medicine, Genetics, Medicine, Humans, Cognitive Dysfunction, polygenic score, Effects of sleep deprivation on cognitive performance, Amyotrophic lateral sclerosis, Cognitive decline, Biology, Anterior cingulate cortex, Temporal cortex, business.industry, Computational Biology, Neurodegenerative Diseases, Articles, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Molecular Medicine, Genetics, Gene Therapy & Genetic Disease, Human medicine, business, Neuroscience, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

Amyotrophic lateral sclerosis (ALS) is a multi‐system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine‐learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post‐mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS., Single nucleotide polymorphisms (SNPs) previously identified through genome‐wide association studies as risk factors for amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) further associate in a polygenic manner with risk for cognitive dysfunction in ALS and related disorders.

Published
2021

6. Pleiotropy analyses using TADs identify genomic regions affecting risk of AD and stroke

Author

Li-San Wang, Gerard D. Schellenberg, Christian J. Stoeckert, Adam C. Naj, and Emily Greenfest-Allen

Subjects
Genetics, Epidemiology, Health Policy, Disease, Biology, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Pleiotropy (drugs), Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Stroke
Published
2020

7. Mapping Alzheimer disease–associated regions in the African American population

Author

Farid Rajabli, Goldie S. Byrd, Christiane Reitz, Gary W. Beecham, Lindsay A. Farrer, Gerard D. Schellenberg, Brian W. Kunkle, Patrice L. Whitehead, Adam C. Naj, Kara L. Hamilton-Nelson, Richard Mayeux, Margaret A. Pericak-Vance, Eden R. Martin, William S. Bush, and Jonathan L. Haines

Subjects
Gerontology, African american population, Epidemiology, business.industry, Health Policy, Disease, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, business
Published
2020

8. Alzheimer’s disease variant portal (ADVP): Harmonized genetics data and evidence collection for Alzheimer’s disease

Author

Pavel P. Kuksa, Wei Fu, Li-San Wang, Adam C. Naj, Kai-Teh Tzeng, Gerard D. Schellenberg, Chia-Lun Liu, Otto Valladares, Yuk Yee Leung, Amanda B. Kuzma, Liming Qu, Shin-Yi Chou, Zivadin Katanic, and Yi Zhao

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Medicine, Neurology (clinical), Disease, Evidence collection, Geriatrics and Gerontology, business
Published
2020

9. LRP10 variants in progressive supranuclear palsy

Author

Leonie J.M. Vergouw, Li-San Wang, Guido J. Breedveld, Vincenzo Bonifati, Marialuisa Quadri, Gerard D. Schellenberg, Wang Z. Chiu, John C. van Swieten, Frank Jan de Jong, Adam C. Naj, Agnita J.W. Boon, Dennis W. Dickson, Shamiram Melhem, Owen A. Ross, Demy J.S. Kuipers, Elizabeth Mlynarksi, Laura Donker Kaat, Laura B. Cantwell, Neurology, and Clinical Genetics

Subjects
0301 basic medicine, Male, Aging, medicine.medical_specialty, Disease, Article, Progressive supranuclear palsy, Cohort Studies, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Internal medicine, Exome Sequencing, medicine, Humans, LDL-Receptor Related Proteins, Aged, Sanger sequencing, business.industry, Dementia with Lewy bodies, General Neuroscience, Genetic Variation, Exons, Middle Aged, medicine.disease, eye diseases, 030104 developmental biology, Cohort, symbols, Female, Neurology (clinical), Supranuclear Palsy, Progressive, Geriatrics and Gerontology, business, Validation cohort, 030217 neurology & neurosurgery, Developmental Biology
Abstract

The aim of this study was to explore whether variants in LRP10, recently associated with Parkinson's disease and dementia with Lewy bodies, are observed in 2 large cohorts (discovery and validation cohort) of patients with progressive supranuclear palsy (PSP). A total of 950 patients with PSP were enrolled: 246 patients with PSP (n = 85 possible (35%), n = 128 probable (52%), n = 33 definite (13%)) in the discovery cohort and 704 patients with definite PSP in the validation cohort. Sanger sequencing of all LRP10 exons and exon-intron boundaries was performed in the discovery cohort, and whole-exome sequencing was performed in the validation cohort. Two patients from the discovery cohort and 8 patients from the validation cohort carried a rare, heterozygous, and possibly pathogenic LRP10 variant (p.Gly326Asp, p.Asp389Asn, and p.Arg158His, p.Cys220Tyr, p.Thr278Ala, p.Gly306Asp, p.Glu486Asp, p.Arg554∗, p.Arg661Cys). In conclusion, possibly pathogenic LRP10 variants occur in a small fraction of patients with PSP and may be overrepresented in these patients compared with controls. This suggests that possibly pathogenic LRP10 variants may play a role in the development of PSP.

Published
2020

10. Machine learning suggests polygenic contribution to cognitive dysfunction in amyotrophic lateral sclerosis

Author

Samuel Maiser, Yuen T. So, Vivianna M. Van Deerlin, Gang Wu, Lauren Elman, James Caress, Evadnie Rampersaud, Colin Quinn, Corey T. McMillan, Murray Grossman, Joanne Wuu, Ted M. Burns, Adam C. Naj, Andrea Swenson, Jin Sha, Carlayne E. Jackson, Wenan Chen, Leo McCluskey, Edward B. Lee, Jeffrey Statland, Katerina Placek, J. Paul Taylor, Philip A. Cook, James C. Gee, J. S. Katz, John Q. Trojanowski, John Ravits, Volkan Granit, Michael Benatar, Rosa Rademakers, David J. Irwin, David Walk, Erik P. Pioro, and Laura Hennessy

Subjects
Temporal cortex, 0303 health sciences, business.industry, Hippocampus, Cognition, medicine.disease, Premotor cortex, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Medicine, Effects of sleep deprivation on cognitive performance, Cognitive decline, Amyotrophic lateral sclerosis, business, Neuroscience, 030217 neurology & neurosurgery, Anterior cingulate cortex, 030304 developmental biology
Abstract

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients, however factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N=327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort, and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N=90) as well as post mortem motor cortical neuronal loss (N=87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.

Published
2019

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

Author

Joshua C. Bis, Li-San Wang, Waleed Nasser, Giuseppe Tosto, Jean-Charles Lambert, Gary W. Beecham, Lucinda Fulton, Eric Boerwinkle, Reinhold Schmidt, Kara L. Hamilton-Nelson, Josée Dupuis, Cornelia M. van Duijn, Yuning Chen, Stéphanie Debette, Devanshi Patel, Philippe Amouyel, Gaël Nicolas, Farid Rajabli, Mark J. Daly, Richard Redon, Hilkka Soininen, Anita L. DeStefano, Aki S. Havulinna, Weixin Wang, Margaret A. Pericak-Vance, Chloé Sarnowski, Gerard D. Schellenberg, William S. Bush, Eden R. Martin, John J. Farrell, Richard A. Gibbs, Richard Mayeux, Emmanuelle Génin, Yi Zhao, Kwangsik Nho, Céline Bellenguez, Kari Mattila, Jean-François Deleuze, William J Salerno, Alzheimer’s Disease Sequencing, Brian W. Kunkle, Dominique Campion, Mikko Hiltunen, Richard K. Wilson, Sudha Seshadri, Paul K. Crane, Otto Valladares, Jennifer E. Below, Adam C. Naj, Timothy A. Thornton, Stacey Gabriel, Jan Konrad, Markus Perola, Mark Lathrop, Namrata Gupta, Badri N. Vardarajan, Bruce M. Psaty, Seppo Helisalmi, Jonathan L. Haines, Yiyi Ma, Honghuang Lin, Laura B. Cantwell, Carlos Cruchaga, Alan E. Renton, Terho Lehtimäki, Anne M. Remes, Michael A. Schmidt, Benjamin M. Neale, M. Arfan Ikram, Lindsay A. Farrer, Myriam Fornage, Daniel P. Howrigan, Ellen M. Wijsman, Mitja I. Kurki, Helena Schmidt, Aarno Palotie, Daniel Lancour, Camille Charbonnier, Daniela Witten, Liming Qu, Najaf Amin, Eric S. Lander, Alison Goate, Donna M. Muzny, Kathryn L. Lunetta, Jaakko Kaprio, Edoardo Marcora, Amanda B. Kuzma, Sven J. van der Lee, Shahzad Ahmad, Kim C. Worley, Christophe Tzourio, Benjamin Grenier-Boley, Jean-François Dartigues, L. Adrienne Cupples, Veikko Salomaa, Jaeyoon Chung, Christiane Reitz, Xueqiu Jian, Xiaoling Zhang, Olivier Quenez, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Helsinki and Uusimaa Hospital District, 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), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Epidemiology

Subjects
Male, 0301 basic medicine, DYSBINDIN GENE DTNBP1, Transcription, Genetic, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, SORL1, PROTEIN, Diseases, Genome-wide association study, SUSCEPTIBILITY, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, DISEASE, ABCA7, 0302 clinical medicine, Exome sequencing, Aged, 80 and over, Genetics, RISK, 3. Good health, Psychiatry and Mental health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Female, RNA, Long Noncoding, Alzheimer's disease, Immunoglobulin gene, EXPRESSION, Kruppel-Like Transcription Factors, Biology, Article, CODING MUTATIONS, 03 medical and health sciences, Cellular and Molecular Neuroscience, Apolipoproteins E, Alzheimer Disease, Exome Sequencing, medicine, Humans, GENOME-WIDE ASSOCIATION, Molecular Biology, Gene, Genotyping, Aged, Amyloid beta-Peptides, Polymorphism, Genetic, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, Immunity, 3112 Neurosciences, Correction, medicine.disease, 030104 developmental biology, Gene Expression Regulation, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunoglobulin G, 3111 Biomedicine, 030217 neurology & neurosurgery
Abstract

The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Published
2018

12. Alzheimer's genetic risk is reduced in primary age-related tauopathy: a potential model of resistance?

Author

Adam C. Naj, Kyra Jefferson-George, David A. Wolk, Vivianna M. Van Deerlin, John Q. Trojanowski, Edward B. Lee, and Corey T. McMillan

Subjects
0301 basic medicine, Apolipoprotein E, Oncology, medicine.medical_specialty, Disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, mental disorders, Genetic model, Genotype, medicine, Genetic risk, Research Articles, business.industry, General Neuroscience, medicine.disease, 3. Good health, 030104 developmental biology, Cohort, Neurology (clinical), Tauopathy, business, 030217 neurology & neurosurgery, Research Article, Cohort study
Abstract

Objective Nearly all adults >50 years of age have evidence for neurofibrillary tau tangles (NFTs) and a significant proportion of individuals additionally develop amyloid plaques (Aβ) consistent with Alzheimer's disease (AD). In an effort to identify the independent genetic risk factors for NFTs and Aβ, we investigated genotypic frequencies of AD susceptibility loci between autopsy‐confirmed AD and primary age‐related tauopathy (PART), a neuropathological condition defined by characteristic neurofibrillary tau tangles (NFTs) with minimal or absent Aβ. Methods General linear models assessed the odds of AD (N = 1190) relative to PART (N = 376) neuropathologically confirmed cases from two independent series: the Penn Brain Bank (PENN; AD N = 312; PART N = 65) and National Alzheimer's Coordinating Center (NACC; AD N = 878; PART N = 311). We also evaluated the odds of Braak stage NFT burden. Results Three genotypes significantly associated with reduced AD risk relative to PART in the PENN (N = 377) and NACC (N = 1189) cohorts including APOE ε4, APOE ε2, and rs6656401 in the CR1 gene. The genotypes rs6733839 in the BIN1 gene and rs28834970 in the PTK2B gene approached significance in the PENN cohort and were significantly associated with reduced AD risk in the NACC cohort. In a combined cohort analysis (N = 1566), APOE ε4 dosage was highly associated with higher Braak stage of NFT burden in Probable PART and AD, but not Definite PART. Interpretation The presence of genotypic differences between PART and AD suggest that PART can provide a genetic model of NFT risk and potential Aβ resistance to inform disease‐modifying therapies.

Published
2018

13. Genomic variants, genes, and pathways of Alzheimer's disease: An overview

Author

Adam C. Naj and Gerard D. Schellenberg

Subjects
0301 basic medicine, Genetic Linkage, Population, Genomics, Genome-wide association study, Disease, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Genetic linkage, medicine, Humans, Dementia, Genetic Predisposition to Disease, education, Genetics (clinical), Genetic association, Genetics, education.field_of_study, Genetic Variation, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, Alzheimer's disease, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Alzheimer's disease (AD) (MIM: 104300) is a highly heritable disease with great complexity in its genetic contributors, and represents the most common form of dementia. With the gradual aging of the world's population, leading to increased prevalence of AD, and the substantial cost of care for those afflicted, identifying the genetic causes of disease represents a critical effort in identifying therapeutic targets. Here we provide a comprehensive review of genomic studies of AD, from the earliest linkage studies identifying monogenic contributors to early-onset forms of AD to the genome-wide and rare variant association studies of recent years that are being used to characterize the mosaic of genetic contributors to late-onset AD (LOAD), and which have identified approximately ∼20 genes with common variants contributing to LOAD risk. In addition, we explore studies employing alternative approaches to identify genetic contributors to AD, including studies of AD-related phenotypes and multi-variant association studies such as pathway analyses. Finally, we introduce studies of next-generation sequencing, which have recently helped identify multiple low-frequency and rare variant contributors to AD, and discuss on-going efforts with next-generation sequencing studies to develop statistically well- powered and comprehensive genomic studies of AD. Through this review, we help uncover the many insights the genetics of AD have provided into the pathways and pathophysiology of AD. © 2016 Wiley Periodicals, Inc.

Published
2016

14. Causal associations between potentially modifiable risk factors and the Alzheimer’s phenome: A Mendelian randomization study

Author

Paul F. O'Reilly, Gerard D. Schellenberg, Adam C. Naj, Li-San Wang, Shea J. Andrews, Richard Mayeux, Brian Fulton-Howard, Edoardo Marcora, Lindsay A. Farrer, Margaret A. Pericak-Vance, Alison Goate, and Jonathan L. Haines

Subjects
Oncology, medicine.medical_specialty, business.industry, Disease, Phenome, Logistic regression, Pulse pressure, Blood pressure, Internal medicine, Mendelian randomization, Medicine, Senile plaques, Age of onset, business
Abstract

Background Potentially modifiable risk factors have been associated with Alzheimer’s disease (AD). However, the causality of these risk factors on AD is unclear. Using Mendelian randomization we evaluated the causal effect of potentially modifiable risk factors on AD and its associated endophenotypes to inform the development of lifestyle interventions that could reduce risk of developing AD. Methods and Findings Genetic instruments for the exposures were selected from genome wide association studies (GWAS) for traits previously linked to AD in observational studies including alcohol intake, physical activity, lipid traits, blood pressure traits, type 2 diabetes, body-mass index (BMI), depression, sleep, social isolation, smoking, oily fish intake, and educational attainment. The outcomes included AD status, AD age of onset survival (AAOS), hippocampal volume, CSF levels of Aβ 42 , tau, and ptau 181 , and neuropathological burden of neuritic plaques, neurofibrillary tangles, and vascular brain injury (VBI). MR estimates were calculated using an inverse variance weighted approach. Genetically predicted educational attainment (OR [CI]: 0.7 [0.63, 0.78]), diastolic blood pressure (DBP) (OR [CI]: 0.99 [0.98, 0.99]), systolic blood pressure (SBP) (OR [CI]: 0.99 [0.99, 1]) and physical activity (OR [CI]: 2.5 [1.47, 4.23]) were causally associated with AD risk. Genetically predicted BMI (HR [CI]: 1.13 [1.07, 1.2]) and educational attainment (HR [CI]: 0.74 [0.68, 0.82]) were causally associated with AAOS. Genetically predicted alcohol consumption (β [CI]: −0.15 [−0.25, −0.05]), broad depressive symptoms (β [CI]: 0.5 [0.2, 0.8]), major depressive disorder (β [CI]: 0.12 [0.05, 0.18]) and physical activity were causally associated with CSF Aβ 42 (β [CI]: 0.25 [0.1, 0.39]). Genetically predicted DBP was causally associated with CSF total Tau (β [CI]: −0.005 [−0.007, −0.002]). Increased risk of VBI were observed for genetically predicted DBP (OR [CI]: 1.05 [1.02, 1.08]), SBP (OR [CI]: 1.06 [1.03, 1.1]), and pulse pressure (OR [CI]: 1.03 [1.01, 1.05]). Increased risk of neuritic plaque burden were observed for genetically predicted LDL-cholesterol (OR [CI]: 1.87 [1.3, 2.69]) and total cholesterol (OR [CI]: 2.03 [1.44, 2.85]). Genetically predicted insomnia symptoms (β [CI]: −0.2 [−0.34, −0.06]) and total cholesterol were associated (β [CI]: −0.06 [−0.1, −0.03]) with hippocampal volume. Potential limitations include weak instrument bias, non-homogenous samples and other implicit limitations of MR analysis. Conclusions Demonstration of a causal relationship between blood pressure, cholesterol levels, BMI, depression, insomnia symptoms, physical activity and educational attainment on the AD phenome strongly support public health programs to educate the public about these preventable causes of AD.

Published
2019
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15. 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

16. 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

17. 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

18. NIAGADS: The NIA Genetics of Alzheimer's Disease Data Storage Site

Author

Adam C. Naj, Yuk Yee Leung, Amanda B. Kuzma, John Malamon, Liming Qu, Daniel Micah Childress, Gerard D. Schellenberg, Prabhakaran Gangadharan, Li-San Wang, Emily Greenfest-Allen, Rebecca Cweibel, Christian J. Stoeckert, Yi Zhao, and Otto Valladares

Subjects
0301 basic medicine, Genetics, Gerontology, Epidemiology, business.industry, Health Policy, Genetic data, Disease, Data sharing, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 030104 developmental biology, 0302 clinical medicine, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Research data
Abstract

Summary Work in the past 10 years has greatly expanded our understanding of Alzheimer's disease (AD) genetics, with more than 20 susceptibility genetic loci discovered in large genome-wide association and sequencing studies. The NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is funded by National Institute on Aging to serve as a one-stop portal for the community to access research data and findings generated from AD genetics projects. In this article, we describe the mission of NIAGADS, available resources, and data sets including the Alzheimer's Disease Sequencing Project, and how researchers may apply for access to genetic data.

Published
2016

19. The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable

Author

Gary W. Beecham, Jesse Mez, Emily H. Trittschuh, John S. K. Kauwe, Richard Sherva, Adam C. Naj, Andrew J. Saykin, Shubhabrata Mukherjee, Alden L. Gross, Robert C. Green, David W. Fardo, Paul K. Crane, Sheila Sutti, and Timothy A. Thornton

Subjects
Male, 0301 basic medicine, Aging, medicine.medical_specialty, Clinical Dementia Rating, Single-nucleotide polymorphism, Disease, Polymorphism, Single Nucleotide, Chromosomes, Article, Executive Function, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, Alzheimer Disease, Memory, Databases, Genetic, medicine, Humans, Genetic Predisposition to Disease, Psychiatry, Aged, Aged, 80 and over, General Neuroscience, Neuropsychology, Genetic data, Heritability, medicine.disease, Phenotype, 030104 developmental biology, Female, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Psychology, 030217 neurology & neurosurgery, Developmental Biology, Clinical psychology
Abstract

Late-onset Alzheimer’s disease (LOAD) can present heterogeneously, with several subtypes recognized, including dysexecutive AD. One way to identify people with dysexecutive AD is to consider the difference between memory and executive functioning, which we refer to as the executive prominent/memory prominent spectrum. We aimed to determine if this spectrum was heritable. We used neuropsychological and genetic data from people with mild LOAD (Clinical Dementia Rating 0.5 or 1.0) from the National Alzheimer’s Coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative. We cocalibrated the neuropsychological data to obtain executive functioning and memory scores and used their difference as a continuous phenotype to calculate its heritability overall and by chromosome. Narrow-sense heritability of the difference between memory and executive functioning scores was 0.68 (standard error 0.12). Single nucleotide polymorphisms on chromosomes 1, 2, 4, 11, 12, and 18 explained the largest fraction of phenotypic variance, with signals from each chromosome accounting for 5%–7%. The chromosomal pattern of heritability differed substantially from that of LOAD itself.

Published
2016

20. Is APOE ε4 required for Alzheimer's disease to develop in TREM2 p.R47H variant carriers?

Author

Amanda B. Kuzma, Adam C. Naj, Gerard D. Schellenberg, Rita Guerreiro, Jose Bras, and Tatiana Orme

Subjects
0301 basic medicine, Genetics, Apolipoprotein E, Histology, Membrane Glycoproteins, business.industry, TREM2, Apolipoprotein E4, Disease, Individual risk, Pathology and Forensic Medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, Alzheimer Disease, Physiology (medical), Medicine, Humans, Neurology (clinical), Allele, Receptors, Immunologic, business, 030217 neurology & neurosurgery
Abstract

Murray and colleagues [1] reported the occurrence of pathologically-confirmed Alzheimer's disease (AD) in cases harbouring the TREM2 p.R47H variant only when APOE e4 alleles were also present. They suggested that the presence of an e4 APOE allele is necessary for the development of AD pathology in TREM2 p.R47H carriers. This is an important hypothesis as it can have significant impact on individual risk assessment and on understanding the mechanisms of disease. This article is protected by copyright. All rights reserved.

Published
2018

21. P1‐149: THE ALZHEIMER'S DISEASE SEQUENCING PROJECT (ADSP) DATA UPDATE 2018

Author

Jason Waligorski, John J. Farrell, Eric Boerwinkle, Yuk Yee Leung, Laura B. Cantwell, Amanda B. Kuzma, Seung Hoan Choi, Sudha Seshadri, Elizabeth L. Appelbaum, Tatiana Foroud, Adam C. Naj, Namrata Gupta, Gerard D. Schellenberg, Kelley Faber, Otto Valladares, Joshua C. Bis, Li-San Wang, Liming Qu, Kara L. Hamilton-Nelson, Anita L. DeStefano, Yi Zhao, Donna M. Muzny, Briana Vogel, Robert S. Fulton, Dolly Reyes-Dumeyer, and William J Salerno

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Medicine, Neurology (clinical), Computational biology, Disease, Geriatrics and Gerontology, business
Published
2018

22. P4‐240: STOP‐GAIN VARIANT IN MICROGLIA‐EXPRESSED GENE GMIP IS ASSOCIATED WITH EARLY‐ONSET ALZHEIMER'S DISEASE

Author

Isabel Santana, Carlos Cruchaga, Sven J. van der Lee, Keeley J. Brookes, John Hardy, Adgc, Joshua C. Bis, Adam C. Naj, Jose Bras, Miguel Pereira, Wiesje M. Flier, Lenore J. Launer, Bruce L. Miller, Valerio Napolioni, Susana Carmona, Gerard D. Schellenberg, Tamar Guetta-Baranes, Henne Holstege, Yuning Chen, Joel H. Kramer, Richard H. Myers, Rita Guerreiro, Anna Karydas, Jennifer S. Yokoyama, J. Nicholas Cochran, Michael D. Greicius, Sudha Seshadri, Yongha Kim, James Turton, Sultan Chaudhury, Gil D. Rabinovici, Raiyan R. Khan, Ethan G. Geier, Kevin Morgan, Cornelia M. van Duijn, Simon Mead, Maria Victoria Fernandez, Summer S. Han, Marc Hulsman, Jason A. Chen, Andre Altmann, and Giovanni Coppola

Subjects
Microglia, Epidemiology, business.industry, Health Policy, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, medicine.anatomical_structure, Developmental Neuroscience, Gene expression, Immunology, medicine, Early-onset Alzheimer's disease, Neurology (clinical), Geriatrics and Gerontology, business
Published
2018

23. One for all and all for One: Improving replication of genetic studies through network diffusion

Author

Lindsay A. Farrer, Gerard C. Schellenberg, Jonathan L. Haines, Daniel Lancour, Simon Kasif, Adam C. Naj, Mark Crovella, Margaret A. Pericak-Vance, and Richard Mayeux

Subjects
0301 basic medicine, Proteomics, Cancer Research, Support Vector Machine, Gene Identification and Analysis, Datasets as Topic, Genome-wide association study, Genetic Networks, Alzheimer's Disease, Pathology and Laboratory Medicine, Genome, Biochemistry, Risk Factors, Medicine and Health Sciences, Protein Interaction Maps, Immune Response, Genetics (clinical), Neurodegenerative Diseases, Genomics, Neurology, Meta-analysis, Protein Interaction Networks, Alzheimer's disease, Network Analysis, Research Article, Prioritization, Computer and Information Sciences, lcsh:QH426-470, Gene prediction, Immunology, Computational biology, Biology, 03 medical and health sciences, Signs and Symptoms, Diagnostic Medicine, Alzheimer Disease, Mental Health and Psychiatry, medicine, Genetics, Genome-Wide Association Studies, Humans, Gene Prediction, Protein Interactions, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, Inflammation, Biology and Life Sciences, Computational Biology, Proteins, Reproducibility of Results, Human Genetics, medicine.disease, Genome Analysis, Replication (computing), lcsh:Genetics, 030104 developmental biology, Genetics of Disease, Dementia, Genome-Wide Association Study
Abstract

Improving accuracy in genetic studies would greatly accelerate understanding the genetic basis of complex diseases. One approach to achieve such an improvement for risk variants identified by the genome wide association study (GWAS) approach is to incorporate previously known biology when screening variants across the genome. We developed a simple approach for improving the prioritization of candidate disease genes that incorporates a network diffusion of scores from known disease genes using a protein network and a novel integration with GWAS risk scores, and tested this approach on a large Alzheimer disease (AD) GWAS dataset. Using a statistical bootstrap approach, we cross-validated the method and for the first time showed that a network approach improves the expected replication rates in GWAS studies. Several novel AD genes were predicted including CR2, SHARPIN, and PTPN2. Our re-prioritized results are enriched for established known AD-associated biological pathways including inflammation, immune response, and metabolism, whereas standard non-prioritized results were not. Our findings support a strategy of considering network information when investigating genetic risk factors., Author summary Integrating multiple types of -omics data is a rapidly growing research area due in part to the increasing amount of diverse and publicly accessible data. In this study, we demonstrated that integration of genetic association and protein interaction data using a network diffusion approach measurably improves reproducibility of top candidate genes. Application of this approach to Alzheimer disease (AD) using a large dataset assembled by the Alzheimer’s Disease Genetics Consortium identified several novel candidate AD genes that are supported by pre-existing knowledge of AD pathobiology. Our findings support a strategy of considering network information when investigating genetic risk factors. Finally, we developed a transparent and easy-to-use R package that can facilitate the extension of our methodology to other phenotypes for which genetic data are available.

Published
2018

24. 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

25. P4-094: EXOME-WIDE ANALYSIS IDENTIFIES NOVEL SEX-SPECIFIC CANDIDATE GENES FOR ALZHEIMER DISEASE

Author

Kara L. Hamilton-Nelson, Margaret A. Pericak-Vance, Gerard D. Schellenberg, Li-San Wang, Gary W. Beecham, Melissa Jean-Francois, Eden R. Martin, Lindsay A. Farrer, Jonathan L. Haines, Badri N. Vardarajan, Richard Mayeux, Timothy J. Hohman, William S. Bush, Brian W. Kunkle, Adam C. Naj, Lissette Gomez, Amanda B. Kuzma, and Lily Wang

Subjects
Candidate gene, Epidemiology, Health Policy, Computational biology, Biology, medicine.disease, Sex specific, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Exome
Published
2019

26. 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

27. 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

28. SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease

Author

Wiesje M. van der Flier, Eckart Rüther, Henne Holstege, Johannes Kornhuber, Jens Wiltfang, Charlotte E. Teunissen, Alison Goate, Piotr Lewczuk, Carlos Cruchaga, David Ramonet, Frank Jessen, Markus M. Nöthen, Oliver Peters, Michael T. Heneka, Adam C. Naj, Markus P. Kummer, Christine Herold, Heike Kölsch, R. Heun, Wolfgang Maier, Philip Scheltens, Lutz Frölich, Amy Gerrish, Julius Popp, Vincent Chouraki, Céline Bellenguez, Alzheimer's Disease Neuroimaging Initiative, Dmitriy Drichel, Tim Becker, Lara Buscemi, André Lacour, Monique M.B. Breteler, Stefan Herms, Michael Hüll, Stefanie Heilmann, Alfredo Ramirez, Per Hoffmann, Eva Louwersheimer, Popp, Julius, Neurology, Laboratory Medicine, Human genetics, and NCA - neurodegeneration

Subjects
Apolipoprotein E, Male, cerebrospinal fluid [Apolipoprotein E4], Apolipoprotein E4, cerebrospinal fluid [Nuclear Proteins], genetics [Alzheimer Disease], Genome-wide association study, cerebrospinal fluid [Amyloid beta-Peptides], pathology [Alzheimer Disease], Cerebrospinal fluid, Cognition, Medizinische Fakultät, Genotype, genetics [Amyloid beta-Peptides], genetics [RNA-Binding Proteins], Cognitive decline, Phosphorylation, genetics [Apolipoprotein E4], Genetics (clinical), Genetics, Serine-Arginine Splicing Factors, Association Studies Articles, Nuclear Proteins, RNA-Binding Proteins, genetics [Nuclear Proteins], General Medicine, Single Nucleotide, amyloid beta-protein (1-42), cerebrospinal fluid [Alzheimer Disease], Female, Alzheimer's disease, Signal Transduction, medicine.medical_specialty, RNA-Binding Proteins/cerebrospinal fluid/genetics, Single-nucleotide polymorphism, tau Proteins, Biology, Polymorphism, Single Nucleotide, Alzheimer Disease, ddc:570, Internal medicine, medicine, Dementia, Humans, cerebrospinal fluid [Peptide Fragments], cerebrospinal fluid [RNA-Binding Proteins], ddc:610, Polymorphism, Molecular Biology, Aged, tau Proteins/cerebrospinal fluid/genetics, Amyloid beta-Peptides, Apolipoprotein E4/cerebrospinal fluid/genetics, Nuclear Proteins/cerebrospinal fluid/genetics, medicine.disease, genetics [Peptide Fragments], Peptide Fragments, genetics [tau Proteins], Amyloid beta-Peptides/cerebrospinal fluid/genetics, Endocrinology, cerebrospinal fluid [tau Proteins], Gene Expression Regulation, Alzheimer Disease/cerebrospinal fluid/genetics/pathology, Peptide Fragments/cerebrospinal fluid/genetics, Genome-Wide Association Study
Abstract

Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aβ1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aβ1-42.

Published
2017

29. [P3–090]: THE ALZHEIMER's DISEASE SEQUENCING PROJECT (ADSP) DATA UPDATE 2017

Author

Rebecca Cweibel, Elizabeth L. Appelbaum, John J. Farrell, Robert S. Fulton, Otto Valladares, Sudha Seshadri, Eric Boerwinkle, Laura B. Cantwell, Tatiana Foroud, Adam C. Naj, Seung Hoan Choi, Namrata Gupta, Liming Qu, Jason Waligorski, Mike Feolo, Gerard D. Schellenberg, Kara L. Hamilton-Nelson, Yuk Yee Leung, Amanda B. Kuzma, Anita L. DeStefano, Han-Jen Lin, Adam Stine, Dolly Reyes-Dumeyer, William J Salerno, Donna M. Muzny, Joshua C. Bis, Li-San Wang, and Kelley Faber

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Medicine, Neurology (clinical), Computational biology, Disease, Geriatrics and Gerontology, business
Published
2017

30. P2-151: THE ALZHEIMER'S DISEASE SEQUENCING PROJECT - FOLLOW UP STUDY (ADSP-FUS): INCREASING ETHNIC DIVERSITY IN ALZHEIMER'S GENETICS RESEARCH

Author

Dolly Reyes-Dumeyer, Margaret A. Pericak-Vance, Larry D. Adams, Gerard D. Schellenberg, Kelley Faber, Clifton L. Dalgard, Brian W. Kunkle, Li-San Wang, Adam C. Naj, Jeffery M. Vance, Katrina Celis, Badri N. Vardarajan, Pedro Ramon Mena, Tatiana Foroud, Michael L. Cuccaro, Amanda B. Kuzma, Eden R. Martin, and Richard Mayeux

Subjects
Gerontology, Epidemiology, business.industry, Health Policy, Follow up studies, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Cultural diversity, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2019

31. Parkinsonism and distinct dementia patterns in a family with the MAPT R406W mutation

Author

John R. Gilbert, Martin A. Kohli, Brian W. Kunkle, Adam C. Naj, Stephan Züchner, Margaret A. Pericak-Vance, and Regina M. Carney

Subjects
Pediatrics, medicine.medical_specialty, Epidemiology, DNA Mutational Analysis, Mutation, Missense, tau Proteins, Disease, Article, Cellular and Molecular Neuroscience, Parkinsonian Disorders, Developmental Neuroscience, mental disorders, medicine, Humans, Missense mutation, Dementia, Family, Early-onset Alzheimer's disease, Exome sequencing, Genetics, business.industry, Health Policy, Parkinsonism, Middle Aged, medicine.disease, Pedigree, nervous system diseases, Psychiatry and Mental health, Disease Progression, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, business, Frontotemporal dementia
Abstract

Background The Arg406Trp (R406W) missense mutation in the microtubule-associated protein-tau gene (MAPT ) is a known cause of early-onset dementia. Various dementia phenotypes have been described, including frontotemporal dementia (FTD), FTD with parkinsonism, and early-onset Alzheimer disease (EOAD)-like presentations. Methods Using whole-exome capture with subsequent sequencing, we identified the R406W mutation in a family with multiple individuals with clinically diagnosed EOAD, in a pattern suggesting autosomal dominant inheritance. We reevaluated all available family members clinically. Results Each of the affected individuals had a course meeting clinical criteria for EOAD. Two distinct disease trajectories were apparent: one rapidly progressive, and the other long and gradual. Four of five affected individuals also manifested parkinsonian symptoms. FTD features were not prominent and, when present, appeared only late in the course of dementia. Conclusions The MAPT R406W mutation is associated with EOAD-like symptoms and parkinsonism without FTD, as well as distinct cognitive courses.

Published
2013

32. Genome‐wide association study of the rate of cognitive decline in Alzheimer's disease

Author

Yorghos Tripodis, Lindsay A. Farrer, Adam C. Naj, Lori B. Chibnik, David A. Bennett, Paul K. Crane, Philip L. De Jager, Richard Sherva, Joshua M. Shulman, Andrew J. Saykin, and Robert C. Green

Subjects
Male, Genotype, Epidemiology, Apolipoprotein E4, Genome-wide association study, Single-nucleotide polymorphism, Disease, Neuropsychological Tests, Biology, Polymorphism, Single Nucleotide, Article, Cellular and Molecular Neuroscience, Developmental Neuroscience, Alzheimer Disease, medicine, Humans, SNP, Allele, Cognitive decline, Aged, Memory and aging, Aged, 80 and over, Genetics, Extracellular Matrix Proteins, Health Policy, medicine.disease, Psychiatry and Mental health, Phenotype, Female, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Cognition Disorders, Follow-Up Studies, Genome-Wide Association Study
Abstract

Background Substantial interindividual variability exists in the disease trajectories of Alzheimer's disease (AD) patients. Some decline rapidly whereas others decline slowly, and there are no known explanations for this variability. We describe the first genome-wide association study to examine rate of cognitive decline in a sample of AD patients with longitudinal measures of cognition. Methods The discovery sample was 303 AD cases recruited in the Alzheimer's Disease Neuroimaging Initiative and the replication sample was 323 AD cases from the Religious Orders Study and Rush Memory and Aging Project. In the discovery sample, Alzheimer's Disease Assessment Scale–cognitive subscale responses were tested for association with genome-wide single-nucleotide polymorphism (SNP) data using linear regression. We tested the 65 most significant SNPs from the discovery sample for association in the replication sample. Results We identified SNPs in the spondin 1 gene ( SPON1 ), the minor alleles of which were significantly associated with a slower rate of decline (rs11023139, P = 7.0 × 10 −11 ) in the discovery sample. A SPON1 SNP 5.5 kb upstream was associated with decline in the replication sample (rs11606345, P = .002). Conclusion SPON1 has not been previously associated with AD risk, but is plausibly related because the gene product binds to the amyloid precursor protein and inhibits its cleavage by β-secretase. These data suggest that SPON1 may be associated with the differential rate of cognitive decline in AD.

Published
2013

33. 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

34. P1‐018: Rare Deleterious And Loss‐of‐Function Variants in OPRL1 and GAS2L2 Contribute to the Risk of Late‐Onset Alzheimer’s Disease: Alzheimer’s Disease Sequencing Project Case‐Control Study

Author

Joshua C. Bis, Gary W. Beecham, Lindsay A. Farrer, Dan Lancour, Brian W. Kunkle, Josée Dupuis, Yiyi Ma, Adam C. Naj, Yuning Chen, Eric Boerwinkle, Xueqiu Jian, Anita L. DeStefano, William J Salerno, William S. Bush, Sudha Seshadri, Gerard D. Schellenberg, Myriam Fornage, and Kara Hamilton

Subjects
0301 basic medicine, Epidemiology, business.industry, Health Policy, Case-control study, Late onset, Disease, Bioinformatics, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 030104 developmental biology, 0302 clinical medicine, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Loss function
Published
2016

35. O1‐03‐03: Identification of Novel Candidate Genes for Early‐Onset Alzheimer's Disease Through Integrated Whole‐Exome Sequencing and Exome Chip Array Association Analysis

Author

Brian W. Kunkle, Badri N. Vardarajan, Adam C. Naj, Holly N. Cukier, Derek M. Dykxhoorn, Sophie Rolati, Patrice L. Whitehead, Regina M. Carney, Michael L. Cuccaro, Jeffery M. Vance, Alzheimer's Disease Genetics Consortium, Lindsay A. Farrer, Jonathan L. Haines, Gerard D. Schellenberg, Eden R. Martin, Christiane Reitz, Gary W. Beecham, Richard Mayeux, and Margaret A. Pericak-Vance

Subjects
0301 basic medicine, Candidate gene, Epidemiology, Health Policy, Computational biology, Biology, Bioinformatics, medicine.disease, 01 natural sciences, 010104 statistics & probability, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 030104 developmental biology, Developmental Neuroscience, medicine, Early-onset Alzheimer's disease, Identification (biology), Neurology (clinical), 0101 mathematics, Geriatrics and Gerontology, Exome, Exome sequencing, Genetic association
Published
2016

36. S4‐02‐01: Alzheimer's Disease Sequencing Project: Case‐Control Analyses

Author

Liming Qu, Kara Hamilton, Gerard D. Schellenberg, Brian W. Kunkle, Josée Dupuis, Adam C. Naj, Anita L. DeStefano, Yuning Chen, Joshua C. Bis, Jean-Charles Lambert, Yi Zhao, Lindsay A. Farrer, William J Salerno, Eden R. Martin, Sven J. van der Lee, Yiyi Ma, Dan Lancour, Sudha Seshadri, Eric Boerwinkle, Xueqiu Jian, William S. Bush, John J. Farrell, Cornelia M. van Duijn, Myriam Fornage, and Céline Bellenguez

Subjects
Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, 05 social sciences, Disease, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Internal medicine, medicine, 0501 psychology and cognitive sciences, Neurology (clinical), Geriatrics and Gerontology, Control (linguistics), business, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Published
2016

37. The Epidemiology and Genetics of Vascular Dementia

Author

Adam C. Naj

Subjects
Candidate gene, business.industry, Genome-wide association study, Disease, medicine.disease, Bioinformatics, Medicine, Dementia, cardiovascular diseases, Cerebral amyloid angiopathy, business, Vascular dementia, Stroke, Neuroscience, Genetic association
Abstract

Vascular dementia (VaD) is dementia resulting from vascular defects such as occlusions or malformations in the brain, typically arising from stroke. Although it is the second most common cause of dementia after Alzheimer's disease, it has a considerably more ambiguous and heterogeneous pathology, complicating the identification of causal genetic risk factors. Successful genetic studies of VaD have included candidate genes studies that have focused on genes contributing to cerebrovascular disease and genes contributing to vascular risk factors upstream of stroke, such as genes related to renin–angiotensin system like angiotension converting enzyme influencing hypertension. Studies of subtypes of VaD with distinct pathologies, such as cerebral amyloid angiopathy, have also succeeded in identifying genes that may contribute to the presentation of VaD even among those without monogenic forms of disease. Finally, genome-wide association studies using high-density genotyping arrays and next-generation sequencing are beginning to identify high penetrance common genetic variants increasing the risk of the disease, and with future studies may identify rare variants driving VaD. Although genetic studies of VaD remain challenging due to varying diagnostic criteria and heterogeneity in disease pathology, studies with larger sample sizes and highly refined phenotypic characterizations of dementia may provide opportunities for the identification of novel genetic contributors to VaD.

Published
2016

38. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Author

Marla Gearing, David G. Clark, Steven L. Carroll, Marianne Johnstone, Darwin L. Conwell, Gregory A. Cote, Sandra Weintraub, Matthew P. Frosch, Stuart Sherman, Badri N. Vardarajan, Joshua A. Sonnen, Lindy E. Harrell, Peter B. Cotton, Lisa L. Barnes, Lawrence S. Honig, Carol A. Miller, Adam Slivka, Michelle A. Anderson, Nadine M. Melhem, David A. Bennett, Joel H. Kramer, Jill P. Smith, Michele D. Lewis, Mary Ganguli, Jean Paul Vonsatte, Thomas J. Montine, Lee-Way Jin, Kenneth B. Fallon, Marilyn S. Albert, Eliezer Masliah, John H. Growdon, Barry Reisberg, Chuanhai Cao, Patricia L. Kramer, Douglas J. Hartman, Allan I. Levey, Jennifer Williamson, Vivianna M. Van Deerlin, Wayne W. Poon, Alison Goate, Vijay P. Singh, Bernie Devlin, Christiane Reitz, Ann C. McKee, Amanda Smith, Neill R. Graff-Radford, Walter A. Kukul, John Baillie, Andres Gelrud, Ranjan Duara, Thomas D. Bird, Clinton B. Wright, Deborah Blacker, Chiao-Feng Lin, Ge Li, Ronald C. Kim, Deborah C. Mash, Debby W. Tsuang, John P. Neoptolemos, Timothy B. Gardner, Kathryn L. Lunetta, Steven G. Younkin, Kara L. Hamilton-Nelson, Ronald L. Hamilton, F. Yesim Demirci, Eric M. Reiman, Charles DeCarli, John M Olichney, Richard Mayeux, Gregory A. Jicha, Michael R. O'Connell, Matt Tector, Eileen H. Bigio, Jonathan D. Glass, M. Ilyas Kamboh, Randall E. Brand, Christopher Lawrence, Steven E. Arnold, Jessica LaRusch, Elaine R. Peskind, David H. Cribbs, M.-Marsel Mesulam, Constantine G. Lyketsos, Michelle L. Kienholz, Frank M. LaFerla, Duane Beekly, Kelley Faber, Salvatore Spina, Gyungah Jun, Thiruvengadam Muniraj, Erik D. Roberson, Anna Karydas, Steven H. Ferris, Bruce L. Miller, Randall L. Woltjer, Li-San Wang, Lon S. Schneider, John C. Morris, John Q. Trojanowski, Jeffrey Kaye, Joseph E. Parisi, Nilufer Ertekin-Taner, Harry V. Vinters, Lidiya Orlichenko, Robert Barber, Chris E. Forsmark, Mary Sano, Bimaljit S. Sandhu, Peter A. Banks, Martin R. Farlow, Bradley T. Hyman, Joseph F. Quinn, Gary W. Beecham, James A. DiSario, Hakon Hakonarson, Daniel C. Marson, Adam C. Naj, Frank Martiniuk, Oscar L. Lopez, Mary E. Money, Julia Mayerle, William Greenhalf, Kathryn Roeder, Adam L. Boxer, Christine M. Hulette, Gerard D. Schellenberg, Georgios I. Papachristou, Douglas Galasko, James R. Burke, Donna B. Stolz, Murray A. Raskind, Peter Simon, Linda J. Van Eldik, Robert A. Hawes, Chang En Yu, Tatiana Foroud, Jonathan L. Haines, Stephen R. Wisniewski, William W. Seeley, Dhiraj Yadav, James J. Lah, C. Mel Wilcox, Sid Gilman, Liana G. Apostolova, Howard J. Rosen, Clinton T. Baldwin, Robert S. Stern, Narcis O. Zarnescu, Dennis W. Dickson, Margaret A. Pericak-Vance, Ashok Raj, Stephen T. Amann, Joseph D. Buxbaum, Ronald C. Petersen, Robert C. Green, David C. Whitcomb, Rudolph E. Tanzi, Lindsay A. Farrer, Helena C. Chui, Laura B. Cantwell, Wendy J. Mack, Samer Alkaade, Nigel J. Cairns, Thomas G. Beach, Frank Ulrich Weiss, Alyssa M. Krasinskas, Elizabeth Head, Nalini M. Guda, Julie A. Schneider, Malcolm B. Dick, Roger N. Rosenberg, Jill R. Murrel, Otto Valladares, Andrew J. Saykin, Huntington Potter, John R. Gilbert, Neil W. Kowall, Joseph Romagnuolo, Markus M. Lerch, Aimee Pierce, Roger L. Albin, John M. Ringman, James B. Leverenz, Carlos Cruchaga, Joshua W. Miller, Lei Yu, M. Michael Barmada, Lambertus Klei, Andrew P. Lieberman, Bernardino Ghetti, Robert Sutton, Kathleen A. Welsh-Bohmer, Juan C. Troncoso, Edward H. Koo, Elizabeth Crocco, Eden R. Martin, Daniel H. Geschwind, and Regina M. Carney

Subjects
Male, Pancreatic disease, Pancreatitis, Alcoholic, Genome-wide association study, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Gene Frequency, Genotype, Genetics, medicine, PRSS2, Humans, Genetic Predisposition to Disease, Trypsin, Allele, Allele frequency, Homozygote, Genetic Variation, medicine.disease, 3. Good health, Hemizygote, 030220 oncology & carcinogenesis, Immunology, Claudins, Mutation, Trypsinogen, Pancreatitis, 030211 gastroenterology & hepatology, Female, Genome-Wide Association Study
Abstract

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).

Published
2012

39. Whole-Exome Sequencing Links a Variant in DHDDS to Retinitis Pigmentosa

Author

Gary W. Beecham, Yvonne J. K. Edwards, Inga Peter, Joseph D. Buxbaum, Adam C. Naj, Guiqing Cai, William Hulme, Ioanna Konidari, Margaret A. Pericak-Vance, Amjad Farooq, Eduardo C. Alfonso, Jeffery M. Vance, David Seo, Juan Young, Stephan Züchner, Martin A. Kohli, Byron L. Lam, Julia E. Dallman, Jonathan L. Haines, Rong Wen, Patrice L. Whitehead, and Susan H. Blanton

Subjects
Male, Rhodopsin, Glycosylation, Sequence analysis, Biology, medicine.disease_cause, Polymerase Chain Reaction, 03 medical and health sciences, 0302 clinical medicine, Locus heterogeneity, Dolichols, Report, Retinitis pigmentosa, Genetics, medicine, Animals, Humans, Genetics(clinical), Allele, Gene, Zebrafish, Genetics (clinical), Exome sequencing, Genes, Dominant, 030304 developmental biology, 0303 health sciences, Mutation, Alkyl and Aryl Transferases, Genetic Variation, Exons, Sequence Analysis, DNA, Zebrafish Proteins, medicine.disease, Pedigree, 3. Good health, Dehydrodolichyl diphosphate synthase, Phenotype, Female, Retinitis Pigmentosa, 030217 neurology & neurosurgery
Abstract

Increasingly, mutations in genes causing Mendelian disease will be supported by individual and small families only; however, exome sequencing studies have thus far focused on syndromic phenotypes characterized by low locus heterogeneity. In contrast, retinitis pigmentosa (RP) is caused by >50 known genes, which still explain only half of the clinical cases. In a single, one-generation, nonsyndromic RP family, we have identified a gene, dehydrodolichol diphosphate synthase (DHDDS), demonstrating the power of combining whole-exome sequencing with rapid in vivo studies. DHDDS is a highly conserved essential enzyme for dolichol synthesis, permitting global N-linked glycosylation. Zebrafish studies showed virtually identical photoreceptor defects as observed with N-linked glycosylation-interfering mutations in the light-sensing protein rhodopsin. The identified Lys42Glu variant likely arose from an ancestral founder, because eight of the nine identified alleles in 27,174 control chromosomes were of confirmed Ashkenazi Jewish ethnicity. These findings demonstrate the power of exome sequencing linked to functional studies when faced with challenging study designs and, importantly, link RP to the pathways of N-linked glycosylation, which promise new avenues for therapeutic interventions.

Published
2011

40. Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease

Author

Badri N. Vardarajan, Gary W. Beecham, Anita L. DeStefano, James M. Jaworski, Timothy A. Thornton, Allison Goate, Farid Rajabli, Elizabeth Blue, Kara L. Hamilton-Nelson, Eric Boerwinkle, Lindsay A. Farrer, Eden R. Martin, Richard Mayeux, Margaret A. Pericak-Vance, J. Haines, Gerard D. Schellenberg, Ellen M. Wijsman, Brian W. Kunkle, Adam C. Naj, Cornelia M. van Duijn, Sandra Barral, Christiane Reitz, Sudha Seshadri, William S. Bush, and Epidemiology

Subjects
0301 basic medicine, Genetics, Whole genome sequencing, Candidate gene, FERMT2, Disease, Biology, medicine.disease, Article, White (mutation), 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Genetic variation, medicine, biology.protein, Neurology (clinical), Alzheimer's disease, Gene, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract

ObjectiveTo identify genetic variation influencing late-onset Alzheimer disease (LOAD), we used a large data set of non-Hispanic white (NHW) extended families multiply-affected by LOAD by performing whole genome sequencing (WGS).MethodsAs part of the Alzheimer Disease Sequencing Project, WGS data were generated for 197 NHW participants from 42 families (affected individuals and unaffected, elderly relatives). A two-pronged approach was taken. First, variants were prioritized using heterogeneity logarithm of the odds (HLOD) and family-specific LOD scores as well as annotations based on function, frequency, and segregation with disease. Second, known Alzheimer disease (AD) candidate genes were assessed for rare variation using a family-based association test.ResultsWe identified 41 rare, predicted-damaging variants that segregated with disease in the families that contributed to the HLOD or family-specific LOD regions. These included a variant in nitric oxide synthase 1 adaptor protein that segregates with disease in a family with 7 individuals with AD, as well as variants in RP11-433J8, ABCA1, and FISP2. Rare-variant association identified 2 LOAD candidate genes associated with disease in these families: FERMT2 (p-values = 0.001) and SLC24A4 (p-value = 0.009). These genes still showed association while controlling for common index variants, indicating the rare-variant signal is distinct from common variation that initially identified the genes as candidates.ConclusionsWe identified multiple genes with putative damaging rare variants that segregate with disease in multiplex AD families and showed that rare variation may influence AD risk at AD candidate genes. These results identify novel AD candidate genes and show a role for rare variation in LOAD etiology, even at genes previously identified by common variation.

Published
2018

41. Association of Scavenger Receptor Class B Type I Polymorphisms With Subclinical Atherosclerosis

Author

Stephen S. Rich, W. H. Linda Kao, Adam C. Naj, Michael West, Wendy S. Post, Bruce A. Wasserman, David M. Herrington, and Annabelle Rodriguez

Subjects
Male, medicine.medical_specialty, Pathology, Genotype, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, Article, chemistry.chemical_compound, Sex Factors, Asian People, Risk Factors, Internal medicine, Genetics, medicine, Humans, SNP, Genetic Predisposition to Disease, Allele, Prospective cohort study, Alleles, Genetics (clinical), Aged, Genetic association, Aged, 80 and over, Cholesterol, Hispanic or Latino, Middle Aged, Scavenger Receptors, Class B, Atherosclerosis, Tunica intima, SCARB1, Black or African American, Carotid Arteries, Phenotype, medicine.anatomical_structure, chemistry, Female, Tunica Intima, Cardiology and Cardiovascular Medicine
Abstract

Background— Little is known about the association of scavenger receptor class B type I ( SCARB1 ) single-nucleotide polymorphisms (SNPs) and subclinical atherosclerosis, particularly in subjects of different racial/ethnic backgrounds. We examined this relationship in the Multi-Ethnic Study of Atherosclerosis. Methods and Results— Forty-three SCARB1 -tagging SNPs were genotyped. Baseline examinations included fasting lipids and subclinical atherosclerosis phenotypes (coronary artery calcification, common carotid intimal-medial artery thickness [CCIMT], and internal carotid intimal-medial artery thickness). Examining SNP associations with different subclinical atherosclerosis phenotypes across multiple racial/ethnic groups with adjustment for multiple covariates, we found that the C allele of SNP rs10846744 was associated with higher CCIMT in African American ( P =0.03), Chinese ( P =0.02), European American ( P =0.05), and Hispanic participants ( P =0.03) and was strongly associated in pooled analyses ( P =0.0002). The results also showed that the association of this SNP with CCIMT was independent of lipids and other well-established cardiovascular risk factors. Stratifying by sex, there seemed to be a strong association of rs10846744 with CCIMT in women, but no genotype-sex interactions were observed. Conclusions— Variation in SCARB1 at rs10846744 was significantly associated with CCIMT across racial/ethnic groups in Multi-Ethnic Study of Atherosclerosis.

Published
2010

42. Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals

Author

Lee-Way Jin, Rudolph E. Tanzi, Lisa L. Barnes, Neill R. Graff-Radford, Joel H. Kramer, Tatiana Foroud, John R. Gilbert, Wayne W. Poon, Philip L. De Jager, Lei Yu, John M. Ringman, James J. Lah, Marla Gearing, David A. Bennett, Susan M. McCurry, Kenneth B. Fallon, Clinton B. Wright, Deborah Blacker, Bradley T. Hyman, Patricia L. Kramer, Joseph F. Quinn, Alison Goate, Gail P. Jarvik, Allan I. Levey, Jennifer Williamson, Mary Ganguli, Carlos Cruchaga, Julie A. Schneider, Amanda Smith, Eric M. Reiman, Lon S. Schneider, Steven H. Ferris, Richard Mayeux, Randall L. Woltjer, Li-San Wang, Goldie S. Byrd, Malcolm B. Dick, Towfique Raj, Steven L. Carroll, Carol A. Miller, Bradley F. Boeve, John S. K. Kauwe, Elaine R. Peskind, Hugh C. Hendrie, R. C. Kim, Jonathan D. Glass, Helena C. Chui, Guiqing Cai, Deborah C. Mash, Gyungah Jun, James Bowen, Marilyn S. Albert, Kathryn L. Lunetta, Huntington Potter, Walter A. Kukull, Paul K. Crane, Neil W. Kowall, Mark W. Logue, Lindsay A. Farrer, Jean Paul G. Vonsattel, Chang-En Yu, Thomas G. Beach, Gary W. Beecham, Erik D. Roberson, John M Olichney, Gerard D. Schellenberg, Harry V. Vinters, Chiao-Feng Lin, Bruce L. Miller, Duane Beekly, Daniel H. Geschwind, Murray A. Raskind, Kara L. Hamilton-Nelson, Jill R. Murrell, Linda J. Van Eldik, Wendy J. Mack, A. Karydas, Douglas Galasko, Barry Reisberg, Thomas O. Obisesan, Aimee Pierce, Andrew McDavid, Salvatore Spina, M.-Marsel Mesulam, Steven T. DeKosky, Andrew P. Lieberman, Ann C. McKee, Robert Barber, Nigel J. Cairns, Roger L. Albin, Bernardino Ghetti, Nilufer Ertekin-Taner, Kathleen A. Welsh-Bohmer, James B. Leverenz, M. Michael Barmada, F. Yesim Demirci, Hakon Hakonarson, Rodney C.P. Go, Oscar L. Lopez, Joseph D. Buxbaum, Adam C. Naj, Frank Martiniuk, Charles DeCarli, Otto Valladares, Andrew J. Saykin, Kelley Faber, Christine M. Hulette, John C. Morris, M. Ilyas Kamboh, Eliezer Masliah, Christine Sato, Steven E. Arnold, James R. Burke, Daniel C. Marson, Edward H. Koo, Ronald C. Petersen, David G. Clark, William W. Seeley, Robert C. Green, Constantine G. Lyketsos, Rosalyn Lang-Walker, John Q. Trojanowski, Jeffrey Kaye, Eileen H. Bigio, Laura B. Cantwell, Matthew P. Frosch, Jonathan L. Haines, Debby W. Tsuang, Juan C. Troncoso, Joshua W. Miller, Denis A. Evans, Kathleen S. Hall, Frank M. LaFerla, Joseph E. Parisi, Elizabeth Crocco, Mary Sano, Mahdi Ghani, Patrick Griffith, Margaret A. Pericak-Vance, Ashok Raj, Christopher S. Carlson, Jennifer J. Manly, Sid Gilman, Thomas J. Montine, Chuanhai Cao, A. Boxer, Ekaterina Rogaeva, Steven G. Younkin, Ronald L. Hamilton, Rong Cheng, Vahram Haroutunian, Peter St George-Hyslop, Liana G. Apostolova, M. Daniele Fallin, Clinton T. Baldwin, Ruchita Rajbhandary, Robert S. Stern, Sandra Weintraub, David H. Cribbs, Lindy E. Harrell, Wayne C. McCormick, Ge Li, Christiane Reitz, Eric B. Larson, Thomas D. Bird, Gregory A. Jicha, Regina M. Carney, Badri N. Vardarajan, Joshua A. Sonnen, Lawrence S. Honig, Joseph H. Lee, John H. Growdon, and Vivianna M. Van Deerlin

Subjects
Genetics, Chicago, Indiana, business.industry, Haplotype, Homozygote, Case-control study, Single-nucleotide polymorphism, Genome-wide association study, Genes, Recessive, Runs of Homozygosity, Polymorphism, Single Nucleotide, Article, Black or African American, Alzheimer Disease, Case-Control Studies, SNP, Medicine, Humans, Neurology (clinical), business, Imputation (genetics), SNP array, Aged, Genome-Wide Association Study
Abstract

Importance Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. Objective To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. Design, Setting, and Participants Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer’s Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. Main Outcomes and Measures The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. Results The African American cohort had a low degree of inbreeding ( F ~ 0.006). In the Alzheimer’s Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb ( P = .004) or greater than 3 Mb ( P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. Conclusions and Relevance To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

Published
2015

43. P1‐001: Prediction of late‐onset Alzheimer's disease‐associated enhancer elements

Author

Chiao-Feng Lin, George Xu, Beth A. Dombroski, Michele Hawk, Li-San Wang, Yih-Chii Hwang, Pavel P. Kuksa, Weixin Wang, Christian Kramer, Adam C. Naj, Schellenberg Gd, and Mitchell Tang

Subjects
Enhancer Elements, Epidemiology, business.industry, Health Policy, Late onset, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Immunology, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2015

44. Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium

Author

Timothy J. Hohman, Marylyn D. Ritchie, Kristin Brown-Gentry, Lindsay A. Farrer, Shubhabrata Mukherjee, Brian W. Kunkle, Tricia A. Thornton-Wells, Adam C. Naj, Scott M. Dudek, Jonathan L. Haines, Eric S. Torstenson, William S. Bush, Margaret A. Pericak-Vance, Eden R. Martin, Richard Mayeux, Gerard D. Schellenberg, and Lan Jiang

Subjects
0301 basic medicine, Male, Risk, Aging, ATP Binding Cassette Transporter, Subfamily B, Calcium Channels, L-Type, Cadherin Related Proteins, Datasets as Topic, Locus (genetics), Single-nucleotide polymorphism, Phosphatidylethanolamine Binding Protein, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Receptors, N-Methyl-D-Aspartate, Saposins, Article, 03 medical and health sciences, 0302 clinical medicine, Sirtuin 1, Locus heterogeneity, Alzheimer Disease, Receptors, Adrenergic, alpha-1, medicine, Humans, Genetic Association Studies, Genetic association, Genetics, Models, Genetic, General Neuroscience, Epistasis, Genetic, Ryanodine Receptor Calcium Release Channel, medicine.disease, Cadherins, 030104 developmental biology, Endophenotype, Disease Progression, Epistasis, Female, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Late-onset Alzheimer disease (AD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance, and gene-gene interactions; however, the investigation of interactions in recent genome-wide association studies has been limited. We used a biological knowledge-driven approach to evaluate gene-gene interactions for consistency across 13 data sets from the Alzheimer Disease Genetics Consortium. Fifteen single nucleotide polymorphism (SNP)-SNP pairs within 3 gene-gene combinations were identified: SIRT1 × ABCB1, PSAP × PEBP4, and GRIN2B × ADRA1A. In addition, we extend a previously identified interaction from an endophenotype analysis between RYR3 × CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1, and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this article highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis.

Published
2015

45. Phosphodiesterase 4D polymorphisms and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study

Author

Barney J. Stern, O. C. Stine, John W. Cole, Jeffrey R. O'Connell, Braxton D. Mitchell, Patrick F. McArdle, Steven J. Kittner, Qing Song, Marcella A. Wozniak, John D. Sorkin, Qin Xu, Gary H. Gibbons, Wayne H. Giles, Adam C. Naj, and Margaret Gallagher

Subjects
Adult, medicine.medical_specialty, Linkage disequilibrium, Adolescent, Population, Single-nucleotide polymorphism, Biology, Linkage Disequilibrium, White People, Article, Gene Frequency, Risk Factors, Untranslated Regions, Internal medicine, Genetics, medicine, Humans, education, Molecular Biology, Allele frequency, Stroke, Conserved Sequence, Genetics (clinical), education.field_of_study, Polymorphism, Genetic, Smoking, Haplotype, Cerebral Infarction, General Medicine, Odds ratio, Middle Aged, medicine.disease, Cyclic Nucleotide Phosphodiesterases, Type 3, Cyclic Nucleotide Phosphodiesterases, Type 4, Black or African American, Genetics, Population, Haplotypes, 3',5'-Cyclic-AMP Phosphodiesterases, Case-Control Studies, Population study, Female
Abstract

An association between polymorphisms within the phosphodiesterase 4D gene (PDE4D) and ischemic stroke was initially reported in older adults from Iceland and has been supported by studies in several other primarily elderly populations. In the present study, we examined the association between PDE4D polymorphisms and early-onset ischemic stroke in a biracial female population. A systematic search for polymorphisms in the highly evolutionary conserved regions of PDE4D was performed on 48 African-American and 48 Caucasian participants. Novel and known polymorphisms were then prioritized and genotyped in the entire study population of 224 cases of first ischemic stroke among women aged 15–49 and 211 age- and ethnicity-balanced control subjects. Forty novel and previously reported polymorphisms with a minor allele frequency greater than 0.05 were determined, with 23 polymorphisms selected for analysis in the full case–control sample. Single nucleotide polymorphism (SNP), linkage disequilibrium and haplotype analyses were performed. SNP rs918592, found in an intron near the 5′ end of the gene, was significantly associated with stroke (age- and race-adjusted odds ratio (OR = 1.5, P = 0.007), with four other SNPs showing significant, albeit less strong, associations. The magnitude of association was similar across African-Americans and Caucasians and across multiple stroke subtypes (e.g. atherosclerotic, lacunar and non-lacunar of undetermined etiology). The association of rs918592 with stroke was confined exclusively to current smokers (OR = 3.2, P = 0.00014), with no association observed among never-smokers (OR = 0.9, P = 0.75) or former smokers (OR = 1.2, P = 0.66), demonstrating a gene–environment interaction (P = 0.03). A strong dose–response relationship was also seen among current smokers. No specific risk haplotypes were identified.

Published
2006

46. Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology

Author

Sally R. Ellingson, Peter T. Nelson, Walter A. Kukull, Li-San Wang, Adam C. Naj, Amanda Partch, David W. Fardo, Sarah E. Monsell, Wang-Xia Wang, Otto Valladares, and Bernard R. Wilfred

Subjects
Male, Pathology, medicine.medical_specialty, Aging, Databases, Factual, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Nerve Tissue Proteins, Neuropathology, Disease, Bioinformatics, Sulfonylurea Receptors, Hippocampus, Polymorphism, Single Nucleotide, Article, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Progranulins, Alzheimer Disease, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, Aged, 80 and over, Hippocampal sclerosis, Sclerosis, business.industry, Dementia with Lewy bodies, Membrane Proteins, General Medicine, Frontotemporal lobar degeneration, Genomics, Middle Aged, medicine.disease, Neurology, Intercellular Signaling Peptides and Proteins, Female, Neurology (clinical), Alzheimer's disease, business
Abstract

Hippocampal sclerosis of aging (HS-Aging) is a common, high morbidity-associated neurodegenerative condition in elderly persons. To understand risk factors for HS-Aging, we analyzed data from the Alzheimer’s Disease Genetics Consortium and correlated the data with clinical and pathologic information from the National Alzheimer’s Coordinating Center database. Overall, 268 research volunteers with HS-Aging and 2957 controls were included; detailed neuropathologic data were available for all. The study focused on single nucleotide polymorphisms previously associated with HS-Aging risk: rs5848 (GRN), rs1990622 (TMEM106B), and rs704180 (ABCC9). Analyses of a subsample that were not previously evaluated (51 HS-Aging cases and 561 controls) replicated the associations of previously identified HS-Aging risk alleles. To test for evidence of gene-gene interactions and genotype-phenotype relationships, pooled data were analyzed. The risk for HS-Aging diagnosis associated with these genetic polymorphisms was not secondary to an association with either Alzheimer disease or dementia with Lewy bodies neuropathologic changes. The presence of multiple risk genotypes was associated with a trend for additive risk for HS-Aging pathology. We conclude that multiple genes play important roles in HS-Aging, which is a distinctive neurodegenerative disease of aging.

Published
2014

47. The Alzheimer's Disease Sequencing Project: Study design and sample selection

Author

Myriam Fornage, Stacey Gabriel, Seung Hoan Choi, Anita L. DeStefano, Lindsay A. Farrer, Eden R. Martin, William S. Bush, Sudha Seshadri, A. Goate, Tatiana Foroud, Bruce M. Psaty, Gerard D. Schellenberg, Margaret A. Pericak-Vance, Joshua C. Bis, Eric Boerwinkle, Richard Mayeux, Daniel C. Koboldt, Ellen M. Wijsman, David E. Larson, C M van Duijn, Gary W. Beecham, Adam C. Naj, William J Salerno, Jonathan L. Haines, and Epidemiology

Subjects
0301 basic medicine, Gerontology, medicine.medical_specialty, Disease, 03 medical and health sciences, Rotterdam Study, 0302 clinical medicine, Framingham Heart Study, Epidemiology, Medicine, Dementia, Clinical/Scientific Notes, Genetics (clinical), business.industry, Public health, medicine.disease, 3. Good health, 030104 developmental biology, Genetic epidemiology, Neurology (clinical), Alzheimer's disease, business, 030217 neurology & neurosurgery
Abstract

Late-onset Alzheimer disease (LOAD) is the leading cause of dementia worldwide, with substantial economic and public health implications.1 LOAD is a neurodegenerative disease characterized by progressive dementia typically manifesting in the seventh to ninth decades. Neuropathological changes precede clinical symptoms by 10–20 years, resulting in clinically asymptomatic individuals carrying neuropathologic features of LOAD.2 Much of the heritability of LOAD remains unexplained, despite LOAD having a high heritability (60%–80%) and despite the identification of the APOE locus, a major genetic determinant for LOAD.3 Genetic analyses have identified more than 25 other variants associated with smaller individual effects on disease risk.4 Acknowledgment: The Alzheimer's Disease Sequencing Project (ADSP) comprises 2 Alzheimer's Disease (AD) genetics consortia and 3 National Human Genome Research Institute (NHGRI)-funded Large Scale Sequencing and Analysis Centers (LSAC). The 2 AD genetics consortia are the Alzheimer's Disease Genetics Consortium (ADGC) funded by the NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by the NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other NIH institutes, and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to G. Schellenberg, L.A. Farrer, M.A. Pericak-Vance, R. Mayeux, and J.L. Haines); U01AG049505 to S. Seshadri; U01AG049506 to E. Boerwinkle; U01AG049507 to E. Wijsman; and U01AG049508 to A. Goate. Data generation and harmonization in the Follow-up Phases is supported by U54AG052427 (to G. Schellenberg and Wang). The ADGC cohorts include Adult Changes in Thought (ACT), the Alzheimer's Disease Centers (ADC), the Chicago Health and Aging Project (CHAP), the Memory and Aging Project (MAP), Mayo Clinic (MAYO), Mayo Parkinson's Disease controls, the University of Miami, the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE), the National Cell Repository for Alzheimer's Disease (NCRAD), the National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA-LOAD), the Religious Orders Study (ROS), the Texas Alzheimer's Research and Care Consortium (TARC), Vanderbilt University/Case Western Reserve University (VAN/CWRU), the Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Washington University Sequencing Project (WUSP), the Columbia University Hispanic–Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA), the University of Toronto (UT), and Genetic Differences (GD). The CHARGE cohorts with funding provided by 5RC2HL102419 and HL105756, include the following: the Atherosclerosis Risk in Communities (ARIC) Study which is conducted as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), the Austrian Stroke Prevention Study (ASPS), the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). The 3 LSACs are the Human Genome Sequencing Center at the Baylor College of Medicine (U54 HG003273), the Broad Institute Genome Center (U54HG003067), and the Washington University Genome Institute (U54HG003079). Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigators institutions and at the National Cell Repository for Alzheimer's Disease (NCRAD, U24AG021886) at Indiana University funded by the NIA. Associated Phenotypic Data used in primary and secondary data analyses were provided by Study Investigators, the NIA-funded Alzheimer's Disease Centers (ADCs), and the National Alzheimer's Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by the NIA and at the Database for Genotypes and Phenotypes (dbGaP) funded by the NIH. This research was supported in part by the Intramural Research Program of the NIH and the National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by the NIA and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations.

Published
2017

48. Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport

Author

Michael L. Cuccaro, Christiane Reitz, John Gilbert, Jonathan L. Haines, Eden R. Martin, Badri N. Vardarajan, Patrice L. Whitehead, Li-San Wang, Sophie Rolati, Regina M. Carney, Jeffery M. Vance, Gary W. Beecham, Brian W. Kunkle, Adam C. Naj, Lindsay A. Farrer, Margaret A. Pericak-Vance, Susan Slifer, Gerard D. Schellenberg, and Richard Mayeux

Subjects
Male, 0301 basic medicine, Vacuolar Proton-Translocating ATPases, medicine.medical_specialty, SORL1, Biology, Bioinformatics, White People, 03 medical and health sciences, Alzheimer Disease, Risk Factors, Internal medicine, PSEN2, medicine, PSEN1, Guanine Nucleotide Exchange Factors, Humans, Exome, Age of Onset, Exome sequencing, Original Investigation, Adaptor Proteins, Signal Transducing, Aged, Aged, 80 and over, Intracellular Signaling Peptides and Proteins, Case-control study, Biological Transport, Hispanic or Latino, Odds ratio, Middle Aged, medicine.disease, 030104 developmental biology, Caribbean Region, Case-Control Studies, Female, Neurology (clinical), Alzheimer's disease, Age of onset, Carrier Proteins
Abstract

Importance Mutations in APP , PSEN1 , and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD. Objective To search for rare variants contributing to the risk for EOAD. Design, Setting, and Participants In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset APP , PSEN1 , and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of-function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer’s Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016. Main Outcomes and Measures Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test–optimal gene tests, respectively. Results Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2 , for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD ( P = 2.05 × 10 −6 ; Bonferroni-corrected P value [BP] = 1.3 × 10 −3 ) and LOAD ( P = 6.22 × 10 −6 ; BP = 4.1 × 10 −3 ). A missense variant in TCIRG1 , present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 × 10 −4 ; BP = 5.0 × 10 −3 ). A missense variant in the LOAD risk gene RIN3 showed suggestive evidence of association with EOAD after Bonferroni correction (OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2 NHW EOAD cases showed suggestive evidence of an association with EOAD as well (OR, 18.63; 95% CI, 1.62-213.45; P = .003; BP = 0.129). Conclusions and Relevance The genes PSD2 , TCIRG1 , RIN3 , and RUFY1 all may be involved in endolysosomal transport—a process known to be important to development of AD. Furthermore, this study identified shared risk genes between EOAD and LOAD similar to previously reported genes, such as SORL1 , PSEN2 , and TREM2 .

Published
2017

49. Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk

Author

Gerard D. Schellenberg, John Hardy, Rodney C.P. Go, Oscar L. Lopez, Richard Mayeux, Jonathan L. Haines, Denis A. Evans, Nilufer Ertekin-Taner, Lindsay A. Farrer, Philip L. De Jager, Walter A. Kukull, Eden R. Martin, Chiao-Feng Lin, Towfique Raj, Laura B. Cantwell, Alison Goate, Rosalyn Lang, Goldie S. Byrd, Mark W. Logue, Tatiana Foroud, Tricia A. Thornton-Wells, Neill R. Graff-Radford, Jeffrey M. Vance, M. Daniele Fallin, Patrick Griffith, Clinton T. Baldwin, Lisa L. Barnes, Margaret A. Pericak-Vance, Paul K. Crane, Adam C. Naj, Ruchita Rajbhandary, Badri N. Vardarajan, Zhi Liu, Joseph D. Buxbaum, Jill R. Murrell, Kathleen S. Hall, Michael L. Cuccaro, Robert C. Green, Thomas O. Obisesan, Timothy J. Hohman, Otto Valladares, Kathryn L. Lunetta, Li-San Wang, Gary W. Beecham, David A. Bennett, Gyungah Jun, Jennifer J. Manly, Christiane Reitz, Eric B. Larson, Regina M. Carney, M. Ilyas Kamboh, Jessica N. Cooke-Bailey, and Hugh C. Hendrie

Subjects
0301 basic medicine, Gerontology, Apolipoprotein E, Male, Genotype, Epidemiology, Sialic Acid Binding Ig-like Lectin 3, Genetic admixture, Genome-wide association study, Disease, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Apolipoproteins E, Developmental Neuroscience, Alzheimer Disease, Medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged, Aged, 80 and over, Chromosome Aberrations, Chi-Square Distribution, business.industry, Health Policy, medicine.disease, Black or African American, Psychiatry and Mental health, 030104 developmental biology, ATP-Binding Cassette Transporters, Female, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, business, Chi-squared distribution, 030217 neurology & neurosurgery, Demography, Cohort study
Abstract

Introduction African-American (AA) individuals have a higher risk for late-onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome-wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)-related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered. Methods We performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status. Results Compared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences. Discussion Exploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.

Published
2014

50. P1‐045: EXOME ARRAY ANALYSIS IDENTIFIES NOVEL RISK VARIANTS FOR ALZHEIMER'S DISEASE WITH ONSET BEFORE 65 YEARS

Author

Adam C. Naj, Carlos Cruchaga, Brian W. Kunkle, Shubhabrata Mukherjee, Robert Graham, Li‐San Wang, Timothy Behrens, Richard Mayeux, Jonathan Haines, Lindsay A. Farrer, Margaret Pericak‐Vance, Gerard D. Schellenberg, and null The Alzheimer's Disease Genetics Consortium

Subjects
Oncology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, medicine, Neurology (clinical), Geriatrics and Gerontology, business, Exome
Published
2014

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