621 results on '"Jonathan L. Haines"'
Search Results
2. Leveraging African American family connectors for Alzheimer's disease genomic studies
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Grace Byfield, Takiyah D. Starks, Ronqeiya Luther, Christopher L. Edwards, Shawnta L. Lloyd, Allison Caban‐Holt, Larry Deon Adams, Jeffery M. Vance, Michael Cuccaro, Jonathan L. Haines, Christiane Reitz, Margaret A. Pericak‐Vance, and Goldie S. Byrd
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2023
3. Assessment of intraretinal hyperreflective foci using multimodal imaging in eyes with age‐related macular degeneration
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Deniz Oncel, Giulia Corradetti, Ye He, Maryam Ashrafkhorasani, Muneeswar Gupta Nittala, Dwight Stambolian, Margaret A. Pericak‐Vance, Jonathan L. Haines, and Srinivas R. Sadda
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Ophthalmology ,General Medicine - Published
- 2023
4. Drusen morphometrics on optical coherence tomography in eyes with age-related macular degeneration and normal aging
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Deniz Oncel, Giulia Corradetti, Yu Wakatsuki, Muneeswar Gupta Nittala, Swetha Bindu Velaga, Dwight Stambolian, Margaret A. Pericak-Vance, Jonathan L. Haines, and SriniVas R. Sadda
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Cellular and Molecular Neuroscience ,Ophthalmology ,Sensory Systems - Published
- 2023
5. Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease
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Jaclyn M, Eissman, Logan, Dumitrescu, Emily R, Mahoney, Alexandra N, Smith, Shubhabrata, Mukherjee, Michael L, Lee, Phoebe, Scollard, Seo Eun, Choi, William S, Bush, Corinne D, Engelman, Qiongshi, Lu, David W, Fardo, Emily H, Trittschuh, Jesse, Mez, Catherine C, Kaczorowski, Hector, Hernandez Saucedo, Keith F, Widaman, Rachel F, Buckley, Michael J, Properzi, Elizabeth C, Mormino, Hyun Sik, Yang, Theresa M, Harrison, Trey, Hedden, Kwangsik, Nho, Shea J, Andrews, Douglas, Tommet, Niran, Hadad, R Elizabeth, Sanders, Douglas M, Ruderfer, Katherine A, Gifford, Xiaoyuan, Zhong, Neha S, Raghavan, Badri N, Vardarajan, Margaret A, Pericak-Vance, Lindsay A, Farrer, Li San, Wang, Carlos, Cruchaga, Gerard D, Schellenberg, Nancy J, Cox, Jonathan L, Haines, C Dirk, Keene, Andrew J, Saykin, Eric B, Larson, Reisa A, Sperling, Richard, Mayeux, Michael L, Cuccaro, David A, Bennett, Julie A, Schneider, Paul K, Crane, Angela L, Jefferson, and Timothy J, Hohman
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Male ,Sex Characteristics ,Cognition ,Multiple Sclerosis ,Alzheimer Disease ,Humans ,Cognitive Dysfunction ,Female ,Genetic Predisposition to Disease ,Neurology (clinical) ,Genome-Wide Association Study - Abstract
Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer’s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer’s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer’s disease. It is well established that there are sex differences in response to Alzheimer’s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20–25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15–44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10−09, β (males) = −0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10−04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer’s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer’s disease may be personalized based on their biological sex and genetic context.
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- 2022
6. Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets
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Jairo Ramos, Laura J. Caywood, Michael B. Prough, Jason E. Clouse, Sharlene D. Herington, Susan H. Slifer, M. Denise Fuzzell, Sarada L. Fuzzell, Sherri D. Hochstetler, Kristy L. Miskimen, Leighanne R. Main, Michael D. Osterman, Andrew F. Zaman, Patrice L. Whitehead, Larry D. Adams, Renee A. Laux, Yeunjoo E. Song, Tatiana M. Foroud, Richard P. Mayeux, Peter St. George‐Hyslop, Paula K. Ogrocki, Alan J. Lerner, Jeffery M. Vance, Michael L. Cuccaro, Jonathan L. Haines, Margaret A. Pericak‐Vance, and William K. Scott
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Abstract
Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI.A total of 1522 individuals screened for CI were genotyped. The outcome studied was AAO for CI individuals or age at last normal exam for CU individuals. Cox mixed-effects models examined association between age and single nucleotide variants (SNVs).Three SNVs were significantly associated (P5 × 10The replicated genome-wide significant association with AAO on chromosome 17 is located in the SHISA6 gene, which is involved in post-synaptic transmission in the hippocampus and is a biologically plausible candidate gene for Alzheimer's disease.
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- 2022
7. Admixture Mapping of Alzheimer’s disease in Caribbean Hispanics identifies a new locus on 22q13.1
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Caghan Kizil, Sanjeev Sariya, Yoon A. Kim, Farid Rajabli, Eden Martin, Dolly Reyes-Dumeyer, Badri Vardarajan, Aleyda Maldonado, Jonathan L. Haines, Richard Mayeux, Ivonne Z. Jiménez-Velázquez, Ismael Santa-Maria, and Giuseppe Tosto
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genetics [Alzheimer Disease] ,Polymorphism, Single Nucleotide ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Caribbean Region ,Alzheimer Disease ,Ethnicity ,genetics [Polymorphism, Single Nucleotide] ,Animals ,Humans ,Drosophila ,ddc:610 ,Molecular Biology ,Zebrafish - Abstract
Late-onset Alzheimer's disease (LOAD) is significantly more frequent in Hispanics than in non-Hispanic Whites. Ancestry may explain these differences across ethnic groups. To this end, we studied a large cohort of Caribbean Hispanics (CH, N = 8813) and tested the association between Local Ancestry (LA) and LOAD ('admixture mapping') to identify LOAD-associated ancestral blocks, separately for ancestral components (European [EUR], African [AFR], Native American[NA]) and jointly (AFR + NA). Ancestral blocks significant after permutation were fine-mapped employing multi-ethnic whole-exome sequencing (WES) to identify rare variants associated with LOAD (SKAT-O) and replicated in the UK Biobank WES dataset. Candidate genes were validated studying (A) protein expression in human LOAD and control brains; (B) two animal AD models, Drosophila and Zebrafish. In the joint AFR + NA model, we identified four significant ancestral blocks located on chromosomes 1 (p value = 8.94E-05), 6 (p value = 8.63E-05), 21 (p value = 4.64E-05) and 22 (p value = 1.77E-05). Fine-mapping prioritized the GCAT gene on chromosome 22 (SKAT-O p value = 3.45E-05) and replicated in the UK Biobank (SKAT-O p value = 0.05). In LOAD brains, a decrease of 28% in GCAT protein expression was observed (p value = 0.038), and GCAT knockdown in Amyloid-β42 Drosophila exacerbated rough eye phenotype (68% increase, p value = 4.84E-09). In zebrafish, gcat expression increased after acute amyloidosis (34%, p value = 0.0049), and decreased upon anti-inflammatory Interleukin-4 (39%, p value = 2.3E-05). Admixture mapping uncovered genomic regions harboring new LOAD-associated loci that might explain the observed different frequency of LOAD across ethnic groups. Our results suggest that the inflammation-related activity of GCAT is a response to amyloid toxicity, and reduced GCAT expression exacerbates AD pathology.
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- 2022
8. Psychometric approaches to defining cognitive phenotypes in the Old Order Amish
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Andrew Zaman, Laura Caywood, Michael Prough, Jason Clouse, Sharlene Harrington, Larry Adams, Denise Fuzzell, Sarada Fuzzell, Renee Laux, Sherri D. Hochstetler, Paula Ogrocki, Alan Lerner, Jeffery M. Vance, Jonathan L. Haines, William K. Scott, Margaret A. Pericak‐Vance, and Michael L. Cuccaro
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Psychiatry and Mental health ,Geriatrics and Gerontology - Published
- 2023
9. Mitochondrial TXNRD2 and ME3 Genetic Risk Scores Are Associated with Specific Primary Open-Angle Glaucoma Phenotypes
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Inas F. Aboobakar, Tyler G. Kinzy, Yan Zhao, Baojian Fan, Louis R. Pasquale, Ayub Qassim, Antonia Kolovos, Joshua M. Schmidt, Jamie E. Craig, Jessica N. Cooke Bailey, Janey L. Wiggs, R. Rand Allingham, Murray Brilliant, Donald L. Budenz, John H. Fingert, Douglas Gaasterland, Teresa Gaasterland, Jonathan L. Haines, Michael A. Hauser, Richard K. Lee, Paul R. Lichter, Yutao Liu, Syoko Moroi, Jonathan Myers, Margaret Pericak-Vance, Anthony Realini, Doug Rhee, Julia E. Richards, Robert Ritch, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Douglas Vollrath, Robert N. Weinreb, Gadi Wollstein, and Donald J. Zack
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Ophthalmology - Published
- 2023
10. Genome-wide association study of brain arteriolosclerosis
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Lincoln MP Shade, Yuriko Katsumata, Timothy J Hohman, Kwangsik Nho, Andrew J Saykin, Shubhabrata Mukherjee, Kevin L Boehme, John SK Kauwe, Lindsay A Farrer, Gerard D Schellenberg, Jonathan L Haines, Richard P Mayeux, Julie A Schneider, Peter T Nelson, and David W Fardo
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Arteriolosclerosis ,Neurology ,Alzheimer Disease ,Brain ,Humans ,Original Articles ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,Polymorphism, Single Nucleotide ,Aged ,Genome-Wide Association Study - Abstract
Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS ( n = 3382) and Stage 2 mega-analysis ( n = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p = [Formula: see text]; rs2603462, p = [Formula: see text]) were significant in the ADNI cohort (rs7902929, p = [Formula: see text]; rs2603462, p = [Formula: see text]). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3. We thus identified putative loci associated with B-ASC risk, but additional replication is needed.
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- 2022
11. The National Institute on Aging Late‐Onset Alzheimer's Disease Family Based Study: A resource for genetic discovery
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Dolly, Reyes-Dumeyer, Kelley, Faber, Badri, Vardarajan, Alison, Goate, Alan, Renton, Michael, Chao, Brad, Boeve, Carlos, Cruchaga, Margaret, Pericak-Vance, Jonathan L, Haines, Roger, Rosenberg, Debby, Tsuang, Robert A, Sweet, David A, Bennett, Robert S, Wilson, Tatiana, Foroud, and Richard, Mayeux
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Genotype ,Epidemiology ,Health Policy ,United States ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Apolipoproteins E ,Developmental Neuroscience ,Alzheimer Disease ,National Institute on Aging (U.S.) ,Humans ,Neurology (clinical) ,Age of Onset ,Geriatrics and Gerontology - Abstract
The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD).Recruitment focused on families with two living affected siblings and a third first-degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E (APOE) genotypes, genome-wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families.APOE genotype modified the age-at-onset in many large families. Novel variants and known variants associated with early- and late-onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics.The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD.
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- 2022
12. Designing a Study for Identifying Genes in Complex Traits
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William K. Scott, Marylyn D. Ritchie, Jonathan L. Haines, and Margaret A. Pericak‐Vance
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- 2021
13. Plasma pTau181 is associated with impaired cognition in the Old Order Amish and adds additional information beyond the known genetic risk factors for AD
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Michael B. Prough, Laura J. Caywood, Jason E. Clouse, Sharlene D. Herington, Susan H. Slifer, Daniel A. Dorfsman, Larry D. Adams, Renee A. Laux, Yeunjoo E. Song, Audrey Lynn, M. Denise Fuzzell, Sarada L. Fuzzell, Sherri D. Miller, Kristy L. Miskimen, Leighanne R. Main, Michael D. Osterman, Paula K. Ogrocki, Alan J. Lerner, Jeffery M. Vance, Michael L. Cuccaro, Jonathan L. Haines, William K. Scott, and Margaret A. Pericak‐Vance
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
14. Novel Loci for Alzheimer Disease Identified by Genome Wide Association Study in Ashkenazi Jews
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Donghe Li, John Farrell, Jesse B. Mez, Eden R. Martin, William S. Bush, Richard Mayeux, Jonathan L. Haines, Margaret A. Pericak‐Vance, Li‐San Wang, Gerard D. Schellenberg, Kathryn L. Lunetta, and Lindsay A. Farrer
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
15. A Haptoglobin (HP) Exon Deletion Polymorphism Alters the Effect of APOE Alleles on Alzheimer’s Disease in European‐Descent People with APOEε4
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Haimeng Bai, Adam C. Naj, Yuk Yee Leung, Li‐San Wang, Gerard D. Schellenberg, Richard Mayeux, Margaret A. Pericak‐Vance, Lindsay A. Farrer, Logan Dumitrescu, Timothy J. Hohman, Brian W. Kunkle, Eden R. Martin, Jonathan L. Haines, and William S. Bush
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
16. Spatial Distribution of Rare Missense Variants Within Protein Structures is Associated with AD Risk
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Bowen Jin, John A Capra, Penelope Benchek, Nicholas R. Wheeler, Adam C. Naj, Kara L. Hamilton‐Nelson, John Farrell, Yuk Yee Leung, Brian W. Kunkle, Badri N Vardarajan, Gerard D. Schellenberg, Richard Mayeux, Li‐San Wang, Lindsay A. Farrer, Margaret A. Pericak‐Vance, Eden R. Martin, Jonathan L. Haines, Dana Crawford, and William S. Bush
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
17. Ancestral Analysis of the Presenilin‐1 G206A Variant Reveals it as a Founder Event on an African Haplotype in the Puerto Rican Population
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Kara L. Hamilton‐Nelson, Anthony J. Griswold, Farid Rajabli, Patrice L. Whitehead, Maricarmen Contreras, Sergio Tejada, Jose Javier Sanchez, Pedro Ramon Mena, Larry D. Adams, Takiyah D. Starks, Concepcion Silva‐Vergara, Michael L. Cuccaro, Jeffery M. Vance, Goldie S. Byrd, Jonathan L. Haines, Gary W. Beecham, Briseida E. Feliciano‐Astacio, Margaret A. Pericak‐Vance, and Katrina Celis
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
18. Mosaic Loss of Chromosome Y in Peripheral Blood Cells and Cognitive Status in the Amish
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Yeunjoo E. Song, Kristy L. Miskimen, Renee A. Laux, M. Denise Fuzzell, Sarada L. Fuzzell, Sherri D. Miller, Leighanne R. Main, Michael D. Osterman, Audrey Lynn, Michael B. Prough, Susan H. Slifer, Larry D. Adams, Laura J. Caywood, Jason E. Clouse, Sharlene D. Herington, Daniel A. Dorfsman, Jeffery M. Vance, Michael L. Cuccaro, Paula K. Ogrocki, Alan J. Lerner, William K. Scott, Margaret A. Pericak‐Vance, William S. Bush, and Jonathan L. Haines
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
19. Depressive Symptoms Associated with an Earlier Age at Onset Differ as a Function of Race‐Ethnicity: An Exploratory Analysis
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Andrew Zaman, Pedro Ramon Mena, Larry D. Adams, Maricarmen Contreras, Faina C Lacroix, Sergio Tejada, Takiyah D. Starks, Briseida E. Feliciano‐Astacio, Concepcion Silva, Allison M Caban‐Holt, Goldie S. Byrd, Izri Martinez, Temitope Ayodele, Penelope Baez, Gabrielle Blackshire, Sara Kennedy, Christiane Reitz, Jonathan L. Haines, Jeffery M. Vance, Margaret A. Vance, and Michael L. Cuccaro
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
20. Multiple Viruses Detected in Human DNA are Associated with Alzheimer Disease Risk
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Marlene Tejeda, John Farrell, Congcong Zhu, Lee Wetzler, Kathryn L. Lunetta, William S. Bush, Eden R Martin, Li‐San Wang, Gerard D. Schellenberg, Margaret A. Pericak‐Vance, Jonathan L. Haines, Lindsay A. Farrer, and Richard Sherva
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
21. Detecting genetic loci for preservation of cognition in the Midwestern United States Amish
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Leighanne R. Main, Yeunjoo E. Song, Renee A. Laux, Kristy L. Miskimen, Michael L. Cuccaro, Paula K. Ogrocki, Alan J. Lerner, Jeffery M. Vance, M. Denise Fuzzell, Sarada L. Fuzzell, Sherri D. Hochstetler, Michael D. Osterman, Audrey Lynn, Daniel A. Dorfsman, Laura J. Caywood, Michael B. Prough, Larry D. Adams, Jason E. Clouse, Sharlene D. Herington, William K. Scott, Margaret A. Pericak‐Vance, and Jonathan L. Haines
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
22. Attitudes and Beliefs About Brain Donation Among Black Americans
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Allison M Caban‐Holt, Shawnta' Lloyd, Takiyah D. Starks, Tayla Ford, Larry D. Adams, Jonathan L. Haines, Gary W. Beecham, Christiane Reitz, Michael L. Cuccaro, Jeffery M. Vance, Margaret A. Pericak‐Vance, and Goldie S. Byrd
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
23. Fine‐mapping of chromosome 9p21 linkage in Puerto Rican Alzheimer disease families
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Katrina Celis, Farid Rajabli, Shaina A Simon, Liyong Wang, Kara L. Hamilton‐Nelson, Larry D. Adams, Pedro Ramon Mena, Patrice L. Whitehead, Derek Van Booven, Briseida E. Feliciano‐Astacio, Angel Chinea, Nereida I Feliciano, Heriberto Acosta, Clifton L. Dalgard, Jonathan L. Haines, Jeffery M. Vance, Michael L. Cuccaro, Gary W. Beecham, Derek M. Dykxhoorn, Anthony J. Griswold, and Margaret A. Pericak‐Vance
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
24. Analysis of Alzheimer Disease Plasma Biomarker pTau‐181 in Individuals of Diverse Admixed Ancestral Backgrounds
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Timo Grimmer, Farid Rajabli, Catherine Garcia‐Serje, Jamie Arvizu, Emma Larkin‐Gero, Patrice L. Whitehead, Kara L. Hamilton‐Nelson, Larry D. Adams, Maricarmen Contreras, Jose Javier Sanchez, Sergio Tejada, Pedro Ramon Mena, Takiyah D. Starks, Mario Cornejo‐Olivas, Maryenela Illanes‐Manrique, Concepcion Silva‐Vergara, Michael L. Cuccaro, Jeffery M. Vance, Briseida E. Feliciano‐Astacio, Goldie S. Byrd, Gary W. Beecham, Jonathan L. Haines, and Margaret A. Pericak‐Vance
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
25. Association of mitochondrial haplogroups and cognitive impairment in the Amish
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Daniel A. Dorfsman, Michael B. Prough, Laura J. Caywood, Jason E. Clouse, Sharlene D. Herington, Susan H. Slifer, Larry D. Adams, Renee A. Laux, Yeunjoo E. Song, Audrey Lynn, M. Denise Fuzzell, Sarada L. Fuzzell, Sherri D. Hochstetler, Kristy L. Miskimen, Leighanne R. Main, Michael D. Osterman, Paula K. Ogrocki, Alan J. Lerner, Jeffery M. Vance, Michael L. Cuccaro, Jonathan L. Haines, Margaret A. Pericak‐Vance, and William K. Scott
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2022
26. Admixture mapping identifies novel Alzheimer's disease risk regions in African Americans
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Farid, Rajabli, Giuseppe, Tosto, Kara L, Hamilton-Nelson, Brian W, Kunkle, Badri N, Vardarajan, Adam, Naj, Patrice G, Whitehead, Olivia K, Gardner, William S, Bush, Sanjeev, Sariya, Richard P, Mayeux, Lindsay A, Farrer, Michael L, Cuccaro, Jeffrey M, Vance, Anthony J, Griswold, Gerard D, Schellenberg, Jonathan L, Haines, Goldie S, Byrd, Christiane, Reitz, Gary W, Beecham, Margaret A, Pericak-Vance, and Eden R, Martin
- Abstract
This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions.We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes.Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p = 2.2 × 10Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus.We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer's disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations.
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- 2022
27. Genomewide Association Study of Retinal Traits in the Amish Reveals Loci Influencing Drusen Development and Link to Age-Related Macular Degeneration
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Michael D. Osterman, Yeunjoo E. Song, Muneeswar Nittala, SriniVas R. Sadda, William K. Scott, Dwight Stambolian, Margaret A. Pericak-Vance, and Jonathan L. Haines
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Macular Degeneration ,Humans ,Retinal Drusen ,General Medicine ,Amish ,Retina ,Genome-Wide Association Study - Abstract
The purpose of this study was to identify genetic risk loci for retinal traits, including drusen, in an Amish study population and compare these risk loci to known risk loci of age-related macular degeneration (AMD).Participants were recruited from Amish communities in Ohio, Indiana, and Pennsylvania. Each participant underwent a basic health history, ophthalmologic examination, and genotyping. A genomewide association analysis (GWAS) was conducted for the presence and quantity of each of three retinal traits: geographic atrophy, drusen area, and drusen volume. The findings were compared to results from a prior large GWAS of predominantly European-ancestry individuals. Further, a genetic risk score for AMD was used to predict the presence and quantity of the retinal traits.After quality control, 1074 participants were included in analyses. Six single nucleotide polymorphisms (SNPs) met criteria for genomewide significance and 48 were suggestively associated across three retinal traits. The significant SNPs were not highly correlated with known risk SNPs for AMD. A genetic risk score for AMD provided significant predictive value of the retinal traits.We identified potential novel genetic risk loci for AMD in a midwestern Amish study population. Additionally, we determined that there is a clear link between the genetic risk of AMD and drusen. Further study, including longitudinal data collection, may improve our ability to define this connection and improve understanding of the biological risk factors underlying drusen development.
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- 2022
28. Polygenic Risk Score for Alzheimer's Disease in Caribbean Hispanics
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Giuseppe Tosto, Guillaume Paré, Ricky Lali, Gerard D Shellenberg, Jonathan L. Haines, Dolly Reyes-Dumeyer, Daniel Felsky, Margaret A. Pericak-Vance, Rafael Lantigua, Richard Mayeux, Ivonne Z. Jimenez-Velazquez, Badri N. Vardarajan, and Sanjeev Sariya
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Male ,0301 basic medicine ,Multifactorial Inheritance ,Disease ,Logistic regression ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Risk Factors ,Statistical significance ,Databases, Genetic ,Replication (statistics) ,Full model ,Humans ,Medicine ,Genetic Predisposition to Disease ,Aged ,Aged, 80 and over ,African american ,business.industry ,Hispanic or Latino ,Middle Aged ,030104 developmental biology ,Caribbean Region ,Neurology ,Cohort ,Female ,Polygenic risk score ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Follow-Up Studies ,Demography - Abstract
Objective Polygenic risk scores (PRSs) assess the individual genetic propensity to a condition by combining sparse information scattered across genetic loci, often displaying small effect sizes. Most PRSs are constructed in European-ancestry populations, limiting their use in other ethnicities. Here we constructed and validated a PRS for late-onset Alzheimer's Disease (LOAD) in Caribbean Hispanics (CH). Methods We employed a CH discovery (N=4,312) and independent validation sample (N=1,850) to construct an ancestry-specific PRS ("CH-PRS") and evaluated its performance alone and with other predictors using the area under curve (AUC) and logistic regression (strength of association with LOAD and statistical significance). We tested if CH-PRS predicted conversion to LOAD in a subsample with longitudinal data (N=1,239). We also tested the CH-PRS in an independent replication CH cohort (N=200) and brain autopsy cohort (N=33). Finally, we tested the effect of ancestry on PRS by employing European and African American discovery cohorts to construct alternative PRSs ("EUR-PRS", "AA-PRS"). Results The full model (LOAD ~ CH-PRS + sex + age + APOE-i4), achieved an AUC=74% (ORCH-PRS =1.51 95%CI=1.36-1.68), raising to >75% in APOE-i4 non-carriers. CH-PRS alone achieved an AUC=72% in the autopsy cohort, raising to AUC=83% in full model. Higher CH-PRS was significantly associated with clinical LOAD in the replication CH cohort (OR=1.61, 95%CI=1.19-2.17) and significantly predicted conversion to LOAD (HR=1.93, CI=1.70-2.20) in the longitudinal subsample. EUR-PRS and AA-PRS reached lower prediction accuracy (AUC=58% and 53%, respectively). Interpretation Enriching diversity in genetic studies is critical to provide an effective PRS in profiling LOAD risk across populations. This article is protected by copyright. All rights reserved.
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- 2021
29. Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women
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Jaeyoon Chung, Anjali Das, Xinyu Sun, Débora R. Sobreira, Yuk Yee Leung, Catherine Igartua, Sahar Mozaffari, Yi‐Fan Chou, Sam Thiagalingam, Jesse Mez, Xiaoling Zhang, Gyungah R. Jun, Thor D. Stein, Brian W. Kunkle, Eden R. Martin, Margaret A. Pericak‐Vance, Richard Mayeux, Jonathan L. Haines, Gerard D. Schellenberg, Marcelo A. Nobrega, Kathryn L. Lunetta, Jayant M. Pinto, Li‐San Wang, Carole Ober, and Lindsay A. Farrer
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Abstract
Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E ε4 (ε4-).To identify novel genes associated with tau-related pathology, we conducted two genome-wide association studies (GWAS) for AD, one among 10,340 ε4- women in the Alzheimer's Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred.We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio [OR] = 1.4, P = 4.9 × 10These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.
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- 2022
30. Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds
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Juan I. Young, Derek M. Dykxhoorn, William K. Scott, Elisa Mcgrath-Martinez, Karen Nuytemans, Olivia K. Gardner, Anthony J. Griswold, Eileen H. Bigio, Jeffery M. Vance, Daniel A. Dorfsman, Changiz Geula, Clifton L. Dalgard, Farid Rajabli, Marla Gearing, Sandra Weintraub, Gary W. Beecham, Kara L. Hamilton-Nelson, M.-Marsel Mesulam, Margaret A. Pericak-Vance, Jonathan L. Haines, Patrice L. Whitehead, Parker Bussies, Katrina Celis, and Liyong Wang
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Male ,0301 basic medicine ,Apolipoprotein E ,Heterozygote ,medicine.medical_specialty ,Epidemiology ,Apolipoprotein E4 ,Cell ,Black People ,Disease ,Biology ,White People ,Article ,Transcriptome ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Developmental Neuroscience ,Alzheimer Disease ,Internal medicine ,medicine ,Humans ,Gene ,Alleles ,Aged ,Aged, 80 and over ,Sequence Analysis, RNA ,Health Policy ,RNA ,Psychiatry and Mental health ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Disease risk ,Female ,lipids (amino acids, peptides, and proteins) ,Neurology (clinical) ,Geriatrics and Gerontology ,030217 neurology & neurosurgery ,Astrocyte - Abstract
INTRODUCTION Apolipoprotein E (APOE) e4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE e4 carriers with European local ancestry (ELA). Cell type specific transcriptional variation between the two local ancestries (LAs) could contribute to this disease risk differences. METHODS Single-nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE e4/e4 AD patients: seven with ELA, four with ALA. RESULTS A total of 60,908 nuclei were sequenced. Within the LA region (chr19:44-46Mb), APOE was the gene most differentially expressed, with ELA carriers having significantly more expression (overall P
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- 2021
31. CHOROIDAL VASCULARITY INDEX AND CHOROIDAL THICKNESS IN EYES WITH RETICULAR PSEUDODRUSEN
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Soumya Jana, Swetha Bindu Velaga, Jay Chhablani, Jonathan L. Haines, Dwight Stambolian, Margaret A. Pericak-Vance, Srinivas R. Sadda, Muneeswar Gupta Nittala, and Kiran Kumar Vupparaboina
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Male ,medicine.medical_specialty ,Fundus Oculi ,Retinal Drusen ,03 medical and health sciences ,0302 clinical medicine ,Vascularity ,Ophthalmology ,medicine ,Humans ,Macula Lutea ,Fluorescein Angiography ,Aged ,Retrospective Studies ,Aged, 80 and over ,Choroid ,business.industry ,Retinal Vessels ,General Medicine ,Middle Aged ,Macular degeneration ,medicine.disease ,eye diseases ,Intensity (physics) ,Reticular pseudodrusen ,030221 ophthalmology & optometry ,Female ,sense organs ,medicine.symptom ,business ,Tomography, Optical Coherence ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
To evaluate choroidal vascularity index (CVI), choroidal thickness, choroidal volume, and choroidal intensity in subjects with nonneovascular age-related macular degeneration (NNVAMD) with and without reticular pseudodrusen (RPD).We included 60 eyes of 35 subjects with NNVAMD (including 30 eyes of 18 subjects with RPD) and 30 eyes of 17 age-matched healthy individuals from the ongoing Amish Eye study. The choroid was segmented from dense volume spectral domain optical coherence tomography scans and choroidal thickness (microns), choroidal intensity (log units), and choroidal volume (mm) from the entire macula (6 × 6 mm) were computed. A central horizontal B-scan was binarized and the luminal and stromal portions of the choroid were segmented. Choroidal vascularity index (%) was calculated as the ratio of luminal area to total choroid area. Choroidal parameters were compared between the groups by pairwise comparisons using the Student's t-test.The CVI was significantly lower in healthy eyes compared to those with RPD (53.43 ± 8.51 vs. 54.76 ± 4.83, P0.001). The CVI was also significantly lower in NNVAMD eyes without RPD compared to those with RPD (50.09 ± 7.51 vs. 54.76 ± 4.83, P = 0.006). There was no difference in CVI between healthy eyes and NNVAMD eyes without RPD (P = 0.84). Choroidal thickness and choroidal volume were significantly higher in NNVAMD without RPD (P0.05); and significantly lower in NNVAMD with RPD (P0.05) when compared with normal eyes. Choroidal intensity was significantly higher in NNVAMD with RPD when compared with normal eyes (P = 0.02) and NNVAMD eyes without RPD (P = 0.001).Multiple choroidal parameters reflecting the status of the choroidal vasculature and stroma seem to be altered in eyes with RPD compared with both normal eyes and NNVAMD eyes without RPD. These findings may provide insights into the pathophysiology of RPD.
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- 2019
32. The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish
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Sharlene D. Herington, Jonathan L. Haines, Sherri D Hochstetler, Jeffery M. Vance, Renee Laux, Yeunjoo E. Song, Jason E. Clouse, Michael D. Osterman, Leighanne R. Main, William K. Scott, Alan J. Lerner, Daniel A. Dorfsman, Sarada Fuzzell, Susan Slifer, Paula Ogrocki, Laura Caywood, Kristy Miskimen, Jairo Ramos, Audrey Lynn, Michael L. Cuccaro, Margaret A. Pericak-Vance, Michael Prough, Larry D. Adams, and M. Denise Fuzzell
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education.field_of_study ,business.industry ,Population ,medicine.disease ,Genetic architecture ,Endogamy ,Medicine ,Dementia ,Molecular Medicine ,Age of onset ,Alzheimer's disease ,business ,education ,Genetics (clinical) ,Demography ,Founder effect ,Cause of death - Abstract
Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States and the proportion of deaths due to AD has been increasing since the year 2000 while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Though APOE remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited from a population of Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. With slightly lower incidence and later age of onset, it is thought that the Amish may hold protective genetic variants for AD. As a founder population that typically practices endogamy, variants that are rare in the general population may be at higher frequency in the Amish population. We characterized the genetic architecture of AD risk in the Amish and compared this to a non-Amish population, elucidating the lower relative importance of APOE and differing genetic architecture of the Amish compared to a general European ancestry population.
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- 2021
33. Association of a locus on chromosome 17 with earlier age at onset of cognitive impairment in a familial Amish dataset
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William K. Scott, Jairo Ramos, Susan H. Slifer, Laura J. Caywood, Michael B. Prough, Jason E. Clouse, Daniel A. Dorfsman, Sharlene D. Herington, M. Denise Fuzzell, Sarada L. Fuzzell, Jane L. Sewell, Sherri D. Miller, Michael D. Osterman, Leighanne R Main, Kristy L. Miskimen, Audrey Lynn, Patrice L. Whitehead, Larry D. Adams, Renee A. Laux, Yeunjoo E. Song, Tatiana M. Foroud, Richard Mayeux, Paula K. Ogrocki, Alan J. Lerner, Jeffery M. Vance, Michael L. Cuccaro, Jonathan L. Haines, and Margaret A. Pericak‐Vance
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2021
34. Assessment of AD‐related plasma biomarkers in diverse ancestral populations
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Anthony J. Griswold, Farid Rajabli, Catherine Garcia‐Serje, Kara L. Hamilton‐Nelson, Larry D. Adams, Sergio Tejada, Pedro Ramon Mena, Takiyah D. Starks, Patrice L. Whitehead, Concepcion Silva‐Vergara, Michael L. Cuccaro, Izri Martinez, Maryenela Illanes‐Manrique, Mario R. Cornejo‐Olivas, Renee A. Laux, Laura J. Caywood, Christiane Reitz, Gary W. Beecham, Goldie S. Byrd, Briseida E. Feliciano‐Astacio, William K. Scott, Jonathan L. Haines, Jeffery M. Vance, and Margaret A. Pericak‐Vance
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2021
35. Preferential preservation of constructional praxis delayed recall compared to word list delayed recall in the Amish
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Michael B. Prough, Laura J. Caywood, Jason E. Clouse, Sharlene D. Herington, Susan H. Slifer, Daniel A. Dorfsman, Larry D. Adams, Renee A. Laux, Yeunjoo E. Song, Audrey Lynn, M. Denise Fuzzell, Sarada L. Fuzzell, Jane L. Sewell, Sherri D. Miller, Kristy L. Miskimen, Leighanne R Main, Michael D. Osterman, Paula K. Ogrocki, Alan J. Lerner, Jairo Ramos, Jeffery M. Vance, Michael L. Cuccaro, Jonathan L. Haines, William K. Scott, and Margaret A. Pericak‐Vance
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2021
36. Does higher educational attainment influence functional capabilities among African Americans with Alzheimer’s disease?
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Faina C Lacroix, Larry D. Adams, Jovita D. Inciute, Jacob Welch, Takiyah D. Starks, Renee A. Laux, Goldie S. Byrd, Jonathan L. Haines, Gary W. Beecham, Michael L. Cuccaro, Jeffery M. Vance, Margaret A. Pericak‐Vance, and Farid Rajabli
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology - Published
- 2021
37. Systems genomics in age-related macular degeneration
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Anneke I. den Hollander, Robert F. Mullins, Luz D. Orozco, Andrew P. Voigt, Hsu-Hsin Chen, Tobias Strunz, Felix Grassmann, Jonathan L. Haines, Jonas J.W. Kuiper, Santa J. Tumminia, Rando Allikmets, Gregory S. Hageman, Dwight Stambolian, Caroline C.W. Klaver, Jef D. Boeke, Hao Chen, Lee Honigberg, Suresh Katti, Kelly A. Frazer, Bernhard H.F. Weber, Michael B. Gorin, and Ophthalmology
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Aging ,Complement system ,Omics ,Retinal Pigment Epithelium ,Neurodegenerative ,Medical Biochemistry and Metabolomics ,Eye ,Ophthalmology & Optometry ,Polymorphism, Single Nucleotide ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,iPSc-RPE ,Macular Degeneration ,Cellular and Molecular Neuroscience ,All institutes and research themes of the Radboud University Medical Center ,Opthalmology and Optometry ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Polymorphism ,Expression quantitative trait locus ,Systems genomics ,Aetiology ,Eye Disease and Disorders of Vision ,Single cell sequencing ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Stem Cell Research - Induced Pluripotent Stem Cell ,Choroid ,Age-related macular degeneration ,Human Genome ,Neurosciences ,Proteins ,Genomics ,Single Nucleotide ,Complement System Proteins ,High-Temperature Requirement A Serine Peptidase 1 ,Stem Cell Research ,Sensory Systems ,Clinical trial ,Induced pluripotent stem cells ,Polygenic risk scores ,Ophthalmology ,Complement Factor H ,Biotechnology - Abstract
Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are ‘omics’ technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci C3, CFB, CFI, CFH, and ARMS2/HTRA1 are currently ongoing, and a phase III clinical trial for C3 inhibition recently showed a modest reduction of lesion growth in geographic atrophy. The EYERISK consortium recently developed a genetic test for AMD that allows genotyping of common and rare variants in AMD-associated genes. Polygenic risk scores (PRS) were applied to quantify AMD genetic risk, and may aid in predicting AMD progression. In conclusion, genomic studies represent a turning point in our exploration of AMD. The results of those studies now serve as a driving force for several clinical trials. Expanding to omics and systems genomics will further decipher function and causality from the associations that have been reported, and will enable the development of therapies that will lessen the burden of AMD.
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- 2022
38. Genetic architecture of RNA editing regulation in Alzheimer's disease across diverse ancestral populations
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Olivia K Gardner, Derek Van Booven, Lily Wang, Tianjie Gu, Natalia K Hofmann, Patrice L Whitehead, Karen Nuytemans, Kara L Hamilton-Nelson, Larry D Adams, Takiyah D Starks, Michael L Cuccaro, Eden R Martin, Jeffery M Vance, William S Bush, Goldie S Byrd, Jonathan L Haines, Gary W Beecham, Margaret A Pericak-Vance, and Anthony J Griswold
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Quantitative Trait Loci ,Black People ,Membrane Transport Proteins ,General Medicine ,Linkage Disequilibrium ,Alzheimer Disease ,Genetics ,Humans ,Genetic Predisposition to Disease ,Original Article ,RNA Editing ,Molecular Biology ,Genetics (clinical) ,LDL-Receptor Related Proteins ,Genome-Wide Association Study - Abstract
Most Alzheimer’s disease (AD)-associated genetic variants do not change protein coding sequence and thus likely exert their effects through regulatory mechanisms. RNA editing, the post-transcriptional modification of RNA bases, is a regulatory feature that is altered in AD patients that differs across ancestral backgrounds. Editing QTLs (edQTLs) are DNA variants that influence the level of RNA editing at a specific site. To study the relationship of DNA variants genome-wide, and particularly in AD-associated loci, with RNA editing, we performed edQTL analyses in self-reported individuals of African American (AF) or White (EU) race with corresponding global genetic ancestry averaging 82.2% African ancestry (AF) and 96.8% European global ancestry (EU) in the two groups, respectively. We used whole-genome genotyping array and RNA sequencing data from peripheral blood of 216 AD cases and 212 age-matched, cognitively intact controls. We identified 2144 edQTLs in AF and 3579 in EU, of which 1236 were found in both groups. Among these, edQTLs in linkage disequilibrium (r2 > 0.5) with AD-associated genetic variants in the SORL1, SPI1 and HLA-DRB1 loci were associated with sites that were differentially edited between AD cases and controls. While there is some shared RNA editing regulatory architecture, most edQTLs had distinct effects on the rate of RNA editing in different ancestral populations suggesting a complex architecture of RNA editing regulation. Altered RNA editing may be one possible mechanism for the functional effect of AD-associated variants and may contribute to observed differences in the genetic etiology of AD between ancestries.
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- 2021
39. Progranulin mutations in clinical and neuropathological Alzheimer's disease
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Badri N, Vardarajan, Dolly, Reyes-Dumeyer, Angel L, Piriz, Rafael A, Lantigua, Martin, Medrano, Diones, Rivera, Ivonne Z, Jiménez-Velázquez, Eden, Martin, Margaret A, Pericak-Vance, William, Bush, Lindsay, Farrer, Jonathan L, Haines, Li-San, Wang, Yuk Yee, Leung, Gerard, Schellenberg, Walter, Kukull, Philip, De Jager, David A, Bennett, Julie A, Schneider, and Richard, Mayeux
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DNA-Binding Proteins ,Progranulins ,Alzheimer Disease ,Mutation ,Humans ,Intercellular Signaling Peptides and Proteins ,Frontotemporal Lobar Degeneration - Abstract
Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology.We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers.Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort.GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with β-amyloid load or AD.
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- 2021
40. An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns
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Bowen Jin, John A. Capra, Penelope Benchek, Nicholas Wheeler, Adam C. Naj, Kara L. Hamilton-Nelson, John J. Farrell, Yuk Yee Leung, Brian Kunkle, Badri Vadarajan, Gerard D. Schellenberg, Richard Mayeux, Li-San Wang, Lindsay A. Farrer, Margaret A. Pericak-Vance, Eden R. Martin, Jonathan L. Haines, Dana C. Crawford, and William S. Bush
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Phenotype ,Gene Frequency ,Alzheimer Disease ,Exome Sequencing ,Genetics ,Mutation, Missense ,Humans ,Membrane Transport Proteins ,Genetic Predisposition to Disease ,Genetics (clinical) ,LDL-Receptor Related Proteins - Abstract
More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use missense rare variants and investigate their biological effect, we examine their association with phenotypes in the context of protein structures. We developed a protein structure–based approach, protein optimized kernel evaluation of missense nucleotides (POKEMON), which evaluates rare missense variants based on their spatial distribution within a protein rather than their allele frequency. The hypothesis behind this test is that the three-dimensional spatial distribution of variants within a protein structure provides functional context to power an association test. POKEMON identified three candidate genes (TREM2, SORL1, and EXOC3L4) and another suggestive gene from the ADSP WES data. For TREM2 and SORL1, two known Alzheimer's disease (AD) genes, the signal from the spatial cluster is stable even if we exclude known AD risk variants, indicating the presence of additional low-frequency risk variants within these genes. EXOC3L4 is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size.
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- 2021
41. Consequences of a Rare Complement Factor H Variant for Age-Related Macular Degeneration in the Amish
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Andrea R, Waksmunski, Kristy, Miskimen, Yeunjoo E, Song, Michelle, Grunin, Renee, Laux, Denise, Fuzzell, Sarada, Fuzzell, Larry D, Adams, Laura, Caywood, Michael, Prough, Dwight, Stambolian, William K, Scott, Margaret A, Pericak-Vance, and Jonathan L, Haines
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Heterozygote ,Macular Degeneration ,Genotype ,Complement Factor H ,Humans ,General Medicine ,Amish ,Polymorphism, Single Nucleotide ,Alleles - Abstract
Genetic variants in the complement factor H gene (CFH) have been consistently implicated in age-related macular degeneration (AMD) risk. However, their functional effects are not fully characterized. We previously identified a rare, AMD-associated variant in CFH (P503A, rs570523689) in 19 Amish individuals, but its functional consequences were not investigated.We performed genotyping for CFH P503A in 1326 Amish individuals to identify additional risk allele carriers. We examined differences for age at AMD diagnosis between carriers and noncarriers. In blood samples from risk allele carriers and noncarriers, we quantified (i) CFH RNA expression, (ii) CFH protein expression, and (iii) C-reactive protein (CRP) expression. Potential changes to the CFH protein structure were interrogated computationally with Phyre2 and Chimera software programs.We identified 39 additional carriers from Amish communities in Ohio and Indiana. On average, carriers were younger than noncarriers at AMD diagnosis, but this difference was not significant. CFH transcript and protein levels in blood samples from Amish carriers and noncarriers were also not significantly different. CRP levels were also comparable in plasma samples from carriers and noncarriers. Computational protein modeling showed slight changes in the CFH protein conformation that were predicted to alter interactions between the CFH 503 residue and other neighboring residues.In total, we have identified 58 risk allele carriers for CFH P503A in the Ohio and Indiana Amish. Although we did not detect significant differences in age at AMD diagnosis or expression levels of CFH in blood samples from carriers and noncarriers, we observed modest structural changes to the CFH protein through in silico modeling. Based on our functional and computational observations, we hypothesize that CFH P503A may affect CFH binding or function rather than expression, which would require additional research to confirm.
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- 2022
42. A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer’s Disease in African Ancestry
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Farid, Rajabli, Gary W, Beecham, Hugh C, Hendrie, Olusegun, Baiyewu, Adesola, Ogunniyi, Sujuan, Gao, Nicholas A, Kushch, Marina, Lipkin-Vasquez, Kara L, Hamilton-Nelson, Juan I, Young, Derek M, Dykxhoorn, Karen, Nuytemans, Brian W, Kunkle, Liyong, Wang, Fulai, Jin, Xiaoxiao, Liu, Briseida E, Feliciano-Astacio, Gerard D, Schellenberg, Clifton L, Dalgard, Anthony J, Griswold, Goldie S, Byrd, Christiane, Reitz, Michael L, Cuccaro, Jonathan L, Haines, Margaret A, Pericak-Vance, and Jeffery M, Vance
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Cancer Research ,Apolipoproteins E ,Genotype ,Alzheimer Disease ,Risk Factors ,Apolipoprotein E4 ,Genetics ,Humans ,Nigeria ,Molecular Biology ,Alleles ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics - Abstract
African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the “protective” direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.
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- 2022
43. Using the PhenX Toolkit to Select Standard Measurement Protocols for Your Research Study
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Tabitha Hendershot, Erin M. Ramos, Catherine A. McCarty, Huaqin Helen Pan, Jonathan L. Haines, Mary L. Marazita, Carol Hamilton, Stephen Hwang, Michelle L Engle, and Lisa Ann Cox
- Subjects
Coronavirus disease 2019 (COVID-19) ,Electronic data capture ,Computer science ,Interdisciplinary Research ,Health Informatics ,Updated Protocol ,standard measures ,General Biochemistry, Genetics and Molecular Biology ,Domain (software engineering) ,genome‐wide association studies (GWAS) ,World Wide Web ,Documentation ,Humans ,Genetic Predisposition to Disease ,General Pharmacology, Toxicology and Pharmaceutics ,Protocol (science) ,Data collection ,General Immunology and Microbiology ,General Neuroscience ,phenotypes ,Human Genetics ,Environmental Exposure ,Environmental exposure ,Data dictionary ,data collection protocols ,Medical Laboratory Technology ,Phenotype ,Databases as Topic ,environmental exposures ,Software ,Genome-Wide Association Study - Abstract
The goals of PhenX (consensus measures for Phenotypes and eXposures) are to promote the use of standard measurement protocols and to help investigators identify opportunities for collaborative research and cross‐study analysis, thus increasing the impact of individual studies. The PhenX Toolkit (https://www.phenxtoolkit.org/) offers high‐quality, well‐established measurement protocols to assess phenotypes and exposures in studies with human participants. The Toolkit contains protocols representing 29 research domains and 6 specialty collections of protocols that add depth to the Toolkit in specific research areas (e.g., COVID‐19, Social Determinants of Health [SDoH], Blood Sciences Research [BSR], Mental Health Research [MHR], Tobacco Regulatory Research [TRR], and Substance Abuse and Addiction [SAA]). Protocols are recommended for inclusion in the PhenX Toolkit by Working Groups of domain experts using a consensus process that includes input from the scientific community. For each PhenX protocol, the Toolkit provides a detailed description, the rationale for inclusion, and supporting documentation. Users can browse protocols in the Toolkit, search the Toolkit using keywords, or use Browse Protocols Tree to identify protocols of interest. The PhenX Toolkit provides data dictionaries compatible with the database of Genotypes and Phenotypes (dbGaP), Research Electronic Data Capture (REDCap) data submission compatibility, and data collection worksheets to help investigators incorporate PhenX protocols into their study design. The PhenX Toolkit provides resources to help users identify published studies that used PhenX protocols. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Using the PhenX Toolkit to support or extend study design
- Published
- 2021
44. Sex differences in the genetic predictors of Alzheimer’s pathology
- Author
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Leslie M. Shaw, Angela L. Jefferson, David A. Bennett, Alison Goate, Timothy J. Hohman, Eric B. Larson, Nancy J. Cox, Marilyn S. Albert, Michael J. Chao, Lisa L. Barnes, Brian W. Kunkle, William S. Bush, Jonathan L. Haines, Paul K. Crane, Walter A. Kukull, Henrik Zetterberg, C. Dirk Keene, Yuetiva Deming, Gerard D. Schellenberg, Shubhabrata Mukherjee, Carlos Cruchaga, Thomas J. Montine, Kaj Blennow, Kara L. Hamilton-Nelson, Matthew J. Huentelman, John Q. Trojanowski, Philip L. De Jager, Elaine R. Peskind, Logan Dumitrescu, Eden R. Martin, Julie A. Schneider, Madhav Thambisetty, Gary W. Beecham, Susan M. Resnick, Sterling C. Johnson, Katherine A. Gifford, Margaret A. Pericak-Vance, and Lori B. Chibnik
- Subjects
Male ,0301 basic medicine ,Apolipoprotein E ,Oncology ,medicine.medical_specialty ,tau Proteins ,Locus (genetics) ,Genome-wide association study ,Disease ,Neuropathology ,Polymorphism, Single Nucleotide ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Internal medicine ,Humans ,Medicine ,Genetic Predisposition to Disease ,Letters to the Editor ,Aged ,Genetic association ,Aged, 80 and over ,Sex Characteristics ,Amyloid beta-Peptides ,business.industry ,030104 developmental biology ,Endophenotype ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Reports ,Sex characteristics - Abstract
Autopsy measures of Alzheimer’s disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer’s disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer’s disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer’s disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10−8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10−8) but not females (P = 0.85, sex-interaction P = 2.9 × 10−4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
- Published
- 2019
45. Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry
- Author
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Carly J. van der Heide, Jessica N. Cooke Bailey, Susan Williams, Dan Milea, José Paulo Cabral de Vasconcellos, Sadiq M. Abdullahi, Douglas E. Gaasterland, Ifeoma N. Asimadu, Sayoko E. Moroi, Hasnaa Lamari, Sarah J. Garnai, Janey L. Wiggs, Donald L. Budenz, R. Rand Allingham, Julia E. Richards, Jonathan L. Haines, Jerome I. Rotter, Michael G. Anderson, Xiuqing Guo, Robert M. Feldman, Michael A. Hauser, Yii-Der Ida Chen, Hugo Freire Nunes, Leon W. Herndon, John F. Ervin, Stephen Akafo, Radha Ayyagari, Thomas J. Hoffmann, Rachel W. Kuchtey, Michèle Ramsay, Prisca Biangoup Nyamsi, Zheng Li, Eric Jorgenson, Kar Seng Sim, Ebenezer Obeng-Nyarkoh, William C. Bromley, Christopher A. Girkin, Robert N. Weinreb, Alberta A H J Thiadens, Serge Resnikoff, William E. Sponsel, Maggie C.Y. Ng, Christine M. Hulette, Donald W. Bowden, Saydou Bakayoko, Jeffrey M. Liebmann, Harvey Dubiner, Suhanya Okeke, Abba Hydara, Ruth J. F. Loos, Adeyinka O. Ashaye, Olusegun Olaniyi, Mahmoud B. Alhassan, Khaled K. Abu-Amero, Christopher J Hammond, Tin Aung, John H. Fingert, Robert P. Igo, Shih-Hsiu Wang, Rui Barroso Schimiti, Pratap Challa, Robert F. Mullins, Rodolfo A. Perez-Grossmann, Nouhoum Guirou, Margaret A. Pericak-Vance, Anthony Okeke, Pieter W.M. Bonnemaijer, Paulo Vinicius Svidnicki, Abdoulaye Napo, Louise R. Pasquale, Joyce Kabwe, Chiea Chuen Khor, Mônica Barbosa de Melo, Girish N. Nadkarni, CM Chuka-Okosa, Neil Risch, Nkiru Kizor-Akaraiwe, Miles J. Flamme-Wiese, Cornelia M. van Duijn, N J Uche, Joseph Msosa, Olusola Olawoye, Linda M. Zangwill, Mariana B. Oliveira, Caroline C W Klaver, Allison E. Ashley Koch, Vital Paulino Costa, Ngoy Janvier Kilangalanga, Trevor R. Carmichael, Xue Qin, Kent D. Taylor, Yutao Liu, Dianne A. Cruz, Epidemiology, and Ophthalmology
- Subjects
Male ,medicine.medical_specialty ,Genotype ,genetic structures ,Open angle glaucoma ,Population ,Black People ,Glaucoma ,Genome-wide association study ,Polymorphism, Single Nucleotide ,01 natural sciences ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,03 medical and health sciences ,0302 clinical medicine ,Meta-Analysis as Topic ,Risk Factors ,Interquartile range ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,030212 general & internal medicine ,0101 mathematics ,education ,Adaptor Proteins, Signal Transducing ,Aged ,Original Investigation ,education.field_of_study ,Amyloid beta-Peptides ,business.industry ,010102 general mathematics ,Case-control study ,General Medicine ,Odds ratio ,Middle Aged ,medicine.disease ,Immunohistochemistry ,eye diseases ,Case-Control Studies ,Female ,Risk assessment ,business ,Glaucoma, Open-Angle ,Genome-Wide Association Study - Abstract
Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.Exposures: Genetic variants associated with primary open-angle glaucoma.Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.
- Published
- 2019
46. Corrigendum: An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease–related patterns
- Author
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Bowen Jin, John A. Capra, Penelope Benchek, Nicholas Wheeler, Adam C. Naj, Kara L. Hamilton-Nelson, John J. Farrell, Yuk Yee Leung, Brian Kunkle, Badri Vadarajan, Gerard D. Schellenberg, Richard Mayeux, Li-San Wang, Lindsay A. Farrer, Margaret A. Pericak-Vance, Eden R. Martin, Jonathan L. Haines, Dana C. Crawford, and William S. Bush
- Subjects
Genetics ,Genetics (clinical) - Published
- 2022
47. COMPARISON OF SPECTRALIS AND CIRRUS OPTICAL COHERENCE TOMOGRAPHY FOR THE DETECTION OF INCOMPLETE AND COMPLETE RETINAL PIGMENT EPITHELIUM AND OUTER RETINAL ATROPHY
- Author
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Federico Corvi, Muneeswar Gupta Nittala, Srinivas R. Sadda, Giulia Corradetti, Margaret A. Pericak-Vance, Jonathan L. Haines, Swetha Bindu Velaga, and Dwight Stambolian
- Subjects
Male ,medicine.medical_specialty ,genetic structures ,Retinal Pigment Epithelium ,chemistry.chemical_compound ,Macular Degeneration ,Atrophy ,Optical coherence tomography ,Ophthalmology ,Medicine ,Humans ,Aged ,Aged, 80 and over ,Retina ,Retinal pigment epithelium ,medicine.diagnostic_test ,business.industry ,Retinal ,General Medicine ,Macular degeneration ,Middle Aged ,medicine.disease ,eye diseases ,Retinal atrophy ,medicine.anatomical_structure ,chemistry ,Cirrus ,Female ,sense organs ,business ,Tomography, Optical Coherence - Abstract
Purpose To evaluate and compare the detection of incomplete and complete retinal pigment epithelial and outer retinal atrophy (iRORA and cRORA) using Spectralis and Cirrus optical coherence tomography (OCT) devices. Methods Subjects with late age-related macular degeneration (AMD) were imaged on the same day with Spectralis and Cirrus OCT. Two masked, independent and experienced retina specialist graders evaluated each case for the presence of cRORA and iRORA lesions. Results A significantly higher number of lesions were observed using Spectralis compared with Cirrus (239 vs 226 and 223 vs 209). Higher number of iRORA lesions were identified with Spectralis (105 vs 90 and 96 vs 82) and no significant difference was observed between devices for cRORA lesions (134 vs 136 and 128 vs 126). When considering the presence or absence of iRORA or cRORA, the agreement between devices for both graders was excellent for cRORA and good for iRORA. Conclusions Spectralis and Cirrus OCT identified a similar number of cRORA lesions, though more iRORA lesions could be detected with Spectralis OCT. These findings may have implications for developing acquisition protocols for trials based on the intended atrophy targets and highlight the importance of using a consistent OCT instrument across a study.
- Published
- 2021
48. Large‐scale sequencing studies expand the known genetic architecture of Alzheimer's disease
- Author
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Diane Xue, William S. Bush, Alan E. Renton, Edoardo A. Marcora, Joshua C. Bis, Brian W. Kunkle, The Alzheimer's Disease Sequencing Project, Eric Boerwinkle, Anita L. DeStefano, Lindsay Farrer, Alison Goate, Richard Mayeux, Margaret Pericak‐Vance, Gerard Schellenberg, Sudha Seshadri, Ellen Wijsman, Jonathan L. Haines, and Elizabeth E. Blue
- Subjects
Psychiatry and Mental health ,Geriatrics ,networks ,pathways ,RC952-954.6 ,Genetics ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,Alzheimer's disease ,RC346-429 ,genetic architecture ,genome ,Research Article - Abstract
Introduction Genes implicated by genome‐wide association studies and family‐based studies of Alzheimer's disease (AD) are largely discordant. We hypothesized that genes identified by sequencing studies like the Alzheimer's Disease Sequencing Project (ADSP) may bridge this gap and highlight shared biological mechanisms. Methods We performed structured literature review of genes prioritized by ADSP studies, genes underlying familial dementias, and genes nominated by genome‐wide association studies. Gene set enrichment analyses of each list identified enriched pathways. Results The genes prioritized by the ADSP, familial dementia studies, and genome‐wide association studies minimally overlapped. Each gene set identified dozens of enriched pathways, several of which were shared (e.g., regulation of amyloid beta clearance). Discussion Alternative study designs provide unique insights into AD genetics. Shared pathways enriched by different genes highlight their relevance to AD pathogenesis, while the patterns of pathway enrichment unique to each gene set provide additional targets for functional studies.
- Published
- 2021
49. Lower Levels of Education Are Associated with Cognitive Impairment in the Old Order Amish
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William K. Scott, Alan J. Lerner, Paula Ogrocki, Sarada Fuzzell, Laura Caywood, Yeunjoo E. Song, Jeffery M. Vance, Patrice L. Whitehead, M. Denise Fuzzell, Jairo Ramos, Michael L. Cuccaro, Renee Laux, Kristy Miskimen, Larry D. Adams, Michael Prough, Margaret A. Pericak-Vance, Jonathan L. Haines, and Aneesa R. Chowdhury
- Subjects
Male ,Population ,Logistic regression ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Dementia ,Humans ,Cognitive Dysfunction ,030212 general & internal medicine ,Cognitive impairment ,education ,Socioeconomic status ,Aged ,Aged, 80 and over ,education.field_of_study ,General Neuroscience ,Cognition ,General Medicine ,Middle Aged ,medicine.disease ,Educational attainment ,Psychiatry and Mental health ,Clinical Psychology ,Logistic Models ,Old Order Amish ,Educational Status ,Female ,Geriatrics and Gerontology ,Psychology ,Amish ,030217 neurology & neurosurgery ,Demography - Abstract
Background: Lower education has been reported to be associated with dementia. However, many studies have been done in settings where 12 years of formal education is the standard. Formal schooling in the Old Order Amish communities (OOA) ends at 8th grade which, along with their genetic homogeneity, makes it an interesting population to study the effect of education on cognitive impairment. Objective: The objective of this study was to examine the association of education with cognitive function in individuals from the OOA. We hypothesized that small differences in educational attainment at lower levels of formal education were associated with risk for cognitive impairment. Methods: Data of 2,426 individuals from the OOA aged 54–99 were analyzed. The Modified Mini-Mental State Examination (3MS-R) was used to classify participants as CI or normal. Individuals were classified into three education categories: 8 years of education. To measure the association of education with cognitive status, a logistic regression model was performed adding age and sex as covariates. Results: Our results showed that individuals who attained lowest levels of education (8 years (OR = 2.96 and 1.85). Conclusion: Even within a setting of low levels of formal education, small differences in educational attainment can still be associated with the risk of cognitive impairment. Given the homogeneity of the OOA, these results are less likely to be biased by differences in socioeconomic backgrounds.
- Published
- 2020
50. Using linkage analysis to identify novel gene‐gene interactions in Alzheimer’s disease
- Author
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Alzheimer’s Disease Sequencing, William S. Bush, Jonathan L. Haines, Nicholas R. Wheeler, and Michelle Grunin
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Genetics ,Novel gene ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Epidemiology ,Genetic linkage ,Health Policy ,Neurology (clinical) ,Disease ,Geriatrics and Gerontology ,Biology ,Gene - Published
- 2020
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