Brian W Kunkle1,2, Michael Schmidt1,2, Hans-Ulrich Klein3,4,5, Adam C Naj6,7, Kara L Hamilton-Nelson1, Eric B Larson8,9, Denis A Evans10,11, Phil L De Jager3,4,5, Paul K Crane7, Joe D Buxbaum12,13,14,15, Nilufer Ertekin-Taner16,17, Lisa L Barnes18,19,20, M Daniele Fallin21, Jennifer J Manly3,4,5, Rodney C P Go22, Thomas O Obisesan23, M Ilyas Kamboh24,25, David A Bennett18,20, Kathleen S Hall26, Alison M Goate13,14,15,27, Tatiana M Foroud28, Eden R Martin1,2, Li-Sao Wang7, Goldie S Byrd29, Lindsay A Farrer30,31,32,33,34, Jonathan L Haines35, Gerard D Schellenberg7, Richard Mayeux3,4,5,36,37, Margaret A Pericak-Vance1,2, Christiane Reitz3,4,5,37, Neill R Graff-Radford16,17, Izri Martinez4, Temitope Ayodele4, Mark W Logue30,38,39, Laura B Cantwell7, Melissa Jean-Francois1, Amanda B Kuzma7, L D Adams1, Jeffery M Vance1,2, Michael L Cuccaro1,2, Jaeyoon Chung30, Jesse Mez31, Kathryn L Lunetta32, Gyungah R Jun31,32,33, Oscar L Lopez25, Hugh C Hendrie26, Eric M Reiman40, Neil W Kowall41, James B Leverenz42, Scott A Small43, Allan I Levey44, Todd E Golde45, Andrew J Saykin28,46,47, Takiyah D Starks29, Marilyn S Albert48, Bradley T Hyman49, Ronald C Petersen50, Mary Sano12, Thomas Wisniewski51, Robert Vassar52, Jeffrey A Kaye53, Victor W Henderson54,55, Charles DeCarli56, Frank M LaFerla57, James B Brewer58, Bruce L Miller59, Russell H Swerdlow60, Linda J Van Eldik61, Henry L Paulson62, John Q Trojanowski63, Helena C Chui64, Roger N Rosenberg65, Suzanne Craft66, Thomas J Grabowski67,68, Sanjay Asthana69, John C Morris70, Stephen M Strittmatter71, Walter A Kukull72,73. 1. The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida. 2. Dr. John T. MacDonald Foundation, Department of Human Genetics, University of Miami, Miami, Florida. 3. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York. 4. Gertrude H. Sergievsky Center, Columbia University, New York, New York. 5. Department of Neurology, Columbia University, New York, New York. 6. Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia. 7. Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia. 8. Department of Medicine, University of Washington, Seattle. 9. Group Health Research Institute, Group Health, Seattle, Washington. 10. Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois. 11. Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois. 12. Department of Psychiatry, Mount Sinai School of Medicine, New York, New York. 13. Department of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, New York. 14. Department of Neuroscience, Mount Sinai School of Medicine, New York, New York. 15. Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York. 16. Department of Neuroscience, Mayo Clinic, Jacksonville, Florida. 17. Department of Neurology, Mayo Clinic, Jacksonville, Florida. 18. Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois. 19. Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois. 20. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois. 21. Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland. 22. Department of Epidemiology, University of Alabama at Birmingham, Birmingham. 23. Howard University, Howard University Hospital, Washington, DC. 24. Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania. 25. Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania. 26. Department of Psychiatry, Indiana University School of Medicine, Indianapolis. 27. Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, New York. 28. Department of Medical and Molecular Genetics, Indiana University, Indianapolis. 29. Maya Angelou Center for Health Equity, Wake Forest School of Medicine, Winston-Salem, North Carolina. 30. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts. 31. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts. 32. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts. 33. Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts. 34. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts. 35. Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio. 36. Department of Psychiatry, Columbia University, New York, New York. 37. Epidemiology, College of Physicians and Surgeons, Columbia University, New York, New York. 38. National Center for PTSD, VA Boston Healthcare System, Boston, Massachusetts. 39. Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts. 40. Arizona Alzheimer's Center, Banner Alzheimer's Institute, Phoenix. 41. Boston University, Boston VA Medical Center, Jamaica Plain, Massachusetts. 42. Cleveland Clinic, Cleveland, Ohio. 43. Columbia University Alzheimer's Disease Research Center, New York, New York. 44. Department of Neurology, Emory University, Atlanta, Georgia. 45. Center for Translational Research in Neurodegenerative Disease (CTRND), University of Florida, Gainesville. 46. Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis. 47. Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis. 48. Johns Hopkins University School of Medicine, Baltimore, Maryland. 49. Massachusetts Alzheimer's Disease Research Center, Department of Neurology, Massachusetts General Hospital, Charlestown. 50. Department of Neurology, Mayo Clinic, Rochester, Minnesota. 51. Center for Cognitive Neurology, New York University, New York. 52. Department of Neurology, Northwestern University, Chicago, Illinois. 53. Aging & Alzheimer Disease Center, Oregon Health & Science University, Portland. 54. Department of Epidemiology & Population Health, Stanford University, Stanford, California. 55. Department of Neurology & Neurological Sciences, Stanford University, Stanford, California. 56. University of California Davis at Medical Center, Sacramento. 57. University of California Irvine, Irvine. 58. Shiley-Marcos Alzheimer's Disease Center, UC San Diego, La Jolla, California. 59. University of California San Francisco, San Francisco. 60. Alzheimer's Disease Research Center, University of Kansas, Kansas City. 61. Sanders-Brown Center on Aging, University of Kentucky, Lexington. 62. Alzheimer Disease Center, University of Michigan, Ann Arbor. 63. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia. 64. University of Southern California, Los Angeles. 65. University of Texas Southwestern Medical Center, Dallas. 66. Wake Forest School of Medicine, Winston-Salem, North Carolina. 67. Department of Radiology, University of Washington, Seattle. 68. Department of Neurology, University of Washington, Seattle. 69. University of Wisconsin, Madison. 70. Department of Neurology, Washington University School of Medicine, St Louis, Missouri. 71. Department of Neurology, Yale University School of Medicine, New Haven, Connecticut. 72. National Alzheimer's Coordinating Center, University of Washington, Seattle. 73. Department of Epidemiology, University of Washington, Seattle.
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 gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures: Diagnosis of Alzheimer disease. Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
Authors: Yann Le Guen; Michael E Belloy; Benjamin Grenier-Boley; Itziar de Rojas; Atahualpa Castillo-Morales; Iris Jansen; Aude Nicolas; Céline Bellenguez; Carolina Dalmasso; Fahri Küçükali; Sarah J Eger; Katrine Laura Rasmussen; Jesper Qvist Thomassen; Jean-François Deleuze; Zihuai He; Valerio Napolioni; Philippe Amouyel; Frank Jessen; Patrick G Kehoe; Cornelia van Duijn; Magda Tsolaki; Pascual Sánchez-Juan; Kristel Sleegers; Martin Ingelsson; Giacomina Rossi; Mikko Hiltunen; Rebecca Sims; Wiesje M van der Flier; Alfredo Ramirez; Ole A Andreassen; Ruth Frikke-Schmidt; Julie Williams; Agustín Ruiz; Jean-Charles Lambert; Michael D Greicius; Beatrice Arosio; Luisa Benussi; Anne Boland; Barbara Borroni; Paolo Caffarra; Delphine Daian; Antonio Daniele; Stéphanie Debette; Carole Dufouil; Emrah Düzel; Daniela Galimberti; Vilmantas Giedraitis; Timo Grimmer; Caroline Graff; Edna Grünblatt; Olivier Hanon; Lucrezia Hausner; Stefanie Heilmann-Heimbach; Henne Holstege; Jakub Hort; Deckert Jürgen; Teemu Kuulasmaa; Aad van der Lugt; Carlo Masullo; Patrizia Mecocci; Shima Mehrabian; Alexandre de Mendonça; Susanne Moebus; Benedetta Nacmias; Gael Nicolas; Robert Olaso; Goran Papenberg; Lucilla Parnetti; Florence Pasquier; Oliver Peters; Yolande A L Pijnenburg; Julius Popp; Innocenzo Rainero; Inez Ramakers; Steffi Riedel-Heller; Nikolaos Scarmeas; Philip Scheltens; Norbert Scherbaum; Anja Schneider; Davide Seripa; Hilkka Soininen; Vincenzo Solfrizzi; Gianfranco Spalletta; Alessio Squassina; John van Swieten; Thomas J Tegos; Lucio Tremolizzo; Frans Verhey; Martin Vyhnalek; Jens Wiltfang; Mercè Boada; Pablo García-González; Raquel Puerta; Luis M Real; Victoria Álvarez; María J Bullido; Jordi Clarimon; José María García-Alberca; Pablo Mir; Fermin Moreno; Pau Pastor; Gerard Piñol-Ripoll; Laura Molina-Porcel; Jordi Pérez-Tur; Eloy Rodríguez-Rodríguez; Jose Luís Royo; Raquel Sánchez-Valle; Martin Dichgans; Dan Rujescu Journal: JAMA Neurol Date: 2022-07-01 Impact factor: 29.907
Authors: Adrienne Tin; Jan Bressler; Jeannette Simino; Kevin J Sullivan; Hao Mei; B Gwen Windham; Michael Griswold; Rebecca F Gottesman; Eric Boerwinkle; Myriam Fornage; Tom H Mosley Journal: Neurology Date: 2022-05-25 Impact factor: 11.800
Authors: Napatsorn Saiyasit; Evan-Angelo R Butlig; Samantha D Chaney; Miranda K Traylor; Nanako A Hawley; Ryleigh B Randall; Hanna V Bobinger; Carl A Frizell; Franklin Trimm; Errol D Crook; Mike Lin; Benjamin D Hill; Joshua L Keller; Amy R Nelson Journal: Front Neurosci Date: 2022-06-29 Impact factor: 5.152
Authors: 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; Jeffery M Vance Journal: PLoS Genet Date: 2022-07-05 Impact factor: 6.020
Authors: Anthony J Griswold; Katrina Celis; Parker L Bussies; Farid Rajabli; Patrice L Whitehead; Kara L Hamilton-Nelson; Gary W Beecham; Derek M Dykxhoorn; Karen Nuytemans; Liyong Wang; Olivia K Gardner; Daniel A Dorfsman; Eileen H Bigio; Marek Marsel Mesulam; Sandra Weintraub; Changiz Geula; Marla Gearing; Elisa McGrath-Martinez; Clifton L Dalgard; William K Scott; Jonathan L Haines; Margaret A Pericak-Vance; Juan I Young; Jeffery M Vance Journal: Alzheimers Dement Date: 2021-02-01 Impact factor: 16.655