Brian W Kunkle1, James Jaworski1, Sandra Barral2, Badri Vardarajan3, Gary W Beecham1, Eden R Martin1, Laura S Cantwell4, Amanda Partch4, Thomas D Bird5, Wendy H Raskind6, Anita L DeStefano7, Regina M Carney8, Michael Cuccaro9, Jeffrey M Vance9, Lindsay A Farrer10, Alison M Goate11, Tatiana Foroud12, Richard P Mayeux13, Gerard D Schellenberg4, Jonathan L Haines14, Margaret A Pericak-Vance15. 1. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA. 2. The Taub Institute of Research on Alzheimer's Disease, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. 3. The Taub Institute of Research on Alzheimer's Disease, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. 4. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 5. Department of Neurology, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA. 6. Department of Medicine, University of Washington, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. 7. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 8. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA. 9. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA. 10. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; Department of Medicine (Biomedical Genetics), Boston University School of Medicine and Public Health, MA, USA; Department of Neurology, Boston University School of Medicine and Public Health, MA, USA; Department of Ophthalmology, Boston University School of Medicine and Public Health, MA, USA; Department of Epidemiology, Boston University School of Public Health, MA, USA. 11. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA. 12. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. 13. The Taub Institute of Research on Alzheimer's Disease, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA; The Department of Epidemiology, School of Public Health, Columbia University, New York, NY, USA. 14. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA. 15. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA. Electronic address: mpericak@med.miami.edu.
Abstract
INTRODUCTION: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. METHODS: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. RESULTS: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. DISCUSSION: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.
INTRODUCTION: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. METHODS: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. RESULTS: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. DISCUSSION: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Joseph H Lee; Sandra Barral; Rong Cheng; Inara Chacon; Vincent Santana; Jennifer Williamson; Rafael Lantigua; Martin Medrano; Ivonne Z Jimenez-Velazquez; Yaakov Stern; Benjamin Tycko; Ekaterina Rogaeva; Yosuke Wakutani; Toshitaka Kawarai; Peter St George-Hyslop; Richard Mayeux Journal: Neurogenetics Date: 2007-10-17 Impact factor: 2.660
Authors: R M Carney; M A Slifer; P I Lin; P C Gaskell; W K Scott; C F Potocky; C M Hulette; K A Welsh-Bohmer; D E Schmechel; J M Vance; M A Pericak-Vance Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2008-07-05 Impact factor: 3.568
Authors: Moran N Cabili; Cole Trapnell; Loyal Goff; Magdalena Koziol; Barbara Tazon-Vega; Aviv Regev; John L Rinn Journal: Genes Dev Date: 2011-09-02 Impact factor: 11.361
Authors: Audrey Y Chu; Franco Guilianini; Harald Grallert; Josée Dupuis; Christie M Ballantyne; Bryan J Barratt; Fredrik Nyberg; Daniel I Chasman; Paul M Ridker Journal: Circ Cardiovasc Genet Date: 2012-11-01
Authors: Alan H Nagahara; David A Merrill; Giovanni Coppola; Shingo Tsukada; Brock E Schroeder; Gideon M Shaked; Ling Wang; Armin Blesch; Albert Kim; James M Conner; Edward Rockenstein; Moses V Chao; Edward H Koo; Daniel Geschwind; Eliezer Masliah; Andrea A Chiba; Mark H Tuszynski Journal: Nat Med Date: 2009-02-08 Impact factor: 53.440
Authors: Reuben Saba; Chelsey D Goodman; Rhiannon L C H Huzarewich; Catherine Robertson; Stephanie A Booth Journal: PLoS One Date: 2008-11-06 Impact factor: 3.240
Authors: Adam C Naj; Honghuang Lin; Badri N Vardarajan; Simon White; Daniel Lancour; Yiyi Ma; Michael Schmidt; Fangui Sun; Mariusz Butkiewicz; William S Bush; Brian W Kunkle; John Malamon; Najaf Amin; Seung Hoan Choi; Kara L Hamilton-Nelson; Sven J van der Lee; Namrata Gupta; Daniel C Koboldt; Mohamad Saad; Bowen Wang; Alejandro Q Nato; Harkirat K Sohi; Amanda Kuzma; Li-San Wang; L Adrienne Cupples; Cornelia van Duijn; Sudha Seshadri; Gerard D Schellenberg; Eric Boerwinkle; Joshua C Bis; Josée Dupuis; William J Salerno; Ellen M Wijsman; Eden R Martin; Anita L DeStefano Journal: Genomics Date: 2018-05-29 Impact factor: 5.736
Authors: Gary W Beecham; J C Bis; E R Martin; S-H Choi; A L DeStefano; C M van Duijn; M Fornage; S B Gabriel; D C Koboldt; D E Larson; A C Naj; B M Psaty; W Salerno; W S Bush; T M Foroud; E Wijsman; L A Farrer; A Goate; J L Haines; Margaret A Pericak-Vance; E Boerwinkle; R Mayeux; S Seshadri; G Schellenberg Journal: Neurol Genet Date: 2017-10-13
Authors: Gary W Beecham; Badri Vardarajan; Elizabeth Blue; William Bush; James Jaworski; Sandra Barral; Anita DeStefano; Kara Hamilton-Nelson; Brian Kunkle; Eden R Martin; Adam Naj; Farid Rajabli; Christiane Reitz; Timothy Thornton; Cornelia van Duijn; Allison Goate; Sudha Seshadri; Lindsay A Farrer; Eric Boerwinkle; Gerard Schellenberg; Jonathan L Haines; Ellen Wijsman; Richard Mayeux; Margaret A Pericak-Vance Journal: Neurol Genet Date: 2018-11-21
Authors: Jeannette Simino; Zhiying Wang; Jan Bressler; Vincent Chouraki; Qiong Yang; Steven G Younkin; Sudha Seshadri; Myriam Fornage; Eric Boerwinkle; Thomas H Mosley Journal: PLoS One Date: 2017-07-13 Impact factor: 3.240
Authors: H N Cukier; B K Kunkle; K L Hamilton; S Rolati; M A Kohli; P L Whitehead; J Jaworski; J M Vance; M L Cuccaro; R M Carney; J R Gilbert; L A Farrer; E R Martin; G W Beecham; J L Haines; M A Pericak-Vance Journal: J Alzheimers Dis Parkinsonism Date: 2017-07-31
Authors: Matthew J Lennon; Simon P Jones; Michael D Lovelace; Gilles J Guillemin; Bruce J Brew Journal: Front Cell Neurosci Date: 2017-03-29 Impact factor: 5.505
Authors: Rong Cheng; Min Tang; Izri Martinez; Temitope Ayodele; Penelope Baez; Dolly Reyes-Dumeyer; Rafael Lantigua; Martin Medrano; Ivonne Jimenez-Velazquez; Joseph H Lee; Gary W Beecham; Christiane Reitz Journal: Alzheimers Dement (Amst) Date: 2018-08-27
Authors: Lisa Uechi; Mahjoubeh Jalali; Jayson D Wilbur; Jonathan L French; N L Jumbe; Michael J Meaney; Peter D Gluckman; Neerja Karnani; Nikita A Sakhanenko; David J Galas Journal: PLoS One Date: 2020-12-03 Impact factor: 3.240