Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease

Brian W Kunkle; James Jaworski; Sandra Barral; Badri Vardarajan; Gary W Beecham; Eden R Martin; Laura S Cantwell; Amanda Partch; Thomas D Bird; Wendy H Raskind; Anita L DeStefano; Regina M Carney; Michael Cuccaro; Jeffrey M Vance; Lindsay A Farrer; Alison M Goate; Tatiana Foroud; Richard P Mayeux; Gerard D Schellenberg; Jonathan L Haines; Margaret A Pericak-Vance

doi:10.1016/j.jalz.2015.05.020

Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease

Alzheimers Dement. 2016 Jan;12(1):2-10. doi: 10.1016/j.jalz.2015.05.020. Epub 2015 Sep 11.

Authors

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

Affiliations

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.

Keywords: Familial; Genetics; High penetrance; Identity by descent; Late-onset Alzheimer's disease; Linkage; Non-Hispanic white.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / genetics*
Apolipoproteins E / genetics
Genetic Linkage*
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Middle Aged
Pedigree
White People / genetics*

Substances

Apolipoproteins E

Abstract

Publication types

MeSH terms

Substances

Grants and funding