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

doi:10.1016/j.jalz.2015.05.020

. 2016 Jan;12(1):2-10.

doi: 10.1016/j.jalz.2015.05.020. Epub 2015 Sep 11.

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

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.

PMID: 26365416
PMCID: PMC4717829
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

Brian W Kunkle et al. Alzheimers Dement. 2016 Jan.

. 2016 Jan;12(1):2-10.

doi: 10.1016/j.jalz.2015.05.020. Epub 2015 Sep 11.

Authors

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.

PMID: 26365416
PMCID: PMC4717829
DOI: 10.1016/j.jalz.2015.05.020

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.

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Figures

**Figure 1**
Manhattan plot of parametric 2-point affecteds-only results (Red lines represent HLOD = 3.5 for significant linkage and 4.0 for highly significant linkage).

**Figure 2**
Shared IBD segments among the four families with LOD* > 0.588 and full IBD sharing for all affected, genotyped family members) in the chromosome 14 linkage region. Red lines represent the minimum shared IBD segment region. Light green lines represent the 1-LOD confidence interval region.

See this image and copyright information in PMC

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References

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[1] Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013;45:1452–8. doi:10.1038/ng.2802. - PMC - PubMed

[2] Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013;45:1452–8. doi:10.1038/ng.2802. - PMC - PubMed

[3] Bird TD. Genetic aspects of Alzheimer disease. Genet Med. 2008;10:231–9. doi:10.1097/GIM.0b013e31816b64dc. - PMC - PubMed

[4] Bird TD. Genetic aspects of Alzheimer disease. Genet Med. 2008;10:231–9. doi:10.1097/GIM.0b013e31816b64dc. - PMC - PubMed

[5] Maher MC, Uricchio LH, Torgerson DG, Hernandez RD. Population genetics of rare variants and complex diseases. Hum Hered. 2012;74:118–28. doi:000346826. - PMC - PubMed

[6] Maher MC, Uricchio LH, Torgerson DG, Hernandez RD. Population genetics of rare variants and complex diseases. Hum Hered. 2012;74:118–28. doi:000346826. - PMC - PubMed

[7] Ramirez A, van der Flier WM, Herold C, Ramonet D, Heilmann S, Lewczuk P, et al. SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease. Hum Mol Genet. 2014;23:1–15. doi:10.1093/hmg/ddu372. - PMC - PubMed

[8] Ramirez A, van der Flier WM, Herold C, Ramonet D, Heilmann S, Lewczuk P, et al. SUCLG2 identified as both a determinator of CSF Aβ1-42 levels and an attenuator of cognitive decline in Alzheimer's disease. Hum Mol Genet. 2014;23:1–15. doi:10.1093/hmg/ddu372. - PMC - PubMed

[9] Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson P V, Bjornsson S, et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012;488:96–9. doi:10.1038/nature11283. - PubMed

[10] Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson P V, Bjornsson S, et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012;488:96–9. doi:10.1038/nature11283. - PubMed

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

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

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