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, Jeffery M Vance, Lindsay A. Farrer, Alison M. Goate, Tatiana Foroud, Richard P. Mayeux, Gerard D. Schellenberg, Jonathan L. HainesMargaret A Pericak-Vance

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 forthis 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.

Original languageEnglish (US)
JournalAlzheimer's and Dementia
DOIs
StateAccepted/In press - 2015

Fingerprint

Alzheimer Disease
Genome
Penetrance
Multigene Family
MicroRNAs
Neurodegenerative Diseases
Genes
Alleles
Alzheimer disease type 2
Confidence Intervals
Mutation
Brain

Keywords

  • Familial
  • Genetics
  • High penetrance
  • Identity by descent
  • Late-onset Alzheimer's disease
  • Linkage
  • Non-Hispanic white

ASJC Scopus subject areas

  • Clinical Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Epidemiology
  • Health Policy

Cite this

Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease. / Kunkle, Brian W.; Jaworski, James; Barral, Sandra; Vardarajan, Badri; Beecham, Gary W; Martin, Eden R; Cantwell, Laura S.; Partch, Amanda; Bird, Thomas D.; Raskind, Wendy H.; Destefano, Anita L.; Carney, Regina M.; Cuccaro, Michael; Vance, Jeffery M; Farrer, Lindsay A.; Goate, Alison M.; Foroud, Tatiana; Mayeux, Richard P.; Schellenberg, Gerard D.; Haines, Jonathan L.; Pericak-Vance, Margaret A.

In: Alzheimer's and Dementia, 2015.

Research output: Contribution to journalArticle

Kunkle, BW, Jaworski, J, Barral, S, Vardarajan, B, Beecham, GW, Martin, ER, Cantwell, LS, Partch, A, Bird, TD, Raskind, WH, Destefano, AL, Carney, RM, Cuccaro, M, Vance, JM, Farrer, LA, Goate, AM, Foroud, T, Mayeux, RP, Schellenberg, GD, Haines, JL & Pericak-Vance, MA 2015, 'Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease', Alzheimer's and Dementia. https://doi.org/10.1016/j.jalz.2015.05.020
Kunkle, Brian W. ; Jaworski, James ; Barral, Sandra ; Vardarajan, Badri ; Beecham, Gary W ; Martin, Eden R ; Cantwell, Laura S. ; Partch, Amanda ; Bird, Thomas D. ; Raskind, Wendy H. ; Destefano, Anita L. ; Carney, Regina M. ; Cuccaro, Michael ; Vance, Jeffery M ; Farrer, Lindsay A. ; Goate, Alison M. ; Foroud, Tatiana ; Mayeux, Richard P. ; Schellenberg, Gerard D. ; Haines, Jonathan L. ; Pericak-Vance, Margaret A. / Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease. In: Alzheimer's and Dementia. 2015.
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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 forthis 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.",
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T1 - Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease

AU - Kunkle, Brian W.

AU - Jaworski, James

AU - Barral, Sandra

AU - Vardarajan, Badri

AU - Beecham, Gary W

AU - Martin, Eden R

AU - Cantwell, Laura S.

AU - Partch, Amanda

AU - Bird, Thomas D.

AU - Raskind, Wendy H.

AU - Destefano, Anita L.

AU - Carney, Regina M.

AU - Cuccaro, Michael

AU - Vance, Jeffery M

AU - Farrer, Lindsay A.

AU - Goate, Alison M.

AU - Foroud, Tatiana

AU - Mayeux, Richard P.

AU - Schellenberg, Gerard D.

AU - Haines, Jonathan L.

AU - Pericak-Vance, Margaret A

PY - 2015

Y1 - 2015

N2 - 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 forthis 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.

AB - 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 forthis 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.

KW - Familial

KW - Genetics

KW - High penetrance

KW - Identity by descent

KW - Late-onset Alzheimer's disease

KW - Linkage

KW - Non-Hispanic white

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