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

TitleGenome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsKunkle 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
JournalAlzheimers Dement
Volume12
Issue1
Pagination2-10
Date Published2016 Jan
ISSN1552-5279
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, European Continental Ancestry Group, Genetic Linkage, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Middle Aged, Pedigree
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.

DOI10.1016/j.jalz.2015.05.020
Alternate JournalAlzheimers Dement
PubMed ID26365416
PubMed Central IDPMC4717829
Grant ListR01 NS069719 / NS / NINDS NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
UF1 AG047133 / AG / NIA NIH HHS / United States
R37AG015473 / AG / NIA NIH HHS / United States
R01 AG028786-02 / AG / NIA NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01-AG025259 / AG / NIA NIH HHS / United States
RC2AG036528 / AG / NIA NIH HHS / United States
1R01 NS069719-01 / NS / NINDS NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
5P50-AG008702-25 / AG / NIA NIH HHS / United States
P30-AG13846 / AG / NIA NIH HHS / United States
U19 AG047133 / AG / NIA NIH HHS / United States
U01AG032934 / AG / NIA NIH HHS / United States