@article{0f3e6efde08d429a996020fd20c8636b,
title = "Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease",
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",
author = "Kunkle, {Brian W.} and James Jaworski and Sandra Barral and Badri Vardarajan and Beecham, {Gary W.} and Martin, {Eden R.} and Cantwell, {Laura S.} and Amanda Partch and Bird, {Thomas D.} and Raskind, {Wendy H.} and Destefano, {Anita L.} and Carney, {Regina M.} and Michael Cuccaro and Vance, {Jeffrey M.} and Farrer, {Lindsay A.} and Goate, {Alison M.} and Tatiana Foroud and Mayeux, {Richard P.} and Schellenberg, {Gerard D.} and Haines, {Jonathan L.} and Pericak-Vance, {Margaret A.}",
note = "Funding Information: The authors thank Drs. Eric Boerwinkle (University of Texas Health Science Center), Josh Bis (University of Washington), and Benjamin Neale (Harvard Medical School) for their help in selection of the families for the analyses presented in this article. We are grateful to the families and staff who participated in this study. This work was supported by National Institute of Health grants R01 AG027944 (M.A.P.-V.), R01 AG019085, R01 AG028786-02 (M.A.P.-V.), RC2AG036528 (M.A.P.-V.and J.L.H.), R37AG015473 (R.M.C.), U01AG032934 (G.D.S.), R01-AG025259 (L.A.F.), P30-AG13846 (L.A.F.), 1R01 NS069719-01(W.H.R.), the Alzheimer Disease Research Center Genetics Core grant 5P50-AG008702-25 (R.M.C.), VA Medical Research Funds (T.D.B.), the Alzheimer''s Association grant IIRG09133827 (M.A.P.-V.), Department of Veterans Affairs Merit Review Award (T.D.B. and W.H.R.), and the VA Puget Sound Health Care System Geriatric Research, Education, and Clinical Center (T.D.B.). The authors thank the International Genomics of Alzheimer''s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chips were funded by the French National Foundation on Alzheimer''s disease and related disorders. EADI was supported by the Labex (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Universit{\'e} de Lille 2, and the Lille University Hospital. GERAD was supported by the Medical Research Council (grant 503480), Alzheimer''s Research UK (grant 503176), the Wellcome Trust (grant 082604/2/07/Z), and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG-12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer''s Association grant ADGC-10-196728. Data sharing: All data from the analyses in this article, including quality control documentation, GWAS array data and phenotype data for each family, and linkage analyses results, are available for download at the National Institute on Aging Genetics of Alzheimer''s Disease Data Storage Site''s ADSP Web site (https://www.niagads.org/adsp/content/home). Applicants must submit a data access request to dbGaP. Applications are reviewed by the ADSP Data Access Committee (DAC) and the NIAGADS Data Use Committee (DUC). ADSP phenotype and sequence data are made available to the research community at large in keeping with the NIH Genomics Data Sharing Policy http://gds.nih.gov/. NIA has established the National Institute on Aging Genetics of Alzheimer''s Disease Data Storage Site (NIAGADS) as a national genetics data repository to facilitate access by qualified investigators to genotypic and phenotypic data for the study of the genetics of late-onset Alzheimer''s disease. NIAGADS is working in partnership with dbGaP (ADSP at dbGaP) to provide ADSP data to the research community. Data can be requested either from dbGaP or NIAGADS. Instructions for application for ADSP data and an explanation of the review process can be found at: ADSP at dbGaP and NIAGADS ADSP Application Instructions. The ADSP has in place a memorandum of understanding: https://www.niagads.org/sites/all/public_files/ADSPdocs/ADSP-MOU.pdf. In the spirit of the clear benefit that ensues from converting such data sets into community resources as rapidly as possible, and in keeping with community expectations for the use of unpublished genome sequence data, it is expected for the first phase of the study called the Discovery Phase, that users of the data will withhold publication until the producers of the data have published their findings. ADSP participants will publish their data in an expeditious fashion in at least one major article reporting the results of the ADSP to be jointly submitted by all the members.",
year = "2016",
month = jan,
day = "1",
doi = "10.1016/j.jalz.2015.05.020",
language = "English (US)",
volume = "12",
pages = "2--10",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
number = "1",
}