Abstract
Objective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families. Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci. Results: A variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040). Conclusions and Relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.
Original language | English |
---|---|
Pages (from-to) | 406-417 |
Number of pages | 12 |
Journal | Annals of Clinical and Translational Neurology |
Volume | 5 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2018 |
Fingerprint
Dive into the research topics of 'Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Annals of Clinical and Translational Neurology, Vol. 5, No. 4, 01.04.2018, p. 406-417.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease
AU - The Alzheimer's Disease Sequencing Project
AU - Vardarajan, Badri N.
AU - Barral, Sandra
AU - Jaworski, James
AU - Beecham, Gary W.
AU - Blue, Elizabeth
AU - Tosto, Giuseppe
AU - Reyes-Dumeyer, Dolly
AU - Medrano, Martin
AU - Lantigua, Rafael
AU - Naj, Adam
AU - Thornton, Timothy
AU - DeStefano, Anita
AU - Martin, Eden
AU - Wang, Li San
AU - Brown, Lisa
AU - Bush, William
AU - van Duijn, Cornelia
AU - Goate, Allison
AU - Farrer, Lindsay
AU - Haines, Jonathan L.
AU - Boerwinkle, Eric
AU - Schellenberg, Gerard
AU - Wijsman, Ellen
AU - Pericak-Vance, Margaret A.
AU - Mayeux, Richard
AU - Mosley,
AU - Cantwell, Laura
AU - Childress, Micah
AU - Chou, Yi Fan
AU - Cweibel, Rebecca
AU - Gangadharan, Prabhakaran
AU - Kuzma, Amanda
AU - Lin, Han Jen
AU - Malamon, John
AU - Mlynarski, Elisabeth
AU - Naj, Adam
AU - Qu, Liming
AU - Schellenberg, Gerard
AU - Valladares, Otto
AU - Wang, Li San
AU - Wang, Weixin
AU - Zhang, Nancy
AU - Below,
AU - Boerwinkle, Eric
AU - Bressler, Jan
AU - Fornage, Myriam
AU - Jian, Xueqiu
AU - Liu, Xiaoming
AU - Bis,
AU - Cruchaga, Carlos
N1 - Funding Information: National Institute on Aging (NIA) and by the National Institutes of Health (NIH), Grant Numbers: 5R37AG015473, RF1AG015473, R56AG051876, 1RF1AG054023, UF1AG047133, U01AG049505, U01AG049506, U01AG049507, U01AG049508 Funding Information: Goate and U01AG052410 to Dr. Pericak-Vance. Data generation and harmonization in the Follow-up Phases is supported by U54AG052427 (to Drs. Schellenberg and Wang). Cohorts sequenced in ADSP: The ADGC cohorts include: Adult Changes in Thought (ACT), the Alzheimer’ Disease Centers (ADC), the Chicago Health and Aging Project (CHAP), the Memory and Aging Project (MAP), Mayo Clinic (MAYO), Mayo Parkinson’s Disease controls, University of Miami, the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology Study (MIRAGE), the National Cell Repository for Alzheimer’s Disease (NCRAD), the National Institute on Aging Late Onset Alzheimer’s Disease Family Study (NIA-LOAD), the Religious Orders Study (ROS), the Texas Alzheimer’s Research and Care Consortium (TARC), Vanderbilt University/Case Western Reserve University (VAN/ CWRU), the Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Washington University Sequencing Project (WUSP), the Columbia University Hispanic-Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA), the University of Toronto (UT), and Genetic Differences (GD). The CHARGE cohorts, with funding provided by 5RC2HL102419 and HL105756, include the following: Atherosclerosis Risk in Communities (ARIC) Study which is carried out as a collaborative study supported by NHLBI contracts (HHSN2682011 00005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268 201100010C, HHSN268201100011C, and HHSN268201 100012C), Austrian Stroke Prevention Study (ASPS), Cardiovascular Health Study (CHS), Erasmus Rucphen Family Study (ERF), Framingham Heart Study (FHS), and Rotterdam Study (RS). CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85 081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629, R01AG15928, and R01AG20098 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The three LSACs are: the Human Genome Sequencing Center at the Baylor College of Medicine (U54 HG003273), the Broad Institute Genome Center (U54HG003067), and the Washington University Genome Institute (U54HG003079). NCRAD and NIAGADS: Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigators institutions, and at the National Cell Repository for Alzheimer’s Disease (NCRAD, U24AG021886) at Indiana University funded by NIA. Associated Phenotypic Data used in primary and secondary data analyses were provided by Study Investigators, the NIA funded Alzheimer’s Disease Centers (ADCs), and the National Alzheimer’s Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by NIA, and at the Database for Genotypes and Phenotypes (dbGaP) funded by NIH. This research was supported in part by the Intramural Research Program of the National Institutes of health, National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by NIA, and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations. Funding Information: EFIGA and WHICAP cohorts: Data collection for this project was supported by the Genetic Studies of Alzheimer's disease in Caribbean Hispanics (Estudio familiar de la genética de la enfermedad de Alzheimer, also known as EFIGA) and the Washington Heights and Inwood Community Aging Project (WHICAP) funded by the National Institute on Aging (NIA) and by the National Institutes of Health (NIH) (5R37AG015473, RF1AG015473, R56AG051876, 1RF1AG054023). We acknowledge the EFIGA and WHICAP study participants and the research and support staff for their contributions to this study. ADSP: The Alzheimer's Disease Sequencing Project (ADSP) is comprised of two Alzheimer's Disease (AD) genetics consortia and three National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSAC). The two AD genetics consortia are the Alzheimer's Disease Genetics Consortium (ADGC) funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institute of Health (NIH) institutes and other foreign governmental and non-governmental organizations. Funding Information: project was supported by the Genetic Studies of Alzheimer’s disease in Caribbean Hispanics (Estudio familiar de la genética de la enfermedad de Alzheimer, also known as EFIGA) and the Washington Heights and Inwood Community Aging Project (WHICAP) funded by the National Institute on Aging (NIA) and by the National Institutes of Health (NIH) (5R37AG015473, RF1AG015473, R56AG051876, 1RF1AG054023). We acknowledge the EFIGA and WHICAP study participants and the research and support staff for their contributions to this study. ADSP: The Alzheimer’s Disease Sequencing Project (ADSP) is comprised of two Alzheimer’s Disease (AD) genetics consortia and three National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSAC). The two AD genetics consortia are the Alzheimer’s Disease Genetics Consortium (ADGC) funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institute of Health (NIH) institutes and other foreign governmental and non-governmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs. Schellen-berg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate and the Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Publisher Copyright: © 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Objective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families. Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci. Results: A variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040). Conclusions and Relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.
AB - Objective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families. Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci. Results: A variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040). Conclusions and Relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.
UR - http://www.scopus.com/inward/record.url?scp=85043571060&partnerID=8YFLogxK
U2 - 10.1002/acn3.537
DO - 10.1002/acn3.537
M3 - Article
C2 - 29688227
AN - SCOPUS:85043571060
SN - 2328-9503
VL - 5
SP - 406
EP - 417
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
IS - 4
ER -