Abstract
Objective To identify genetic variation influencing late-onset Alzheimer disease (LOAD), we used a large data set of non-Hispanic white (NHW) extended families multiply-affected by LOAD by performing whole genome sequencing (WGS). Methods As part of the Alzheimer Disease Sequencing Project, WGS data were generated for 197 NHW participants from 42 families (affected individuals and unaffected, elderly relatives). A two-pronged approach was taken. First, variants were prioritized using heterogeneity logarithm of the odds (HLOD) and family-specific LOD scores as well as annotations based on function, frequency, and segregation with disease. Second, known Alzheimer disease (AD) candidate genes were assessed for rare variation using a family-based association test. Results We identified 41 rare, predicted-damaging variants that segregated with disease in the families that contributed to the HLOD or family-specific LOD regions. These included a variant in nitric oxide synthase 1 adaptor protein that segregates with disease in a family with 7 individuals with AD, as well as variants in RP11-433J8, ABCA1, and FISP2. Rare-variant association identified 2 LOAD candidate genes associated with disease in these families: FERMT2 (p-values = 0.001) and SLC24A4 (p-value = 0.009). These genes still showed association while controlling for common index variants, indicating the rare-variant signal is distinct from common variation that initially identified the genes as candidates. Conclusions We identified multiple genes with putative damaging rare variants that segregate with disease in multiplex AD families and showed that rare variation may influence AD risk at AD candidate genes. These results identify novel AD candidate genes and show a role for rare variation in LOAD etiology, even at genes previously identified by common variation.
Original language | English (US) |
---|---|
Article number | e286 |
Journal | Neurology: Genetics |
Volume | 4 |
Issue number | 6 |
DOIs | |
State | Published - Dec 1 2018 |
Externally published | Yes |
ASJC Scopus subject areas
- Clinical Neurology
- Genetics(clinical)
Access to Document
Fingerprint Dive into the research topics of 'Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease'. Together they form a unique fingerprint.
Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease. / Beecham, Gary W.; Vardarajan, Badri; Blue, Elizabeth; Bush, William; Jaworski, James; Barral, Sandra; Stefano, Anita De; Hamilton-Nelson, Kara; Kunkle, Brian; Martin, Eden R.; Naj, Adam; Pericak-Vance, Margaret A.; Reitz, Christian; Thornton, Timothy; Duijn, Cornelia van; Goate, Allison; Seshadri, Sudha; Farrer, Lindsay A.; Boerwinkle, Eric; Schellenberg, Gerard; Haines, Jonathan L.; Wijsman, Ellen; Mayeux, Richard; Pericak-Vance, Margaret A.
In: Neurology: Genetics, Vol. 4, No. 6, e286, 01.12.2018.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease
AU - Beecham, Gary W.
AU - Vardarajan, Badri
AU - Blue, Elizabeth
AU - Bush, William
AU - Jaworski, James
AU - Barral, Sandra
AU - Stefano, Anita De
AU - Hamilton-Nelson, Kara
AU - Kunkle, Brian
AU - Martin, Eden R.
AU - Naj, Adam
AU - Pericak-Vance, Margaret A.
AU - Reitz, Christian
AU - Thornton, Timothy
AU - Duijn, Cornelia van
AU - Goate, Allison
AU - Seshadri, Sudha
AU - Farrer, Lindsay A.
AU - Boerwinkle, Eric
AU - Schellenberg, Gerard
AU - Haines, Jonathan L.
AU - Wijsman, Ellen
AU - Mayeux, Richard
AU - Pericak-Vance, Margaret A.
N1 - Funding Information: The Article Processing Charge was funded by the authors. Funding Information: The Alzheimer’s Disease Sequencing Project (ADSP) comprises 2 Alzheimer disease (AD) genetics consortia and 3 National Human Genome Research Institute–funded Large Scale Sequencing and Analysis Centers (LSAC). The 2 AD genetics consortia are the Alzheimer’s Disease Genetics Consortium (ADGC) funded by the National Institute on Aging (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 NIH institutes and other foreign governmental and nongovernmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs. Farrer, Haines, Mayeux, Pericak-Vance, and Schellenberg); 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. Goate, U01AG052410 to Dr. Pericak-Vance, and U01 AG052409 to Drs. Seshadri and Fornage. Data generation and harmonization in the Follow-up Phases is supported by U54AG052427 to Drs. Schellenberg and Wang. The ADGC cohorts include: Adult Changes in Thought (ACT supported by NIA grant U01AG006781 to Drs. Larson and Crane), the Alzheimer’s 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 supported by NIA grant RF1AG054023 to Dr. Mayeux) and the Washington University Sequencing Project (WUSP), the Columbia University Hispanic-Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA supported by NIA grant RF1AG015473 to Dr. Mayeux), the University of Toronto (UT), and Genetic Differences (GD). Analysis of ADGC cohorts was supported by NIA grants R01AG048927 and RF1AG057519 to Dr. Farrer. Efforts of ADGC investigators were also supported by grants from the NIA (R03AG054936) and National Library of Medicine (R01LM012535). The CHARGE cohorts are supported in part by NHLBI infrastructure grant HL105756 (Psaty) and RC2HL102419 (Boerwinkle), and the neurology working group is supported by the NIA R01 grant AG033193. The CHARGE cohorts participating in the ADSP include the following: Austrian Stroke Prevention Study (ASPS), ASPS-Family study, and the Prospective Dementia Registry-Austria (ASPS/PRODEM-Aus), the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). ASPS is funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180 and the Medical University of Graz. The ASPS-Fam is funded by the Austrian Science Fund (FWF) project I904, the EU Joint Programme— Neurodegenerative Disease Research (JPND) in frame of the BRIDGET project (Austria, Ministry of Science) and the Medical University of Graz and the Steiermärkische Krankenanstalten Gesellschaft. PRODEM-Austria is supported by the Austrian Research Promotion agency (FFG) (Project No. 827462) and by the Austrian National Bank (Anniversary Fund, project 15435). ARIC research is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data in ARIC is collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA, and NIDCD) and with previous brain MRI examinations funded by R01-HL70825 from the NHLBI. CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the NHLBI with additional contribution from the NINDS. Additional support was provided by R01AG023629, R01AG15928, and R01AG20098 from the NIA. FHS research is supported by NHLBI contracts N01-HC-25195 and HHSN268201500001I. This study was also supported by additional grants from the NIA (R01s AG054076, AG049607, and AG033040) and NINDS (R01 NS017950). The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from the Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. Genetic data sets are also supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/ Netherlands Organization for Scientific Research (NWO), Netherlands Consortium for Healthy Aging (NCHA), project 050-060-810. All studies are grateful to their participants, faculty, and staff. The content of these manuscripts is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the U.S. Department of Health and Human Services. The ADES-FR study was funded by grants from the Clinical Research Hospital Program from the French Ministry of Health (GMAJ, PHRC, 2008/067), the CNR-MAJ, the JPND PERADES, the GENMED labex (LABEX GENMED ANR-10-LABX-0013), and the FP7 AgedBrainSysBio. Whole exome sequencing in the 3C-Dijon study was funded by the Fondation Leducq. This work was supported by the France Génomique National infrastructure, funded as part of the Investissements d’Avenir program managed by the Agence Nationale pour la Recherche (ANR-10-INBS-09), the Centre National de Recherche en Génomique Humaine, the National Foundation forAlzheimer’s disease and related disorders, the Institut Pasteur de Lille, Inserm, the Lille Métropole Communauté Urbaine council, and the French government’s LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer’s disease). The 3C Study supports are listed on the Study Website (three-city-study.com). The FinnAD Study at the University of Tampere was supported by The Academy of Finland: grants 286284 (T.L.), Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association. 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). Funding Information: Supported by the NIH, primarily the National Institute on Aging (NIA), the National Heart, Lung, and Blood Institute, and the National Human Genome Research Institute. Primary support includes the Alzheimer’s Disease Genetics Consortium funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), 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). Additional funding of contributing sites is noted below in the acknowledgements.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Objective To identify genetic variation influencing late-onset Alzheimer disease (LOAD), we used a large data set of non-Hispanic white (NHW) extended families multiply-affected by LOAD by performing whole genome sequencing (WGS). Methods As part of the Alzheimer Disease Sequencing Project, WGS data were generated for 197 NHW participants from 42 families (affected individuals and unaffected, elderly relatives). A two-pronged approach was taken. First, variants were prioritized using heterogeneity logarithm of the odds (HLOD) and family-specific LOD scores as well as annotations based on function, frequency, and segregation with disease. Second, known Alzheimer disease (AD) candidate genes were assessed for rare variation using a family-based association test. Results We identified 41 rare, predicted-damaging variants that segregated with disease in the families that contributed to the HLOD or family-specific LOD regions. These included a variant in nitric oxide synthase 1 adaptor protein that segregates with disease in a family with 7 individuals with AD, as well as variants in RP11-433J8, ABCA1, and FISP2. Rare-variant association identified 2 LOAD candidate genes associated with disease in these families: FERMT2 (p-values = 0.001) and SLC24A4 (p-value = 0.009). These genes still showed association while controlling for common index variants, indicating the rare-variant signal is distinct from common variation that initially identified the genes as candidates. Conclusions We identified multiple genes with putative damaging rare variants that segregate with disease in multiplex AD families and showed that rare variation may influence AD risk at AD candidate genes. These results identify novel AD candidate genes and show a role for rare variation in LOAD etiology, even at genes previously identified by common variation.
AB - Objective To identify genetic variation influencing late-onset Alzheimer disease (LOAD), we used a large data set of non-Hispanic white (NHW) extended families multiply-affected by LOAD by performing whole genome sequencing (WGS). Methods As part of the Alzheimer Disease Sequencing Project, WGS data were generated for 197 NHW participants from 42 families (affected individuals and unaffected, elderly relatives). A two-pronged approach was taken. First, variants were prioritized using heterogeneity logarithm of the odds (HLOD) and family-specific LOD scores as well as annotations based on function, frequency, and segregation with disease. Second, known Alzheimer disease (AD) candidate genes were assessed for rare variation using a family-based association test. Results We identified 41 rare, predicted-damaging variants that segregated with disease in the families that contributed to the HLOD or family-specific LOD regions. These included a variant in nitric oxide synthase 1 adaptor protein that segregates with disease in a family with 7 individuals with AD, as well as variants in RP11-433J8, ABCA1, and FISP2. Rare-variant association identified 2 LOAD candidate genes associated with disease in these families: FERMT2 (p-values = 0.001) and SLC24A4 (p-value = 0.009). These genes still showed association while controlling for common index variants, indicating the rare-variant signal is distinct from common variation that initially identified the genes as candidates. Conclusions We identified multiple genes with putative damaging rare variants that segregate with disease in multiplex AD families and showed that rare variation may influence AD risk at AD candidate genes. These results identify novel AD candidate genes and show a role for rare variation in LOAD etiology, even at genes previously identified by common variation.
UR - http://www.scopus.com/inward/record.url?scp=85060848844&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060848844&partnerID=8YFLogxK
U2 - 10.1212/NXG.0000000000000286
DO - 10.1212/NXG.0000000000000286
M3 - Article
AN - SCOPUS:85060848844
VL - 4
JO - Neurology: Genetics
JF - Neurology: Genetics
SN - 2376-7839
IS - 6
M1 - e286
ER -