Journal
ALZHEIMERS RESEARCH & THERAPY
Volume 13, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13195-021-00808-5
Keywords
Alzheimer’ s disease; Genetics; Whole-exome sequencing; Exome-wide association; Age adjustment; Cox regression; RAB10; TAOK2; USH2A; RIN3; KIF21B
Categories
Funding
- Iqbal Farrukh & Asad Jamal Fund
- National Institutes of Health [AG066206, AG060747, AG047366]
- Alzheimer's Association [AARF-20-683984]
- European Union's Horizon 2020 research and innovation program [890650]
- Alzheimer's Disease (AD) genetics consortia
- National Human Genome Research Institute (NHGRI)
- NIA [U01 AG032984, R01AG023629, R01AG15928, R01AG20098, R01s AG054076, AG049607, AG033040, U24AG021886, P30 AG019610, P30 AG013846, P30 AG062428-01, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, U01AG016976, U24AG041689]
- Cohorts for Heart and Aging Research in Genomic Epidemiology (CHAR GE) - NIA [R01 AG033193]
- National Heart, Lung, and Blood Institute (NHLBI)
- National Institute of Health (NIH)
- Adult Changes in Thought (ACT) [UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657]
- Alzheimer's Disease Centers (ADC) [P30 AG019610, P30 AG013846, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P50 AG005134, P50 AG016574, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161]
- The Alzheimer's Disease Centers (ADC) [P50 AG047366, P30 AG010129, P50 AG016573, P50 AG016570, P50 AG005131, P50 AG023501, P30 AG035982, P30 AG028383, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG033514, P50 AG005681, P50 AG047270]
- Chicago Health and Aging Project (CHAP) [R01 AG11101, RC4 AG039085, K23 AG030944]
- Indianapolis Ibadan [P30 AG010133, R01 AG009956]
- Memory and Aging Project (MAP) [R01 AG17917]
- Mayo Clinic (MAYO) [P50 AG016574, (R01 AG032990, U01 AG046139, R01 NS080820, RF1 AG051504]
- Mayo Parkinson's Disease controls [NS039764, NS071674, 5RC2HG005605]
- University of Miami [R01 AG027944, R01 AG028786, R01 AG019085, IIRG09133827, A2011048]
- Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study (MIRAGE) [R01 AG09029, R01 AG025259]
- National Cell Repository for Alzheimer's Disease (NCRAD) [U24 AG21886]
- National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA-LOAD) [R01 AG041797]
- Religious Orders Study (ROS) [P30 AG10161, R01 AG15819]
- Darrell K Royal Texas Alzheimer's Initiative
- Vanderbilt University/Case Western Reserve University (VAN/CWRU) [R01 AG027944, R01 AG028786, R01AG019757, R01 AG021547, P01 NS026630]
- Washington Heights-Inwood Columbia Aging Project (WHICAP) [RF1 AG054023]
- University of Washington Families (VA Research Merit Grant) [NIA: P50AG005136, R01AG041797, NINDS: R01NS069719]
- Columbia University Hispanic Estudio Familiar de Influencia Genetica de Alzheimer (EFIGA) [RF1 AG015473]
- Wellcome Trust
- Medical Research Council
- Canadian Institutes of Health Research
- Genetic Differences (GD) [R01 AG007584]
- National Heart, Lung, and Blood Institute (NHLBI) [HL105756, RC2HL102419]
- National Institute on Aging (NIA) R01 grant [AG033193]
- Austrian Science Fond (FWF) [P20545-P05, P13180]
- Medical University of Graz
- Austrian Science Fund (FWF) [I904]
- EU Joint Programme -Neurodegenerative Disease Research (JPND)
- Steiermarkische Krankenanstalten Gesellschaft
- Austrian Research Promotion agency (FFG) [827462]
- Austrian National Bank (Anniversary Fund) [15435]
- NHLBI [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01-HL70825, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, U01HL130114, N01-HC-25195, HHSN268201500001I]
- National Institute of Neurological Disorders and Stroke (NINDS)
- NIND S [R01 NS017950]
- European Commission FP6 STRP grant [018947 (LSHG-CT-2006-01947)]
- European Community's Seventh Framework Programme (FP7/2007-2013)/grant by the European Commission under the programme Quality of Life and Management of the Living Resources of 5th Framework Programme [HEALTH-F4-2007-201413, QLG2-CT-2002-01254]
- Netherlands Organization for Scientific Research
- Russian Foundation for Basic Research (NWO-RFBR) [047.017.043]
- Erasmus Medical Center, Rotterdam
- Erasmus University, Rotterdam
- Netherlands Organization for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- municipality of Rotterdam
- Netherlands Organization of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]
- Genetic Laboratory of the Department of Internal Medicine
- Erasmus MC
- Research Institute for Diseases in the Elderly [014-93-015]
- Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]
- Intramural Research Program of the National Institutes of Health, National Library of Medicine
- NIH
- NIA/NIH [U01 AG016976]
- The NIA [P50 AG005146, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P50 AG023501, P30 AG035982, P30 AG062421-01, P30 AG062422-01, P30 AG062429-01]
- The NIA [P30 AG028383, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG005681, P50 AG047270, P30 AG053760, P30 AG049638, P30 AG062715-01]
- [UF1AG047133]
- [U01AG049505]
- [U01AG049506]
- [U01AG049507]
- [U01AG049508]
- [U01AG052411]
- [U01AG052410]
- [U01 AG052409]
- Marie Curie Actions (MSCA) [890650] Funding Source: Marie Curie Actions (MSCA)
Ask authors/readers for more resources
Background Many Alzheimer's disease genetic association studies do not properly account for age, hindering variant discovery. By modeling variable AD risk across age, significant statistical power gains can be achieved. Our novel AD-age score and Cox regression technique led to the discovery and replication of novel AD-associated variants.
Background Many Alzheimer's disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery. Methods Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases). Results Modeling variable AD risk across age results in 5-10% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3, and TAOK2 genes. Conclusion Our AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.
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