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Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

TitleEffects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.
Publication TypeJournal Article
Year of Publication2014
AuthorsNaj, AC, Jun, G, Reitz, C, Kunkle, BW, Perry, W, Park, YSon, Beecham, GW, Rajbhandary, RA, Hamilton-Nelson, KL, San Wang, L-, Kauwe, JSK, Huentelman, MJ, Myers, AJ, Bird, TD, Boeve, BF, Baldwin, CT, Jarvik, GP, Crane, PK, Rogaeva, E, M Barmada, M, F Demirci, Y, Cruchaga, C, Kramer, PL, Ertekin-Taner, N, Hardy, J, Graff-Radford, NR, Green, RC, Larson, EB, St George-Hyslop, PH, Buxbaum, JD, Evans, DA, Schneider, JA, Lunetta, KL, M Kamboh, I, Saykin, AJ, Reiman, EM, De Jager, PL, Bennett, DA, Morris, JC, Montine, TJ, Goate, AM, Blacker, D, Tsuang, DW, Hakonarson, H, Kukull, WA, Foroud, TM, Martin, ER, Haines, JL, Mayeux, RP, Farrer, LA, Schellenberg, GD, Pericak-Vance, MA, Albert, MS, Albin, RL, Apostolova, LG, Arnold, SE, Barber, R, Barnes, LL, Beach, TG, Becker, JT, Beekly, D, Bigio, EH, Bowen, JD, Boxer, A, Burke, JR, Cairns, NJ, Cantwell, LB, Cao, C, Carlson, CS, Carney, RM, Carrasquillo, MM, Carroll, SL, Chui, HC, Clark, DG, Corneveaux, J, Cribbs, DH, Crocco, EA, DeCarli, C, DeKosky, ST, Dick, M, Dickson, DW, Duara, R, Faber, KM, Fallon, KB, Farlow, MR, Ferris, S, Frosch, MP, Galasko, DR, Ganguli, M, Gearing, M, Geschwind, DH, Ghetti, B, Gilbert, JR, Glass, JD, Growdon, JH, Hamilton, RL, Harrell, LE, Head, E, Honig, LS, Hulette, CM, Hyman, BT, Jicha, GA, Jin, L-W, Karydas, A, Kaye, JA, Kim, R, Koo, EH, Kowall, NW, Kramer, JH, LaFerla, FM, Lah, JJ, Leverenz, JB, Levey, AI, Li, G, Lieberman, AP, Lin, C-F, Lopez, OL, Lyketsos, CG, Mack, WJ, Martiniuk, F, Mash, DC, Masliah, E, McCormick, WC, McCurry, SM, McDavid, AN, McKee, AC, Mesulam, M, Miller, BL, Miller, CA, Miller, JW, Murrell, JR, Olichney, JM, Pankratz, VS, Parisi, JE, Paulson, HL, Peskind, E, Petersen, RC, Pierce, A, Poon, WW, Potter, H, Quinn, JF, Raj, A, Raskind, M, Reisberg, B, Ringman, JM, Roberson, ED, Rosen, HJ, Rosenberg, RN, Sano, M, Schneider, LS, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Tanzi, RE, Thornton-Wells, TA, Trojanowski, JQ, Troncoso, JC, Valladares, O, Van Deerlin, VM, Van Eldik, LJ, Vardarajan, BN, Vinters, HV, Vonsattel, JPaul, Weintraub, S, Welsh-Bohmer, KA, Williamson, J, Wishnek, S, Woltjer, RL, Wright, CB, Younkin, SG, Yu, C-E, Yu, L
Corporate AuthorsAlzheimer Disease Genetics Consortium
JournalJAMA Neurol
Volume71
Issue11
Pagination1394-404
Date Published2014 Nov
ISSN2168-6157
KeywordsAdult, Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors
Abstract

IMPORTANCE: Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.

OBJECTIVES: To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium.

DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.

MAIN OUTCOMES AND MEASURES: Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria.

RESULTS: Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P < .005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242).

CONCLUSIONS AND RELEVANCE: We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

DOI10.1001/jamaneurol.2014.1491
Alternate JournalJAMA Neurol
PubMed ID25199842
PubMed Central IDPMC4314944
Grant ListP30 AG013854 / AG / NIA NIH HHS / United States
P50 MH060451 / MH / NIMH NIH HHS / United States
K01 AG030514 / AG / NIA NIH HHS / United States
MH60451 / MH / NIMH NIH HHS / United States
R01 AG022374 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
R01 AG17917 / AG / NIA NIH HHS / United States
M01 RR000096 / RR / NCRR NIH HHS / United States
RC2 AG036528 / AG / NIA NIH HHS / United States
P30 AG028377 / AG / NIA NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
P50 AG008671 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
U01 AG10483 / AG / NIA NIH HHS / United States
R01 AG035137 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
P50 AG005128 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 AG031581 / AG / NIA NIH HHS / United States
P30AG10133 / AG / NIA NIH HHS / United States
G-0907 / / Parkinson's UK / United Kingdom
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
P50 AG016577 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
R01 AG013616 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
UL1 RR029893 / RR / NCRR NIH HHS / United States
P50 AG016575 / AG / NIA NIH HHS / United States
/ / Medical Research Council / United Kingdom
AG05128 / AG / NIA NIH HHS / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P50 NS039764 / NS / NINDS NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
RC2 AG036502 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
1R01AG035137 / AG / NIA NIH HHS / United States
R01 MH080295 / MH / NIMH NIH HHS / United States
P01 AG03991 / AG / NIA NIH HHS / United States
R01 AG026390 / AG / NIA NIH HHS / United States
RC2 AG036535 / AG / NIA NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
AG010491 / AG / NIA NIH HHS / United States
P30 AG08051 / AG / NIA NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
NS39764 / NS / NINDS NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
089703 / / Wellcome Trust / United Kingdom
AG041718 / AG / NIA NIH HHS / United States
R01 AG012101 / AG / NIA NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
5R01AG022374 / AG / NIA NIH HHS / United States
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P50 AG016570 / AG / NIA NIH HHS / United States
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P30 AG008017 / AG / NIA NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
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P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
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P30 ES013508 / ES / NIEHS NIH HHS / United States
UO1 AG06781 / AG / NIA NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
AG025688 / AG / NIA NIH HHS / United States
AG027944 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
R37 AG015473 / AG / NIA NIH HHS / United States
U24 AG026395 / AG / NIA NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
R01 CA129769 / CA / NCI NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
U01 AG010483 / AG / NIA NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R01 AG041797 / AG / NIA NIH HHS / United States
P50 AG005144 / AG / NIA NIH HHS / United States
P01 AG010491 / AG / NIA NIH HHS / United States
R01 AG034504 / AG / NIA NIH HHS / United States
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5R01AG012101 / AG / NIA NIH HHS / United States
R01 AG030653 / AG / NIA NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
AG034504 / AG / NIA NIH HHS / United States
R01 AG30146 / AG / NIA NIH HHS / United States
R01 AG017173 / AG / NIA NIH HHS / United States
R01 AG025259 / AG / NIA NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
P50 AG016582 / AG / NIA NIH HHS / United States
R01 AG041718 / AG / NIA NIH HHS / United States
5R01AG013616 / AG / NIA NIH HHS / United States
P50 AG016576 / AG / NIA NIH HHS / United States
100140 / / Wellcome Trust / United Kingdom
P30 AG028383 / AG / NIA NIH HHS / United States
AG019757 / AG / NIA NIH HHS / United States
MO1RR00096 / RR / NCRR NIH HHS / United States
R01 AG026916 / AG / NIA NIH HHS / United States
081864 / / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom
R01 NS059873 / NS / NINDS NIH HHS / United States
HG004610 / HG / NHGRI NIH HHS / United States
AG021547 / AG / NIA NIH HHS / United States
UL1RR02777 / RR / NCRR NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States