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

Publication ,  Journal Article
Naj, AC; Jun, G; Reitz, C; Kunkle, BW; Perry, W; Park, YS; Beecham, GW; Rajbhandary, RA; Hamilton-Nelson, KL; Wang, L-S; Kauwe, JSK; Myers, AJ ...
Published in: JAMA Neurol
November 2014

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.

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Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

November 2014

Volume

71

Issue

11

Start / End Page

1394 / 1404

Location

United States

Related Subject Headings

  • Risk Factors
  • Prospective Studies
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genetic Loci
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Naj, A. C., Jun, G., Reitz, C., Kunkle, B. W., Perry, W., Park, Y. S., … Yu, L. (2014). Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study. JAMA Neurol, 71(11), 1394–1404. https://doi.org/10.1001/jamaneurol.2014.1491
Naj, Adam C., Gyungah Jun, Christiane Reitz, Brian W. Kunkle, William Perry, Yo Son Park, Gary W. Beecham, et al. “Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.JAMA Neurol 71, no. 11 (November 2014): 1394–1404. https://doi.org/10.1001/jamaneurol.2014.1491.
Naj AC, Jun G, Reitz C, Kunkle BW, Perry W, Park YS, et al. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study. JAMA Neurol. 2014 Nov;71(11):1394–404.
Naj, Adam C., et al. “Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.JAMA Neurol, vol. 71, no. 11, Nov. 2014, pp. 1394–404. Pubmed, doi:10.1001/jamaneurol.2014.1491.
Naj AC, Jun G, Reitz C, Kunkle BW, Perry W, Park YS, Beecham GW, Rajbhandary RA, Hamilton-Nelson KL, Wang L-S, Kauwe JSK, Huentelman MJ, Myers AJ, Bird TD, Boeve BF, Baldwin CT, Jarvik GP, Crane PK, Rogaeva E, Barmada MM, Demirci FY, 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, Kamboh MI, 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, Alzheimer Disease Genetics Consortium, 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 JP, Weintraub S, Welsh-Bohmer KA, Williamson J, Wishnek S, Woltjer RL, Wright CB, Younkin SG, Yu C-E, Yu L. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study. JAMA Neurol. 2014 Nov;71(11):1394–1404.

Published In

JAMA Neurol

DOI

EISSN

2168-6157

Publication Date

November 2014

Volume

71

Issue

11

Start / End Page

1394 / 1404

Location

United States

Related Subject Headings

  • Risk Factors
  • Prospective Studies
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Genetic Loci