Format

Send to

Choose Destination
JAMA Neurol. 2014 Nov;71(11):1394-404. doi: 10.1001/jamaneurol.2014.1491.

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

Naj AC1, Jun G2, Reitz C3, Kunkle BW4, Perry W4, Park YS5, Beecham GW6, Rajbhandary RA4, Hamilton-Nelson KL4, Wang LS7, Kauwe JS8, Huentelman MJ9, Myers AJ10, Bird TD11, Boeve BF12, Baldwin CT13, Jarvik GP14, Crane PK15, Rogaeva E16, Barmada MM17, Demirci FY17, Cruchaga C18, Kramer PL19, Ertekin-Taner N20, Hardy J21, Graff-Radford NR20, Green RC22, Larson EB23, St George-Hyslop PH24, Buxbaum JD25, Evans DA26, Schneider JA27, Lunetta KL28, Kamboh MI29, Saykin AJ30, Reiman EM31, De Jager PL32, Bennett DA33, Morris JC34, Montine TJ35, Goate AM18, Blacker D36, Tsuang DW37, Hakonarson H38, Kukull WA39, Foroud TM40, Martin ER6, Haines JL41, Mayeux RP42, Farrer LA43, Schellenberg GD7, Pericak-Vance MA6; Alzheimer Disease Genetics Consortium, Albert MS44, Albin RL45, Apostolova LG46, Arnold SE47, Barber R48, Barnes LL49, Beach TG50, Becker JT51, Beekly D52, Bigio EH53, Bowen JD54, Boxer A55, Burke JR56, Cairns NJ57, Cantwell LB7, Cao C58, Carlson CS59, Carney RM10, Carrasquillo MM60, Carroll SL61, Chui HC62, Clark DG63, Corneveaux J9, Cribbs DH64, Crocco EA10, DeCarli C65, DeKosky ST66, Dick M67, Dickson DW60, Duara R68, Faber KM40, Fallon KB61, Farlow MR69, Ferris S70, Frosch MP71, Galasko DR72, Ganguli M73, Gearing M74, Geschwind DH75, Ghetti B76, Gilbert JR6, Glass JD77, Growdon JH78, Hamilton RL79, Harrell LE63, Head E80, Honig LS81, Hulette CM82, Hyman BT78, Jicha GA83, Jin LW84, Karydas A55, Kaye JA85, Kim R86, Koo EH72, Kowall NW87, Kramer JH88, LaFerla FM89, Lah JJ77, Leverenz JB35, Levey AI77, Li G90, Lieberman AP91, Lin CF7, Lopez OL92, Lyketsos CG93, Mack WJ94, Martiniuk F95, Mash DC96, Masliah E97, McCormick WC15, McCurry SM98, McDavid AN59, McKee AC87, Mesulam M99, Miller BL55, Miller CA100, Miller JW84, Murrell JR101, Olichney JM65, Pankratz VS102, Parisi JE103, Paulson HL104, Peskind E90, Petersen RC12, Pierce A64, Poon WW67, Potter H58, Quinn JF105, Raj A58, Raskind M90, Reisberg B106, Ringman JM46, Roberson ED63, Rosen HJ55, Rosenberg RN107, Sano M108, Schneider LS109, Seeley WW55, Smith AG58, Sonnen JA35, Spina S76, Stern RA110, Tanzi RE78, Thornton-Wells TA111, Trojanowski JQ7, Troncoso JC112, Valladares O7, Van Deerlin VM7, Van Eldik LJ113, Vardarajan BN114, Vinters HV115, Vonsattel JP116, Weintraub S117, Welsh-Bohmer KA118, Williamson J81, Wishnek S4, Woltjer RL119, Wright CB120, Younkin SG60, Yu CE15, Yu L121.

Author information

1
Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia.
2
Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts4Department of Biostatistics, Boston University, Boston, Massachusetts5Department of Ophthalmology, Boston University, Boston, Massachusetts.
3
Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York7Gertrude H. Sergievsky Center, Columbia University, New York, New York8Department of Neurology, Columbia University, New York, New.
4
John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.
5
The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida.
6
John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida9The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida.
7
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
8
Department of Biology, Brigham Young University, Provo, Utah.
9
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
10
Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, Florida.
11
Department of Neurology, University of Washington, Seattle15Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
12
Department of Neurology, Mayo Clinic, Rochester, Minnesota.
13
Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts.
14
Department of Genome Sciences, University of Washington, Seattle18Division of Medical Genetics, Department of Medicine, University of Washington, Seattle.
15
Department of Medicine, University of Washington, Seattle.
16
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.
17
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
18
Department of Psychiatry and Hope Center Program on Protein Aggregation and Neurodegeneration, School of Medicine, Washington University in St Louis, St Louis, Missouri.
19
Department of Neurology, Oregon Health & Science University, Portland24Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland.
20
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida26Department of Neurology, Mayo Clinic, Jacksonville, Florida.
21
Institute of Neurology, University College London, London, England.
22
Division of Genetics, Department of Medicine, and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
23
Department of Medicine, University of Washington, Seattle29Group Health Research Institute, Group Health Cooperative, Seattle, Washington.
24
Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada30Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, England.
25
Department of Neuroscience, Mount Sinai School of Medicine, New York, New York32Department of Psychiatry, Mount Sinai School of Medicine, New York, New York33Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York.
26
Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.
27
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois36Neuropathology, Department of Pathology, Rush University Medical Center, Chicago, Illinois.
28
Department of Biostatistics, Boston University, Boston, Massachusetts.
29
Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania37Alheimer Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
30
Department of Medical and Molecular Genetics, Indiana University, Indianapolis39Department of Radiology and Imaging Sciences, Indiana University, Indianapolis.
31
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona40Arizona Alzheimer's Consortium, Phoenix41Department of Psychiatry, University of Arizona, Phoenix42Banner Alzheimer's Institute, Phoenix, Arizona.
32
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology and Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts44Program in Medical and Population Genetics, Broad Ins.
33
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois45Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
34
Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri47Department of Neurology, Washington University in St Louis, St Louis, Missouri.
35
Department of Pathology, University of Washington, Seattle.
36
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts50Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston.
37
Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington51Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle.
38
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
39
Department of Epidemiology, University of Washington, Seattle.
40
Department of Medical and Molecular Genetics, Indiana University, Indianapolis.
41
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee55Vanderbilit Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee.
42
Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York57Gertrude H. Sergievsky Center, Columbia University, New York, New York58Department of Neurology, Columbia University, New York, New York.
43
Genetics Program, Department of Medicine, Boston University, Boston, Massachusetts4Department of Biostatistics, Boston University, Boston, Massachusetts5Department of Ophthalmology, Boston University, Boston, Massachusetts59Department of Epidemiology, Bos.
44
Department of Neurology, Johns Hopkins University, Baltimore, Maryland.
45
Department of Neurology, University of Michigan, Ann Arbor63Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, Michigan64Michigan Alzheimer Disease Center, Ann Arbor.
46
Department of Neurology, University of California Los Angeles, Los Angeles.
47
Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia.
48
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth.
49
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois68Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois.
50
Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, Arizona.
51
Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
52
National Alzheimer's Coordinating Center, University of Washington, Seattle.
53
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois73Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois.
54
Swedish Medical Center, Seattle, Washington.
55
Department of Neurology, University of California San Francisco, San Francisco.
56
Department of Medicine, Duke University, Durham, North Carolina.
57
Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri.
58
USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa.
59
Fred Hutchinson Cancer Research Center, Seattle, Washington.
60
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida.
61
Department of Pathology, University of Alabama at Birmingham, Birmingham.
62
Department of Neurology, University of Southern California, Los Angeles.
63
Department of Neurology, University of Alabama at Birmingham, Birmingham.
64
Department of Neurology, University of California Irvine, Irvine.
65
Department of Neurology, University of California Davis, Sacramento.
66
University of Virginia School of Medicine, Charlottesville.
67
Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine.
68
Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida.
69
Department of Neurology, Indiana University, Indianapolis.
70
Department of Psychiatry, New York University, New York.
71
C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown.
72
Department of Neurosciences, University of California San Diego, La Jolla.
73
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
74
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia93Emory Alzheimer's Disease Center, Emory University, Atlanta, Georgia.
75
Neurogenetics Program, University of California Los Angeles, Los Angeles.
76
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis.
77
Department of Neurology, Emory University, Atlanta, Georgia.
78
Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston.
79
Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, Pennsylvania.
80
Sanders-Brown Center on Aging, Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington.
81
Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, New York.
82
Department of Pathology, Duke University, Durham, North Carolina.
83
Sanders-Brown Center on Aging, Department Neurology, University of Kentucky, Lexington.
84
Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento.
85
Department of Neurology, Oregon Health & Science University, Portland103Department of Neurology, Portland Veterans Affairs Medical Center, Portland, Oregon.
86
Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine.
87
Department of Neurology, Boston University, Boston, Massachusetts105Department of Pathology, Boston University, Boston, Massachusetts.
88
Department of Neuropsychology, University of California San Francisco, San Francisco.
89
Department of Neurobiology and Behavior, University of California Irvine, Irvine.
90
Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle.
91
Department of Pathology, University of Michigan, Ann Arbor.
92
Alheimer Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
93
Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland.
94
Department of Preventive Medicine, University of Southern California, Los Angeles.
95
Department of Medicine - Pulmonary, New York University, New York.
96
Department of Neurology, University of Miami, Miami, Florida.
97
Department of Neurosciences, University of California San Diego, La Jolla113Department of Pathology, University of California San Diego, La Jolla.
98
School of Nursing Northwest Research Group on Aging, University of Washington, Seattle.
99
Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois115Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
100
Department of Pathology, University of Southern California, Los Angeles.
101
Department of Medical and Molecular Genetics, Indiana University, Indianapolis95Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis.
102
Department of Biostatistics, Mayo Clinic, Rochester, Minnesota.
103
Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota119Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
104
Department of Neurology, University of Michigan, Ann Arbor.
105
Department of Neurology, Oregon Health & Science University, Portland.
106
Department of Psychiatry, New York University, New York120Alzheimer's Disease Center, New York University, New York.
107
Department of Neurology, University of Texas Southwestern, Dallas.
108
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York.
109
Department of Neurology, University of Southern California, Los Angeles122Department of Psychiatry, University of Southern California, Los Angeles.
110
Department of Neurology, Boston University, Boston, Massachusetts.
111
Vanderbilit Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee.
112
Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
113
Sanders-Brown Center on Aging, Department of Anatomy and Neurobiology, University of Kentucky, Lexington.
114
Department of Neurology, Columbia University, New York, New York.
115
Department of Neurology, University of California Los Angeles, Los Angeles125Department of Pathology & Laboratory Medicine, University of California Los Angeles, Los Angeles.
116
Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, New York.
117
Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Chicago, Illinois127Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
118
Department of Medicine, Duke University, Durham, North Carolina128Department of Psychiatry & Behavioral Sciences, Duke University, Durham, North Carolina.
119
Department of Pathology, Oregon Health & Science University, Portland.
120
Evelyn F. McKnight Brain Institute, Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida.
121
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois.

Erratum in

  • JAMA Neurol. 2014 Nov;71(11):1457.

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.

PMID:
25199842
PMCID:
PMC4314944
DOI:
10.1001/jamaneurol.2014.1491
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Grant support

Publication types

MeSH terms

Grant support

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center