Using CSF biomarkers to replicate genetic associations in Alzheimer’s disease.

Schott JM; ADNI Investigators.

Collaborators: Abdi H, Abdul Hadi N, Abdulkadir A, Abdullah A, Achuthan A, Adluru
N, Aggarwal N, Aghajanian J, Agyemang A, Ahdidan J, Ahmad D, Ahmed F, Ahmed S,
Ahmed F, Akbarifar R, Akhondi-Asl A, Aksu Y, Alcauter S, Alexander D, Alin A,
Alshuft H, Alvarez-Linera J, Amin-Mansour A, Anderson J, Anderson D, Andorn A,
Andrews KA, Ang A, Angersbach S, Ansarian R, Abhishek AM, Appannah A, Arfanakis
K, Arif M, Armentrout S, Arrighi M, Arumughababu SV, Arunagiri V, Ashe-McNalley
C, Ashford W, Le Page A, Avants B, Aviv R, Avula R, Ayache N, Ayan-Oshodi M,
Ayhan M, Sumana BV, Bach Cuadra M, Bagepally B, Bahar Fuchs A, Baird G, Baker S,
Baker J, Bakker A, Baladandayuthapani V, Barbash S, Barillot C, Barker W,
Bartlett J, Bartley M, Baruchin A, Battaglini I, Bauer C, Bayley P, Becker J,
Beckett L, Bednar M, Bedner A, Beg MF, Bekris L, Belaroussi B, Belloch V,
Belmokhtar N, Ben Ahmed O, Bender JD, Bendib MM, Benois-Pineau J, Bhagchandani S,
Bienkowska K, Biffi A, Bilgin G, Billing B, Bishop C, Bittner D, Björnsdotter M,
Black S, Bloss C, Blunck Y, Bocti C, Bohorquez A, Bokde A, Boone J, Boord P, Boot
B, Borrie M, Boudousq V, Bourgeat P, Bouttout H, Bowman D, Bowman G, Boxer A,
Bozoki A, Bracard S, Braskie M, Breitner J, Bresell A, Brewer J, Brickhouse M,
Brickman A, Britschgi M, Broadbent S, Brock B, Brown M, Buchsbaum M, Buerger K,
Bunce D, Burnham S, Burns J, Burzykowski T, Butler T, Cabeza R, Cabral G, Caffery
T, Cai Z, Callhoff J, Calvini P, Campbell N, Carbotti A, Carle A, Carmasin J,
Carmasin J, Carpenter J, Carvalho J, Casanova R, Casey A, Cash D, Cash D, Cataldo
R, Cella M, Chadaga A, Chakravarty M, Chang I, Chao L, Chaovalitwongse WA, Charil
A, Chatterjee S, Che-Wei C, Chen K, Chen G, Chen S, Chen R, Chen IJ, Chen JT,
Chen C, Chen J, Chen Q, Chen H, Cheng WC, Cheng X, Cheng B, Cherkas Y, Chertkow
H, Chiang G, Chiao P, chibane MB, Chida N, Chin S, Ching C, Chisholm J, Cho SS,
Cho C, Choe J, Choubey S, Chowbina S, Ciocia G, Clark D, Clarkson M, Clerc S,
Climer S, Clunie D, Coen M, Coimbra A, Compton D, Conover J, Coubard O, Coulin S,
Coulson E, Cover KS, Crans G, Crawford K, Croop R, Crum W, Cui Y, Da L, Dai Y,
Daiello L, Daiello L, Darkner S, Darnell R, Davatzikos C, DavidPrakash B,
Davidson C, Davis M, de Bruijne M, DeCarli C, Decker S, DeDuck K, Dehghan H,
Della Rosa PA, DeOrchis V, Dépy Carron D, Desikan R, Desjardins B,
deToledo-Morrell L, Devanand D, Devanarayan V, Devier D, Devous M, Di X, Di J,
Diaz-Arrastia R, Diciotti S, Dickerson B, Dickie DA, Dickinson P, Dill V, Ding X,
Dinov I, Dobosh B, Dobson H, Dodge H, Dolman A, Dolmo BC, Dong W, Donohue M, Dore
V, Dorflinger E, Dowling M, Dowling M, Dragicevic N, Dricot L, Duchesne S, Duff
K, Dukart J, Durazzo T, Dutta J, DWors R, Egefjord L, Elcoroaristizabal X,
Emahazion T, Emahazion T, Endres C, Epstein N, Ereshefsky L, Eskildsen S,
Espinosa A, Esposito M, Ewers M, Ewers M, Falcone G, Fan J, Fan Y, Fan Z, Fang Z,
Farahibozorg S, Farahmandpoor Z, Farb N, Fardo D, Farias S, Farnum M, Farrer L,
Fatke B, Faux N, Favilla S, Fazlollahi A, Feldman B, Félix Z, Fennema-Notestine
C, Fernandes M, Fernandez S, Fernandez E, Ferrari R, Ferrer E, Fetterman B,
Figurski M, Fillit H, Finch S, Finger E, Fiot JB, Flenniken D, Fletcher E, Flores
C, Flynn Longmire C, Focke N, Forsythe A, Fox A, Fox A, Foxhall S, Franko E,
Frederick B, Freeman R, Freire R, Friedrich CM, Friesenhahn M, Frisoni G,
Fritzsche K, Fujiwara K, Fullerton T, Gaffour Y, Galbraith S, Galvin B, Gamst A,
Gan K, Gao S, Garcia G, Garg G, Gaser C, Gastineau E, Gattaz W, Gaubert M,
Gaudreau A, Gauthier S, Gavidia G, Gemme G, Geraci J, Gholipour F, Ghosh S, Ghosh
D, Gieschke R, Gill R, Gillespie W, Gispert JD, Gitelman D, Gkontra X, Gleason C,
Glymour MM, Godbey M, Gold B, Goldberg T, Goldman J, Gomar J, Gonzalez-Beltran A,
Gore C, Gorriz JM, Goto M, Gou JI, Gradkowski W, Grasela T, Gray K, Gregory E,
Greicius M, Grill J, Grolmusz V, Gross A, Gross A, Grydeland H, Guignot I,
Guillaume B, Guilloux F, Guo LH, Guo H, Gupta V, Gurney G, Guyot J, Haas M,
Habeck C, Habte F, Haight T, Hajaj C, Hajiesmaeili M, Hajjar I, Hammarstrom P,
Han Z, Han D, Hanna Y, Hanna-Pladdy B, Hao Y, Hardy P, Harrison J, Harvey D,
Harvey D, Hassanzadeh O, Hayashi T, Haynes JD, He Y, He H, Head D, Heckemann R,
Heegaard N, Heidarieh SM, Heidebrink J, Hellyer P, Helwig M, Henderson D, Herholz
K, Hess C, Hill S, Hisaka A, Ho Ming AY, Hobart J, Hochstetler H, Hofer S,
Hoffman J, Holder D, Hollingworth P, Holmes R, Hong L, Hong H, Hong Q, Honigberg
L, Hoogenraad F, Hope T, Hot T, Hsieh H, Hsu A, Hu M, Hu W, Hu X, Hu C, Hua WY,
Huang X, Huang CJ, Huang Y, Huang J, Huang Z, Huentelman M, Huppertz HJ, Hurt S,
Hussain M, Hutchins J, Hwang S, Hyun J, Ifeachor E, Iglesias M, Ikari Y,
Ikonomidou V, Iman A, Imani F, Inlow M, Inoue L, Insel P, Irizarry M, Ishibashi
T, Ishii K, Ito K, Iwatsubo T, Jacks A, Jacobson M, Jacqmin P, Jaeger M, Jaeger
P, Jagger R, Jagust W, Janousova E, Jara H, Jedynak B, Jefferson A, Jenq J, Jiang
T, Jiang C, Jiao Y, Jiaolong Q, Jin K, Johnson S, Johnson J, Johnson K, Jones R,
Jones G, Jones M, Joshi R, Joshi S, Joshi A, Jouvent E, Juengling F, Jung W,
Junjie Z, Muthamma KG, Kabilan M, Kairui Z, Kaludov N, Kam HJ, Kamakura V, Kamer
A, Kanakaraj S, Kanchev V, Kaneko T, Kaneta T, Kang JH, Kang H, Kang J,
Karantzoulis S, Katz I, Kaushik SS, Kauwe J, Kauwe J, Kawashima S, Kaye E, Kazemi
S, Ke H, Kelleher T, Kennedy R, Keogh B, Kerchner G, Kerr D, Keshava N, Khalil A,
Khondker Z, Khondker Z, Kiddle S, Kihara T, Killeen N, Killiany R, Kim JH, Kim
JH, Kim D, Kim D, Kimberg D, King R, Kingery L, Kirby J, Kirsch W, Klein G,
Klimas M, Kline R, Klopfenstein E, Koen J, Koenig L, Koikkalainen J, Kokomoor A,
Kong X, Kong X, Koppel J, Korolev I, Kotamarti RM, Krahnke T, Krams M, Kraybill
M, Kuceyeski A, Kuceyeski A, Kumar V, Kumar Roy P, Kuo J, Kyrtsos CR, Labib V,
Labrish C, Lai S, Lakatos A, Lalonde F, Lam SC, Landau S, Lane B, Langbaum J,
Langford D, Lanius V, Lasch S, Latella M, Lau H, Leatherday C, Lebedev A, Lee S,
Lee Ja, Lee D, Lee G, Legal S, Lei H, Lemaitre H, Lenfant P, Leonards U, Leong J,
Leoutsakos JM, Leung YY, Leung K, Levey A, Li M, Li L, Li J, Li Y, Li M, Li J, Li
Y, Li Y, Li J, Li W, Li X, Li R, Li Q, Liang K, Liang P, Liao S, Liao W, Liaquat
S, Liaw C, Liberman G, Lilley P, Lim JS, Lin F, Lin X, Linninger A, Liu S, Liu X,
Liu G, Liu Y, Liu Y, Liu T, Liu L, Liu M, Liu T, Liu W, Liu C, Liu T, Liu Y, Liu
X, Liu T, Liu H, Liu D, Liu X, Liu Y, Llido J, Lo R, Lobach I, Lobanov V,
Lockhart A, Long X, Long Z, Long M, Looi J, Lu Y, Lu PH, Lu H, Lucena N, Luis J,
Lukas C, Lukic A, Luo X, Luo S, Luo L, Luo W, Luo X, Ma SL, Ma SM, Mackin S, Mada
M, Madabhushi A, Madeira S, Magland J, Mahanta MS, Maikusa N, Maldjian J, Malpas
C, Mandal I, Mandal P, Mang A, Mangin JF, Manjon J, Mantri N, Manzour A, Marcus
D, Margolin R, Marrett S, Marshall G, Martinez Gonzalez A, Martinez Torteya A,
Martins R, Mather M, Mathis C, Matoug S, Mattei P, Matthews D, Mattis P,
McCarroll S, McConathy J, McDonald C, McEvoy L, McGeown W, McGinnis S, McGonigle
J, Randal McIntosh A, McIntyre J, McLaren D, McMillan C, McQuail J, Meadowcroft
M, Meda S, Melie-Garcia L, Melrose R, Mendelson A, Mendez M, Menendez E, Meng M,
Meng M, Meredith J, Meyer M, Meyer C, Mez J, Mickael G, Mikula M, Miller M,
Millikin C, Mintun M, Mitchell M, Mitsis E, Mon A, Moore D, Morabito FC, Birgani
PM, Moratal D, Morimoto B, Morris J, Morris J, Mortamet B, Moscato P,
Mourao-Miranda J, Mueller S, Mueller K, Mukherjee S, Mukund N, Mulder E, Mungas
D, Munir K, Murayama S, Murphy K, Sairam N, Nagata K, Nair A, Narayana P,
Nasrabadi S, Nativio R, Nazeri A, Nejad L, Nekooei S, Nemeth I, Nencka A,
Nettiksimmons J, Neu S, Ng YB, Nguyen N, Nguyen H, Nichols T, Niecko T, Nielsen
C, Niethammer M, Nishio T, Noda A, Nordstrom M, Noshad S, Notomi K, Novak N,
Nutakki GC, O’Charoen S, Obisesan T, Oh J, Okonkwo O, Rikkert MO, Oliveira J,
Oliveira A, Oliver R, Olmos S, Oltra J, Ong R, Osadebey M, Osadebey M,
Ostrowitzki S, Ovando Vazquez CM, Overholser R, Anishiya P, Chitra PK, Pa J, Pa
J, Palanisamy P, Pan S, Pan G, Pan Z, Pande Y, Pardo J, Pardoe H, Park H, Park L,
Park J, Park S, Parker C, Patel Y, Patil M, Patil A, Pawlak M, Payoux P, Pennec
X, Pereira F, Perlbarg V, Perneczky R, Peters F, Petitti D, Petrella J, Petrou M,
Peyrat JM, Pham Ngoc PT, Phillips J, Phillips N, Pian WT, Pierson R, Piovezan M,
Pipitone J, Pirraglia E, Planes X, Podhorski A, Poirier J, Pomara N, Popov V,
Poppenkv J, Potkin S, Potter G, Poulin S, Prastawa M, Prince J, Priya K,
Pruessner J, Qiu W, Qu A, Qualls CD, Quarg P, Quinlan J, Rabbia M, Rajagovindan
R, Rajeesh R, Ramadubramani V, Ramage A, Ramirez A, Randolph C, Rao A, Rao H,
Reed B, Reid A, Reilhac A, Reiner P, Reinsberger C, Reiss P, Ren J, Retico A,
Rhatigan L, Rhinn H, Rhoades E, Ribbens A, Richard E, Richards J, Richter M,
Riddle W, Ridgway G, Ringman J, Rizk-Jackson A, Rizzi M, Rodriguez N, Rodriguez
L, Rodriguez-Vieitez E, Rogalski E, Rojas Balderrama J, Rokicki J, Romero K,
Rosand J, Rosen O, Rostant O, Rousseau F, Roy M, Rubright J, Rucinski M, Ruiz A,
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Sakata M, Salama M, Salazar D, Saman S, Sanchez L, Sanders E, Sankar T, Santhamma
S, Sarwinda D, Sasaki T, Sasaya T, Sato H, Sattlecker M, Savio A, Saykin A,
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Sghedoni R, Shah JH, Shahbaba B, Shams S, Shankle W, Shattuck D, Shaw L, Shen J,
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A, Simpson D, Simpson I, Singh L, Singh N, Sinha N, Siuciak J, Sjögren N, Skinner
J, Skudlarski P, Smith M, Smith C, Snyder P, Soares H, Soldan A, Soldea O,
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Defining cases and controls on the basis of biomarkers rather than clinical
diagnosis may reduce sample sizes required for genetic studies. The aim of this
study was to assess whether characterizing case/control status on the basis of
cerebrospinal fluid (CSF) profile would increase power to replicate known genetic
associations for Alzheimer’s disease (AD). Independent of clinical diagnosis,
Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects with 2 CSF biomarkers
for AD (Aβ1-42 < 192 pg/mL and tau phosphorylated at threonine 181 (p-tau) > 23
pg/mL, “CSF-positive”) were compared with those without CSF evidence for AD
(Aβ1-42 > 192 pg/mL and 181-phosphorylated tau < 23 pg/mL, “CSF-negative”). Minor
allele frequency (MAF) and odds ratios (ORs) between these 2 groups were
calculated for 7 single-nucleotide polymorphisms (SNPs) of interest. Two hundred
thirty-two individuals were CSF-positive and 94 CSF-negative. There were no
differences in age (74.7 ± 7.2 vs. 75.0 ± 6.5 years, p = 0.7), but significant
differences in Mini Mental State Examination (MMSE) (25.9 ± 2.6 vs. 28.2 ± 1.7, p
< 0.001) between the CSF-positive and CSF-negative groups. Significant
differences in MAF (p < 0.05, uncorrected) were seen for CR1 (rs1408077; OR,
1.59; 95% confidence interval [CI], 1.01-2.49), PICALM (rs541458; OR, 0.68, 95%
CI, 0.47-0.98), TOMM40 (rs2075650; OR, 4.30; 95% CI, 2.61-7.06); and possession
of 1 or more APOE ε4 alleles (OR, 9.84; 95% CI, 5.48-17.67). These results
suggest that using biomarkers of AD pathology to define case and control status
may increase power in genetic association studies.

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