US 2003.017O678A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0170678A1 Tanzi et al. (43) Pub. Date: Sep. 11, 2003 (54) GENETIC MARKERS FOR ALZHEIMER'S Related U.S. Application Data DISEASE AND METHODS USING THE SAME (60) Provisional application No. 60/348,065, filed on Oct. (75) Inventors: Rudolph E. Tanzi, Hull, MA (US); 25, 2001. Provisional application No. 60/336,983, Kenneth David Becker, San Diego, CA filed on Nov. 2, 2001. (US); Gonul Velicelebi, San Diego, CA (US); Kathryn J. Elliott, San Diego, Publication Classification CA (US); Xin Wang, San Diego, CA (US); Lars Bertram, Brighton, MA (51) Int. C.7 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - C12O 1/68 (US); Aleister J. Saunders, (52) U.S. Cl. .................................................................. 435/6 Philadelphia, PA (US); Deborah Lynne Blacker, Newton, MA (US) (57) ABSTRACT Correspondence Address: HELLER EHRMAN WHITE & MCAULIFFE LLP Genetic markers associated with Alzheimer's disease are 4350 LA JOLLAVILLAGE DRIVE provided. Also provided are methods of determining the 7TH FLOOR presence or absence in a Subject of one or more polymor SAN DIEGO, CA 92122-1246 (US) phisms associated with Alzheimer's disease and methods of determining the level of risk for Alzheimer's disease in a (73) Assignee: Neurogenetics, Inc. Subject. Further provided are nucleic acid compositions and kits for use in determining the presence or absence in a (21) Appl. No.: 10/281,456 Subject of one or more polymorphisms associated with Alzheimer's disease and kits for determining the level of (22) Filed: Oct. 25, 2002 risk for Alzheimer's disease in a Subject. Patent Application Publication Sep. 11, 2003 Sheet 1 of 34 US 2003/0170678A1 C V O l Patent Application Publication Sep. 11, 2003 Sheet 2 of 34 US 2003/0170678A1 V O L Patent Application Publication Sep. 11, 2003 Sheet 3 of 34 US 2003/0170678A1 H Patent Application Publication Sep. 11, 2003 Sheet 5 of 34 US 2003/0170678A1 Patent Application Publication Sep. 11, 2003 Sheet 6 of 34 US 2003/0170678A1 L V O L Patent Application Publication Sep. 11, 2003 Sheet 7 of 34 US 2003/0170678A1 Patent Application Publication Sep. 11, 2003 Sheet 8 of 34 US 2003/0170678A1 V O Patent Application Publication Sep. 11, 2003 Sheet 9 of 34 US 2003/0170678A1 V O Patent Application Publication Sep. 11, 2003 Sheet 10 of 34 US 2003/0170678A1 Patent Application Publication Sep. 11, 2003 Sheet 11 of 34 US 2003/0170678A1 US 2003/0170678A1 - ve O co o rt wr l Mr. Mr. Patent Application Publication US 2003/0170678A1 Patent Application Publication Sep. 11, 2003 Sheet 14 of 34 US 2003/0170678A1 Genes on Chromosome 1 O Cytogenetic O CMOAT CANALICULAR MULTISPECIFIC ORGANIC ANION TRANSPORTER . " O ATP-BINDING CASSETTE, SUB-FAMILY C ABCC2 (CFTR/MRP), MEMBER 2 GDB:6089489 10q24-10q24 • ABC O MRP2 o CMRP o DJS o ATP-BINDIN SUB-FAMILY D ABCDIP2 o ALD1OP1E.I.S.S." GDB99641383,3'- LIMAB1 ABLIM LIMACT IN BINDING PROTEIN 1 GDB.7173461 10q25-10q25 o IMATIN ACADSB o ACYL-COENZYME A DEHYDROGENASE, GDB-388699 F5. SHORT/BRANCHED CHAIN ACTA2 e ACTSA GDB:1251.97 10q22 ce o ACTIN, ALPHA 2, SMOOTH MUSCLE, AORTA - - - 10q24. ARP1 (ACTIN-RELATED PROTEIN 1, YEASI) 10q24.2- ACTR1A\ HOMOLOG A (CENTRACTIN ALPHA) CDB:9958719 10q24.3UQ4. o ARP1 o A DISINTEGRIN AND METAL LOPROTEINASE DOMAIN 12 (MELTRIN ALPHA) GDB:9958807 10q26.3- ADAM12 O MLTN 10q26.3 o MCMP o MTNA O A DISINTEGRIN AND METAL LOPROTEASE GDB:4573992 10O26.3-q o ADENOSINE DEAMINASE, RNA-SPECIFIC, B2 ADARB2 (HOMOLOG OF RAT BLUE) GDB:5929209 10p15-10p15 o RED2 o HRED2 a ADDL 10q24.2 ADD •. ADDUCINA55 N. 3 (GAMMA) -GDB:6O45066 - 10q24.3(4.4 s HS.81 10 ADK to HS.94.382 GDB:1 18979 3. N 8 ADENOSINE KINASE -- o ADORA2L CDB. 128572 10q25.5- ADOR2- . ADENOSINE A2 RECEPTOR-LIKE 1 10q26.5+. oO ADRARADRA2 GDB:120538:1 10q25qZo ADRA2A o ADRA2R - 1025. ADRENERGIC, ALPHA-2A-, RECEPTOR Patent Application Publication Sep. 11, 2003 Sheet 15 of 34 US 2003/0170678A1 Cytogenetic O HS.999.13 10 25 ADRB1 a ADRB1R GDB: 19654 :55, ADRENERGIC, BETA-1-, RECEPTOR q AF10 ALL1 FUSED GENE FROM CHROMOSOME 10 GDB:9954451 10p12-10p12 o DDH a DIHYDRODIOL DEHYDROGENASE 1 (TRANS 1,2-DIHYDROBENZENE-1,2-DIOL 1 OD14 AKR1C1 ACIDDEHYDROGENASE, BINDING) HIGH AFFINITY BILE GDB.202890 10p14.p14 o HS.78183 o DDH 0 MBAB DDH2 DIHYDRODIOL DEHYDROGENASE 2 (TRANS- GDB:385038 10p15 AKR1C2 1,2-DIHYDROBENZENE-1,2-DIOL - || 10p14. DEHYDROGENASE) O ALDO-KETO REDUCTASE FAMILY 1. MEMBER C3 (3-ALPHA HYDROXYSTEROID GDB:9864779 | 10p15-10p15 AKR1C3 DEHYDROGENASE, TYPE II) a O KAAO 119 O CHDR 10p15 AKR1C4 O CHLORDECONE REDUCTASE GDB:127896 15:3. HS.76790 ALDOAP2 o ALDOLASEPSEUDOGENE A, FRUCTOSE-BISPHOSPHATE2 GDB11895GDB:118995 || 10qter.10pter ALOX5 e ARACHIDONATE 5-LIPOXYGENASE GDB:132455 10q11.2- o HS.894.99 - 10q11.2. o ANKYRIN-LIKE REPEAT PROTEIN o CARP ALRP o C-193 GDB:9993042 o CYTOKINE INDUCIBLE NUCLEAR PROTEIN o CARDIAC ANKYRIN REPEAT PROTEIN O HS.96029 rrd. - ANK3 o ANKRIS3,HS.75893 NODE OF RANVIER (ANKYRING) SPB-29. 3. ANKRD2 O ANKYRIN REPEAT DOMAIN 2 (STRETCH GDB:10795364 10q23.1 RESPONSIVE MUSCLE) - 10q25.1 O ANX11 ANXA11 o ANNEXIN XI (56KD AUTOANTIGEN) GDB:313076 10q22-10q25 HS.75510 Ya O ANX2P3 ANXA2P3 : Fic GDB:120553 10q21 o ANX2L3 - 10q22. ... ANNEXIN II (LIPOCORTIN II) PSEUDOGENE 3 ass, GDB:369042 3. 3. ANNEXIN VII (SYNEXIN qZ.Z. FIG. 2B Patent Application Publication Sep. 11, 2003 Sheet 16 of 34 US 2003/0170678A1 Cytogenetic O ANX8 10q11.2- ANXA8 O ANNEXIN VIII GDB. 128069 5:3. o HS.87268 AP3M1 ADAPTOR-RELATED PROTEIN COMPLEX 3, GDB: 0013490 10q22.1- MU 1 SUBUNIT --- 100.22.5 o ADIPOSE SPECIFIC 2 GOB:9958.670 10-10 - 10q25.1- | ARPP o ANKYRIN REPEAT PROTEIN GDB:11499581 10q25.1 o ATP5C1 o ATP SYNTHASE, H+TRANSPORTING, MITOCHONDRIAL F1 COMPLEX, GAMMA 10q22-10q23 ATP5C1 POLYPEPIDE 1 CD8:137187 14q22.2- o ATP SYNTHASE, H+TRANSPORTING, 14q22.3 MITOCHONDRIAL F1 COMPLEX, GAMMA POLYPEPTIOE-LIKE 1 ATP5 e ATP SYNTHASE, H+ TRANSPORTING, MITOCHONDRIAL FO COMPLEX, SUBUNIT F6 • ATP SYNTHASE, H+ TRANSPORTING, 10pter-1 Oqter MITOCHONORIAL ATPM e ATP5A HS,73851 HS.451 - 10p15 o MURINE LEUKEMIA VIRAL (BMI-1) GDB:249556 10p13. ONCOGENE HOMOLOG ACVRLK3 BONE MORPHOGENETIC PROTEIN BMPR1A REPOR, TYPE 1A GDB:23.0245 o ACTIVIN A RECEPTOR, TYPE II-LIKE KINASE 3. o HBRAG BRAC 0 KIAAO598 GDB: 10013998 10q26-10q26 o B-CELL RAG ASSOCIATED PROTEIN - m BS69 o ADENOVIRUS 5 E1A BINDING PROTEIN GDB9958263 10-10 BTRC o BETA-TRANSDUCIN REPEAT CONTAINING GDB:995,5268 10q24-10q25 e BUB3 (BUDDING UNINHIBITED BY N BENZIMIDAZOLES 5, YEAST) HOMOLOG ur-ma o CACNLB2 o MYSB m - CACNB2 o CALCIUM CHANNEL VOLTAGE-DEPENDENT, GDB. 132014 10p12-10p12 BETA 2 SUBUNIT • MYASTHENIC (LAMBERT-EATON) SYNDROME ANTIGEN B FIG. 2C Patent Application Publication Sep. 11, 2003 Sheet 17 of 34 US 2003/0170678A1 Symbol Alioses Cytogenetic Location callsCALML5 ao CALMODULIN-IKECLP 3 GDB.p 138290 10pter103. CAMKG CAMK2G o CALCIUM/CALMODULIN-DEPENDENT GDB: 138469 10q22 PROTEIN KINASE (CAM KINASE) II GAMMA - 10q22. o CASPASE 7, APOPTOSIS-RELATED CYSTEINE PRO EASE CASP7 o MCH3 GDB:5750011 10q25-10q25 o CMH-1 o ICE-AP3 CORNEAL DYSTROPHY OF BOWMAN'S LAYER TYPE II (THIEL-BEHNKE) CDTB GDB:69 19860 10q23-10q24 CDC2 O Fl DMISION CYCLE 2, G1 TO S AND G2 TO GDB:119052 10q21.1 - O. HS.58,393 10q21.1 CADHERIN RELATED 23 - o DEAFNESS, AUTOSOMAL RECESSIVE 12 GDB. 1591799 10q21-10q22 • USHER SYNDROME 1 D (AUTOSOMAL : FSTEROL 25-HYDROXASE GDB9954776. 10q25-10q25 CHAT CHOLINE ACETYLTRANSFERASE GDB.119775 ER3. o UBIQUTOUSCONSERVED HELIX-LOOP-HELIXKINASE s o IKK1 10q24 o NFKBIKA GDB:46241 O KBKA 10q25. o IKK-ALPHA • TCF16 CMD1 C SEGi to 1C GDB:9140455 10q21-10q25 • COLLAGEN, TYPE XIII, ALPHA 1 GDB:1 19789 3. a BPAG2 COL17A COLLAGEN, TYPE XVII, ALPHA 1 o BULLOUS PEMPHIGOID ANTIGEN 2 (18OKD) e BP18O n 9 BCD1 e CORE PROMOTER ELEMENT BENDING COPEB PROTEIN GDB:9120625 10p15-10p15 9 B-CELL, DERVED 1 - . e CPBP e CYTOCHORME C OXIDASE SUBUNIT 5 COX15 COX115 (YEAST) HOMOLOG, CYTOCHROME C GDB9862902 10q24-10q24 OXIDASE ASSEMBLY PROTEIN FIG. 2D Patent Application Publication Sep. 11, 2003 Sheet 18 of 34 US 2003/0170678A1 Cytogenetic CARBOXYPEPTIDASE N, POLYPEPTIDE 1, CPN1 5OKD GDB,9835951 10pter-10qter 0 CPNE1 . o CAMP RESPONSIVE ELEMENT MODULATOR GOB:269801 o HS.79 106 O CHONOROTIN SULFATE PROTEOCLYCAN 6 (BAMACAN) BAM GDB:9958904 10q25-10q25- CSPG6 o HCAP CHONDROITIN SULFATE PROTEOGLYCAN 6 (BAMACAN) o CTSL 10q11.2- CSLL1 o CATHEPSIN L-LIKE 1 saan-n-GDB-250757. 1021, 10q22 CSLL2 O CATHEPSIN L-LIKE 2 GDB250758 1022, d d. 10q22.5- CTSLL3 CATHEPSIN L-LIKE 3 GDB,250760 6,231. O MGA1 CUBN o CUBILINRECEPTOR) (INTRINSIC FACTOR-COBALAMIN GDB,6360496049 O MEGALOBLASTIC ANEMA 1 • CUG TRIPLET REPEAT, RNA-BINDING PROTEIN 2 CUGBP2 O ELAV-TYPE RNA-BINDING PROTEIN GDB:9958105 | 10p15-10p13 O ETR-3 o NAPOR-2 CUL4B O CULLIN 4B GDB:9955.179 10pter-10qter o HS. 1363 o CYTOCHROME P450, SUBFAMILY XVII GDB: 119829 CYP17 (STEROID 17-ALPHA-HYDROXYLASE), ADRENAL HYPERPLASIA ge:Episo, SUB FAMILY WA • P450RAI - o CYP2C17 CYTOCHROME P450, SUBFAMILY IIC N (MEPHENYTOIN 4-HYDROXYLASE), pOLYPEPTIDE 17 CYP2C8 o HS.702 y GDB:128983 10q24-10q24 o P450IIC17 o CYTOCHROME P450, SUBFAMILY IIC (MEPHENYTOIN 4-HYDROXYLASE), POLYPEPTIDE 17 FIG. 2E Patent Application Publication Sep. 11, 2003 Sheet 19 of 34 US 2003/0170678A1 - r Cytogenetic o CYP2C a CYTOCHROME P450, SUBFAMILY IIC (MEPHENYTOIN 4-HYDROXYLASE), CYP2C19 EPIDE 19 GDB:1198.31 o CYTOCHROME P450, SUBFAMILY IIC (MEPHENYTOIN 4-HYDROXYLASE) o P450IIC 19 o CYTOCHROME P450, SUBFAMILY IIC 10q24.1- CYP2C8 (MEPHENYTOIN 4-HYDROXYLASE), GDB:127450 10241, W POLYPEPTIDE 8 CYP2C10 o CYTOCHROME P450, SUBFAMILY IIC CYP2C (MEPHENYTOIN 4-HYDROXYLASE), GDB.