US 20040014109A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0014109 A1 Pericalk-Vance et al. (43) Pub. Date: Jan. 22, 2004 (54) METHODS AND GENES ASSOCIATED WITH Related U.S. Application Data SCREENING ASSAYS FOR AGE AT ONSET AND COMMON NEURODEGENERATIVE (60) Provisional application No. 60/382,880, filed on May DISEASES 23, 2002. Provisional application No. 60/396,233, filed on Jul. 16, 2002. Provisional application No. (76) Inventors: Margaret A. Pericak-Vance, Chapel 60/428,876, filed on Nov. 25, 2002. Hill, NC (US); Jeffery M. Vance, Chapel Hill, NC (US); Jonathan L. Publication Classification Haines, Brentwood, TN (US); John Gilbert, Oxford, NC (US); Yi-Ju Li, (51) Int. Cl." ....................................................... C12O 1/68 Durham, NC (US) (52) U.S. Cl. .................................................................. 435/6 Correspondence Address: MYERS BIGELSIBLEY & SAJOVEC (57) ABSTRACT PO BOX 37428 RALEIGH, NC 27627 (US) The present invention discloses methods of Screening a Subject for Alzheimer's disease and/or Parkinson's disease (21) Appl. No.: 10/444,347 comprising detecting the presence or absence of a marker or functional polymorphism associated with a gene linked to (22) Filed: May 23, 2003 Alzheimer's disease and/or Parkinson's disease. Patent Application Publication Jan. 22, 2004 Sheet 1 of 4 US 2004/0014109 A1 OS22 CCS 248 d1 OS 213 OS 230 dOS 237 di Os239 10S677 d1 OS2327 c OS 4.32 s dOS2 C10s,225 OS227 dOs208 d10s A26 d1 OS 1423 2 s di Osal 2 dOS 89 Patent Application Publication Jan. 22, 2004 Sheet 2 of 4 US 2004/0014109 A1 120 D1 OSS 83 DOS677* 30 DOS 239 135 138 150 D OS 230 *Peak marker for multipoint AAO analysis on NIMH dataset. ** Peak marker for multipoint AAO analysis on overall datasets. Figure 2. Overview of chromosome Oq. Patent Application Publication Jan. 22, 2004 Sheet 3 of 4 US 2004/0014109 A1 Figure 3 D10S1239, LOD=2.62 for the D10S1237, LOD=155 combined AD and LOD=2.39 for PD PD datasets for AD SCD NDUFB8 GSTO GSTO2 PRSS Genes - - - sistazart - - 3: - Position O 13 05 102.4 103.4 105.3 115.4 23.5 (MB) - TroT-T-I-T-o-o-o-o-Tre SNP 1 2 3 45 67 89 10 ll-14 Patent Application Publication Jan. 22, 2004 Sheet 4 of 4 US 2004/0014109 A1 - - - Cld NS C r 2. dNS divS Old NS 6d NS 8 NS -sans-39d NS GdNS - tdNS 8 d N S |gS. ds S.I 3d NS sd gl. 2 dNS O' 92 O'C 9 O' 90 O'O US 2004/0014109 A1 Jan. 22, 2004 METHODS AND GENES ASSOCATED WITH develop Signs of parkinsonism, including bradykinesia, SCREENING ASSAYS FOR AGE AT ONSET AND rigidity, and gait abnormalities. Conversely, dementia is a COMMON NEURODEGENERATIVE DISEASES major factor in Parkinson's disease, and the two disorders both exhibit degeneration of cholinergic neurons in the CROSS REFERENCE TO RELATED nucleus basalis of Meynert. Another pathological Similarity APPLICATIONS is the presence of Similar Staining C-Synuclein Lewy bodies (LB) in both disorders, Supporting the premise that the two 0001. The present application claims priority to Provi diseases may share a common pathway leading to LB sional Application No. 60/382,880 filed May 23, 2002, formation (See, Lippa et al., Arch Neurol 58:1817-1820 Provisional Application No. 60/396,233 filed Jul. 16, 2002, (2001)). APOE, a well-proven risk factor for Alzheimier's and Provisional Application No. 60/428,876 filed Nov. 25, disease, has been Suggested to be involved in the risk for 2002, the disclosures of which are hereby incorporated by Parkinson's disease as well, although others have failed to reference in their entireties. confirm these findings. Khan et al., Ann Neurol 49:665-668 (2001). The taugene, a major element in the neurofibulary STATEMENT OF FEDERAL SUPPORT tangles of Alzheimer's disease, has recently been shown to 0002 This invention was made with support from the be associated with Parkinson's disease as well (See, Martin United States Federal government under grant numbers R01 et al.). These similarities are likely not derived from the NS31153, P50 NS39764, P01 NS26630, NS31153, biologic events that initiate the Start of each disease but AG05128, AG13308, AG11268, AG10123, AG19085, rather from overlapping neuropathic pathways involved in MH52453 and MH59528 from the National Institutes of the progression of each disorder. Health. The United States Government has certain rights in 0006 Several recent reports have focused attention on this invention. chromosome 10q for Alzheimer's disease, (Bertram et al., Science 290:2302-2305 (2000); Ertekin-Taner et al., Science FIELD OF THE INVENTION 290:2303-2304 (2000); Myers et al., Science 290:2304-2305 0003. This invention concerns methods of screening for (2000); Pericak-Vance) but have been inconsistent in local Alzheimer's disease and/or Parkinson's disease by the ization (FIG. 2). Only the region identified by Bertram et al. Screening of genetic risk factors. (2000) by use of the NIMH family-sample data set maps near the present region. FIG. 2 depicts the map positions of BACKGROUND OF THE INVENTION published linkage regions for risk genes on chromosome 10q and the present linkage Findings for AAO genes. The 0004 Genetic studies of common complex neurodegen linkage effect on chromosome 10q spans the different data erative diseases, Such as Alzheimer's disease and Parkin Sets used in the analyses. Three independent risk-gene Son's disease, have focused on the identification of risk studies (Ertekin-Taner et al.; Myers et al.; and Pericak-Vance genes as targets for development of new treatments and et al.) identified an overlapping region (between D10S1225 improved diagnoses. This approach has identified the amy and D10S1211) that is ~47 cM proximal to the present loid precursor protein (APP) (Goate et al., Nature 349:704 linkage region for AAO. For Parkinson's disease, no risk 706 (1991)), presenilin 1 (PS1) (Sherrington et al., Nature genes have yet been reported on chromosome 10. See, Scott 375:754-760 (1995)), presenilin 2 (PS2) (Levy-Lahad et al., et al. 2001. Science 269:973-977 (1995); Rogaev et al., Nature 376:775 778 (1995)), and apolipoprotein E (APOE) (Corder et al., 0007 GSTO1 (or called GSTO1-1) is a member of the Science 261:921-923 (1993)) genes as contributing to risk in glutathione S-transferase (GST) family of genes that utilize Alzheimer's disease. APP, PS1, and PS2 cause rare early glutathione in reactions and contribute to the biotransfor onset autosomal dominant Alzheimer's disease (5% of mation and disposition of many compounds, including Alzheimer's disease cases), whereas APOE is associated drugs, carcinogens, and the products of oxidative StreSS. with both risk and age at onset (AAO) in late-onset familial GSTO1 is known to be expressed in a wide range of tissues, Alzheimer's disease, as well as in late- and early-onset specifically neural glial cells Board et al., J Biol. Chem. 275, Sporadic Alzheimer's disease. Similarly, three genes have 24798 (2000). GSTO1 is unusual in that it has a different been identified to associate with risk in Parkinson's disease: substrate profile than other members of this family, notably C-synuclein (Polymeropoulos et al., Science 274:1197–1199 a glutathione dependent thiotransferase activity Similar to (1996)) for rare autosomal dominant early-onset Parkinson's glutaredoxins. In addition, Dulhunty et al. have reported that disease, Parkin (Abbas et al., Hum Mol Genet 8:567-574 in cells containing ryanodine receptors it may have a role in (1999)) for rare autosomal recessive juvenile parkinsonism protecting from calcium-induced apotosis. J. Biol. Chem. and autosomal recessive early-onset Parkinson's disease, 276,3319 (2001). Zakharyan et al. have implicated it in the and tau (Martin et al., JAMA 286:224.5-2250 (2001)) for biotransformation of inorganic arsenic as well. Chem. ReS. classic Parkinson's disease. Genomic Screens in both Par Toxicol. 14, 1051 (2001). kinson's disease (Destefano et al., Neurology 57:1124-1126 0008 Identification of further genes would open new (2001); Scott et al., JAMA 286:2239-2244 (2001)) and avenues of research with the potential to delay onset beyond Alzheimer's disease (Kehoe et al., Hum Mol Genet 8:237 the natural life span. Present knowledge about genes con 245 (1999); Pericak-Vance et al., Exp Gerontol 35:1343 tributing to AAO in neurodegenerative diseases clearly lags 1352 (2000) have recently localized additional but, as yet, behind the understanding of genes contributing to risk. unknown risk genes. Recently, there has been growing interest in using AAO 0005 Both Alzheimier's disease and Parkinson's disease information as a quantitative trait, to identify genes that are neurodegenerative, late-AAO disorders. Clinically, a influence onset of disease (Daw et al., Am J Hum Genet Significant number of patients with Alzheimer's disease 64:839-851 (1999), Daw et al., Am J Hum Genet 66:196-204 US 2004/0014109 A1 Jan. 22, 2004 (2000); Duggirala et al. Am J Hum Genet 64:1127-1140 DETAILED DESCRIPTION OF THE (1999)). Rapid development of methods of mapping quan EMBODIMENTS titative trait loci (QTLS) for general pedigrees (Goldgar, Am J Hum Genet 47.957-967 (1990); Amos, Am J Hum Genet 0016. As noted above, the present invention provides a 54:535-543 (1994); Blangero et al. Genet Epidemiol 14:959 method of Screening (e.g., diagnosing, detecting, determin 964 (1997)) has now made the search for novel genes ing or prognosing) for Alzheimer's disease and/or Parkin affecting AAO feasible. Nevertheless, the genetic basis for Son's disease in a Subject.