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(12) Patent Application Publication (10) Pub. No.: US 2013/0072391 A1 KANG Et Al US 2013 0072391A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0072391 A1 KANG et al. (43) Pub. Date: Mar. 21, 2013 (54) COMPOSITION, KIT, AND METHOD FOR Publication Classification DAGNOSINGADHD RISK (51) Int. Cl. C40B 30/04 (2006.01) C40B 40/06 (2006.01) (75) Inventors: Changwon KANG, Daejeon (KR): C7H 2L/04 (2006.01) Eunjoon KIM, Daejeon (KR); Jae-Won GOIN 2L/64 (2006.01) Kim, Seoul (KR); Eunjin KIM, Daejeon (52) U.S. Cl. (KR); Hyejung WON, Daejeon (KR): USPC ................ 506/9: 436/501; 435/6.11:506/16; Won MAH, Daejeon (KR); Soo-Churl 536/23.5 CHO, Seoul (KR) (57) ABSTRACT The following disclosure relates to a technology of genotyp (73) Assignees: SNU R&DB FOUNDATION, Seoul ing a particular single nucleotide polymorphism (SNP) hav ing significant association with attention deficit hyperactivity (KR); KOREA ADVANCED disorder (ADHD) and using the SNP genotypes for predicting INSTITUTE OF SCIENCE AND the risk of ADHD. The present invention relates to providing TECHNOLOGY, Daejeon (KR) a method of predicting ADHD risk by identifying the nucle otide of rS5508181 SNP in GIT1, which is C or T at the 24926.101st residue on human chromosome 17, and a linkage (21) Appl. No.: 13/446,711 disequilibrium block harboring rs5508181. Further, the present invention relates to a composition for diagnosing ADHD risk, including a probe for detecting the SNP or a primer for amplifying the chromosomal region, and a diag (22) Filed: Apr. 13, 2012 nosing kit having the probe immobilized on a Surface thereof. Therefore, the method, the composition and the kit for diag (30) Foreign Application Priority Data nosing ADHD risk according to the following disclosure are useful technologies that can conveniently classify riskgroups Sep. 20, 2011 (KR) ........................ 10-2011-0094918 for ADHD at high sensitivity. US 2013/0072391 A1 Mar. 21, 2013 COMPOSITION, KIT, AND METHOD FOR tors (Premont R. T. et al., Proc. Natl. Acad. Sci. USA 95: DAGNOSINGADHD RISK 14082-14087, 1998; Claig A. et al., Proc. Natl. Acad. Sci. USA97: 1119-1124, 2000). It has been known that, in rodent CROSS-REFERENCE TO RELATED brains, GIT1 affects various nerve functions, including Syn APPLICATIONS apse formation, and in particular, Git1-null mice (Gitl) showed impaired dendritic outgrowth, reduced spine density, 0001. This application claims priority under 35 U.S.C. impaired fear responses and reduced adaptation to new and S119 to Korean Patent Application No. 10-2011-0094918, changing environments (Menon P. et al., Brain Res 1317:218 filed on Sep. 20, 2011 in the Korean Intellectual Property 226, 2010; Schmalzigauget al., Neurosci. Lett. 458:79-93, Office, the disclosure of which is incorporated herein by 2009). Therefore, the present inventors noticed these func reference in its entirety. tions of GIT1, and analyzed the association of the GIT1 gene with ADHD susceptibility through a patient-control study, TECHNICAL FIELD and as a result, first found that a single nucleotide polymor 0002 The following disclosure relates to a technology of phism (SNP) located in an intron of the GIT1 gene is signifi typing a particular single nucleotide polymorphism (SNP) cantly associated with ADHD susceptibility. having significant association with attention deficit hyperac 0006. The SNP is a polymorphism with high frequency, tivity disorder (ADHD) and using the SNP genotypes as a which is present on the human genome at a ratio of 0.1% marker to predict the risk of ADHD, and more particularly to (about 1 nucleotide per 1000 nucleotides). SNP refers to a a composition for diagnosing ADHD risk, including a poly position in a genome where one nucleotide (or base pair) is nucleotide having CorT nucleotide at the 24926.101st residue substituted with another nucleotide (or base pair), for on human chromosome 17 and a method of predicting the risk example, one genome has a C nucleotide while another of ADHD by identifying the nucleotide of rs5508181 SNP in genome has T nucleotide. In addition, an individual may have the GIT1 gene. Further, the present invention relates to a only one allele in both copies of autosomal chromosomes composition for diagnosing the risk of ADHD, including a (homozygous genotype, for example, T/T), while another probe for typing the SNP or a primer for amplifying the individual may have two differentalleles in the two autosome chromosomal region, and a diagnosing kit having the probe copies (heterozygous genotype, for example, C(T). This immobilized on a surface thereof. variation of one nucleotide may cause synthesis of variant 0003. Therefore, the method of predicting, and the com amino acids due to variation of codon (missense mutation) or position and the kit for diagnosing according to the following synthesis of a truncated protein due to generation of a stop disclosure are useful technologies that can conveniently clas codon (nonsense mutation). Therefore, it is obvious that pres sify risk groups for ADHD at high sensitivity, so as to prevent ence or absence of the polymorphism is associated with sev in advance or early detect the risk groups. eral disorders (Patent Document 1; Korean Patent Registra tion No. 10-1012601, Patent Document 2: Korean Patent BACKGROUND Registration No. 10-1057262), and it has been strongly rec ognized that it is important to accurately determine presence 0004 Attention deficit hyperactivity disorder (ADHD) is and absence of polymorphism (SNP typing), for the purpose more common in childhood than adulthood, and is referred to of diagnosis, genetic screening or treatment, or the like. In as a state characterized by persistentinattention, hyperactiv addition, SNP is a polymorphism maker that is used when ity, and impulsivity. When these symptoms are ignored with genes related to genetic predisposition to disorders or medi out being treated, they lead to continuous difficulties in lives cine reactivity are searched for, and receives attention as throughout childhood, and in many cases, these symptoms important genetic information for tailor-made medical treat may linger even during the adolescence and adulthood (Bar ment. key R. A., Attention deficit hyperactivity disorder. A Hand 0007. Therefore, the present inventors identified that the book for Diagnosis and Treatment, Guilford, N.Y., 2006). SNP located in an intron of the GIT1 gene can be used to 0005. It has been reported that neurochemical factors, predict genetic disposition for ADHD, and completed the genetic factors, and environmental factors are the causes of ADHD. Particularly, an association between dopamine, present invention. which is a neurotransmitter, and ADHD has been known CITED DOCUMENTS (Swanson J M et al., Neuropsychol. Rev. 17:39-59, 2007). Many ADHD susceptibility loci identified by genome linkage Patent Documents or association studies do not contain dopamine-related genes Such as dopamine carriers (Franke B. et al., Hum. Genet. 0008 (Patent Document 1) Korean Patent No. 126:13-50, 2009). Therefore, various genetic predispositions 10-10 12601: Composition for Predicting the Risk of are determined to affect this disorder. Recent genome-wide Developing Breast Cancer, Registration Date: 2011 Jan. linkage and association study results in relation to ADHD 27, Applicant: MACROGEN INC have reported that several ADHD-susceptibility associated 0009 (Patent Document 2) Korean Patent No. genetic variations may be located in a chromosomal locus 10-1057262: Biomarker for diagnosis of aspirin hypersen comprising of 17q11, 17 ul, and 17p12 on human chromo sitivity, method for manufacturing the same, and method some 17 (Ogdie M. N. et al., Am. J. Hum. Genet. 75:661-668, for diagnosis of aspirin hypersensitivity using the same, 2004; Ogdie M N et al., Am. J. Hum. Genet. 72:1268-1279, Registration Date: 2011 Aug. 9, Applicant: Soonchunhy 2003: Acros-Burgos Met al., Am. J. Hum. Genet. 75:998 ang University Industry Academy Cooperation Foundation 1014, 2004). GIT1, which is one of proteins encoded by genes present in this locus, is one of adaptor proteins with a GTPase Non-Patent Documents activating protein domain, and it is known to regulate various 0010 (Non-patent Document 1) Swanson J. M. et al., G protein-coupled receptors including B2-adrenergic recep Neuropsychol. Rev. 17:39-59, 2007 US 2013/0072391 A1 Mar. 21, 2013 0011 (Non-patent Document 2) Franke B. et al., Hum. 0025. Meanwhile, a linkage disequilibrium (hereinafter, Genet, 126:13-50, 2009 LD) region is a region where a particular section on the 0012 (Non-patent Document 3) Ogdie M. N. et al., Am. J. genome is so short that a cross-over hardly occurs for gen Hum. Genet. 75:661-668, 2004 erations. Therefore, genetic information located in the section 0013 (Non-patent Document 4) Ogdie M N et al., Am. J. is the same and almost conserved for generations. The SNP Hum. Genet. 72:1268-1279, 2003 having a significant association with the risk of ADHD, of the 0014 (Non-patent Document 5) Acros-Burgos M. et al., present invention, is a variation presentata particularlocus on Am. J. Hum. Genet. 75:998-1014, 2004 genome. In addition, polymorphisms are explored where cor 0015 (Non-patent Document 6) Premont R.T. et al., Proc. relation coefficiency (r-square) with the ADHD-associated Natl. Acad. Sci. USA95: 14082-14087, 1998 rs550818 SNP is exhibited 0.95 or more, and polymorphisms 0016 (Non-patent Document 7) Claig A. et al., Proc. Natl. are explored where an LD (D") with the ADHD-associated Acad. Sci. USA 97: 1119-1124, 2000 rS550818 SNP is exhibited 0.95 or more. Therefore, all other variations located in the LD block harboring the rs550818 0017 (Non-patent Document 8) Menon P. et al., Brain SNP in the GIT1 gene also have the same genetic information Res. 1317:218-226, 2010 as the SNP, and thus, the LD block harboring the rs550818 0018 (Non-patent Document 9) Schmalzigauget al., Neu SNP in the GIT1 gene can be also provided as a composition rosci.
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