Association of Rare Recurrent Genetic Variations to Attention-Deficit, Hyperactivity Disorder (ADHD) and Methods of Use Thereof for the Diagnosis and Treatment of the Same

Abstract

Compositions and methods for the detection and treatment of ADHD are provided.

What is claimed is: 
     
         1 . A method for detecting an increased risk for developing attention deficit hyperactivity disorder (ADHD) in a test subject, comprising,
 a) obtaining a nucleic acid sample from said subject and determining whether said sample contains at least one informative SNP indicative of the presence an ADHD associated copy number variation (CNV), wherein if said SNP is detected, said patient has an increased risk for developing ADHD, wherein said SNP containing nucleic acid is selected from the group of SNPs consisting of those provided in Table 13.   
     
     
         2 . The method as claimed in  claim 1 , wherein the target nucleic acid is amplified prior to detection. 
     
     
         3 . The method of  claim 1 , wherein the step of detecting the presence of said SNP is performed using a process selected from the group consisting of detection of specific hybridization, measurement of allele size, restriction fragment length polymorphism analysis, allele-specific hybridization analysis, single base primer extension reaction, and sequencing of an amplified polynucleotide. 
     
     
         4 . The method as claimed in  claim 1 , wherein in the target nucleic acid is DNA. 
     
     
         5 . The method of  claim 1 , wherein nucleic acids comprising said SNP are obtained from an isolated cell of a human test subject. 
     
     
         6 . A method for identifying therapeutic agents which alter neuronal signaling and/or neuronal cell morphology, comprising
 a) providing cells expressing at least one CNV containing nucleic acid as claimed in  claim 1 ;   b) providing cells which express the cognate wild type sequences corresponding to the CNV containing nucleic acid of step a);   c) contacting the cells of steps a) and b) with a test agent and   d) analyzing whether said agent alters neuronal signaling and/or morphology of cells of step a) relative to those of step b), thereby identifying agents which alter neuronal signaling and morphology.   
     
     
         7 . The method of  claim 6  wherein said agent is selected from the group consisting of a mGluR positive allosteric modulators (PAM), a mGluR negative allosteric modulator (NAM), and a tachykinin-3/neurokinin-3 receptor (TACR3/NK3R) antagonist. 
     
     
         8 . The method of  claim 7  wherein said mGluR PAM is selected from the group consisting of AMN082, ADX63365, ADX50938, and ADX71149. 
     
     
         9 . The method of  claim 7  wherein said mGluR NAM is selected from the group consisting of LY341495 and ADX48621. 
     
     
         10 . The method of  claim 7  wherein said TACR3/NK3R antagonist is selected from the group consisting of GSK1144814 and SB223412 (Talnetant). 
     
     
         11 . The method of  claim 6  wherein said therapeutic has efficacy for the treatment of ADHD or other related neurodevelopmental disorders. 
     
     
         12 . A method for the treatment of ADHD in a patient in need thereof comprising administration of an effective amount of the agent identified by  claim 6 . 
     
     
         13 . The method of  claim 12 , wherein said agent modulates metabotropic glutamate receptor gene activity. 
     
     
         14 . A multiplex SNP panel comprising nucleic acids informative of the presence of ADHD associated CNVs, wherein said panel contains the nucleic acids provided in Table 13. 
     
     
         15 . A vector comprising at least one of the SNP-containing nucleic acids of  claim 14 . 
     
     
         16 . A host cell comprising the vector of  claim 15 . 
     
     
         17 . A solid support comprising the ADHD related SNP containing nucleic acid of  claim 14 . 
     
     
         18 . A kit for performing the method of  claim 1 , comprising a multiplex SNP panel comprising nucleic acids informative of the presence of ADHD associated CNVs in an isolated nucleic acid sample, wherein said panel contains the nucleic acids provided in Table 13. 
     
     
         19 . The kit of  claim 18 , wherein said panel is affixed to a solid support. 
     
     
         20 . The kit of  claim 18 , wherein said panel is provided in silico. 
     
     
         21 . A method of treating attention-deficit hyperactivity disorder (ADHD) in a human subject determined to have at least one single nucleotide polymorphism (SNP) indicative of the presence of an ADHD-associated copy number variation, said at least one SNP being selected from the group consisting of SNPs set out in Table 13, the method comprising administering to said human subject a therapeutically effective amount of at least one member of agents set forth in Table 1. 
     
     
         22 . A method of treating attention-deficit hyperactivity disorder (ADHD) in a human subject determined to have at least one single nucleotide polymorphism (SNP) indicative of the presence of an ADHD-associated copy number variation, said at least one SNP being selected from the group consisting of SNPs set out in Table 13, the method comprising administering to said human subject a therapeutically effective amount of at least one member of the piracetam family of nootropic agents. 
     
     
         23 . The method of  claim 21  or  22 , wherein said SNP is a deletion in at least one of the following: glutamate receptor, metabotropic 5 (GRM 5), glutamate receptor, metabotropic 7 (GRM 7), glutamate receptor, metabotropic 8 (GRM 8). 
     
     
         24 . The method of  claim 21  or  22 , wherein said SNP is a duplication of glutamate receptor, metabotropic 1. 
     
     
         25 . The method of  claim 21  or  22 , wherein said nootropic agent is a pyroglutamide. 
     
     
         26 . The method of  claim 25 , wherein said pyroglutamide is (+)-5-oxo-D-prolinepiperidinamide monohydrate (NS-105). 
     
     
         27 . A method for detecting an increased risk for developing attention deficit hyperactivity disorder (ADHD) in a test subject, comprising,
 a) obtaining a nucleic acid sample from said subject and determining whether said sample contains an ADHD associated copy number variation (CNV), wherein if said CNV is detected, said patient has an increased risk for developing ADHD, wherein said CNV containing nucleic acid is selected from the group of CNVs present in genes consisting of those provided in Table 21.   
     
     
         28 . A method for identifying therapeutic agents which alter neuronal signaling and/or neuronal cell morphology, comprising
 a) providing cells expressing at least one CNV containing nucleic acid as claimed in  claim 27 ;   b) providing cells which express the cognate wild type sequences corresponding to the CNV containing nucleic acid of step a);   c) contacting the cells of steps a) and b) with a test agent and   d) analyzing whether said agent alters neuronal signaling and/or morphology of cells of step a) relative to those of step b), thereby identifying agents which alter neuronal signaling and morphology.   
     
     
         29 . A method of treating attention-deficit hyperactivity disorder (ADHD) in a human subject determined to have at least CNV indicative of the presence of an ADHD, said at least one CNV being selected from the group consisting of CNVs set out in Table 21, the method comprising administering to said human subject a therapeutically effective amount of at least one member of the piracetam family of nootropic agents.