Diagnostic markers of mood disorders and methods of use thereof
First Claim
1. A method of determining a probability of response of a subject of known clinical history to a pharmaceutical agent for a mood disorder, the method comprising:
- correlating (i) a mutational burden at one or more nucleotide positions in genes drawn from the group consisting essentially of ADRBK2, BNDF, GSK3B, GRK3, IMPA1, IMPA2, INPP1, MARCKS, NTRK2 and/or NR1I2 within a sample taken from the subject of known clinical history with (ii) a mutational burden at one or more corresponding nucleotide positions in a control sample having known clinical history and response outcomes to the pharmaceutical agent; and
determining from the correlating the probability of response of the subject to the pharmaceutical agent.
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Abstract
The present invention relates to methods for the diagnosis, evaluation, and treatment of mood disorders, particularly bipolar disorder. In particular, patient test samples are analyzed for the presence and amount of members of a panel of biallelic markers comprising one or more specific markers for bipolar treatment and one or more non-specific markers for bipolar treatment. A variety of markers are disclosed for assembling a panel of markers for such diagnosis and evaluation. Algorithms for determining proper treatment are disclosed. A diagnostic kit for a panel of said markers is disclosed. In various aspects, the invention provides methods for the early detection and differentiation of mood disorders or bipolar treatment. Methods for screening therapeutic compounds for mood disorders are disclosed. The invention (1) gives methods providing rapid, sensitive and specific assays that can greatly increase the number of patients that can receive beneficial treatment and therapy, thereby reducing the costs associated with incorrect diagnosis, and (2) provides methods for improved therapies.
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Citations
36 Claims
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1. A method of determining a probability of response of a subject of known clinical history to a pharmaceutical agent for a mood disorder, the method comprising:
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correlating (i) a mutational burden at one or more nucleotide positions in genes drawn from the group consisting essentially of ADRBK2, BNDF, GSK3B, GRK3, IMPA1, IMPA2, INPP1, MARCKS, NTRK2 and/or NR1I2 within a sample taken from the subject of known clinical history with (ii) a mutational burden at one or more corresponding nucleotide positions in a control sample having known clinical history and response outcomes to the pharmaceutical agent; and
determining from the correlating the probability of response of the subject to the pharmaceutical agent. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
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19. A method for detecting the presence of, or the risk of developing, post-traumatic stress disorder in a human, said method comprising:
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determining in a biological sample from the human the presence of a nucleic acid sequence having a mutational burden relating to a mutation in genes of the group consisting essentially of the BNDF gene at nucleotide position given by the RS# and genetic position 2049045 and chr11;
27650817.the IMPA2 gene at nucleotide position given by the RS# and genetic position 971362 and chr18;
11970618,the IMPA2 gene at nucleotide position given by the RS# and genetic position 971363 and chr18;
11970460,the INPP1 gene at nucleotide position given by the RS# and genetic position 972691 and chr2;
191053261,the INPP1 gene at nucleotide position given by the RS# and genetic position 2016037 and chr2;
191042763,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1619120 and chr9;
84531750,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1565445 and chr9;
84846625,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1387923 and chr9;
84870190, andmutations in linkage disequilibrium with any of the aforementioned nucleotides, or combinations thereof; and
finding one or more nucleotide positions in a sequence region corresponding to a wildtype genomic DNA sequence; and
comparing the determined nucleic acid sequence having the mutational burden to the wildtype genomic DNA sequence to detect the presence of, or the risk of developing, post-traumatic stress disorder in the human.
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20. A method for evaluating a compound for use in diagnosis or treatment of bipolar disorder, the method comprising:
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contacting a predetermined quantity of the compound with cultured cybrid cells or animal model having genomic DNA originating from a neuronal rho or human embryonic immortal kidney cell line and from tissue of a human having both (1) a disorder that is associated with bipolar disorder and, (2) a mutational burden relating to a mutation in genes of the group consisting essentially of the BNDF gene at nucleotide position given by the RS# and genetic position 2049045 and chr11;
27650817.the IMPA2 gene at nucleotide position given by the RS# and genetic position 971362 and chr18;
11970618,the IMPA2 gene at nucleotide position given by the RS# and genetic position 971363 and chr18;
11970460,the INPP1 gene at nucleotide position given by the RS# and genetic position 972691 and chr2;
191053261,the INPP1 gene at nucleotide position given by the RS# and genetic position 2016037 and chr2;
191042763,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1619120 and chr9;
84531750,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1565445 and chr9;
84846625,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1387923 and chr9;
84870190, andmutations in linkage disequilibrium with any of the aforementioned nucleotides;
or combinations thereof;
measuring a phenotypic trait in the cybrid cells or animal model that correlates with the presence of said mutational burden and that is not present in cultured cybrid cells or an animal model having genomic DNA originating from a neuronal rho cell line and genomic DNA originating from tissue of a human free of a disorder that is associated with bipolar disorder; and
correlating any change in the phenotypic trait with the effectiveness of the compound. - View Dependent Claims (21, 22)
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23. A method for diagnosing bipolar disorder, said method comprising:
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determining, in a nucleic acid sequence of a biological sample from a human a mutational burden according to a mutation in genes of the group consisting essentially of the BNDF gene at nucleotide position given by the RS# and genetic position 2049045 and chr11;
27650817.the IMPA2 gene at nucleotide position given by the RS# and genetic position 971362 and chr18;
11970618,the IMPA2 gene at nucleotide position given by the RS# and genetic position 971363 and chr18;
11970460,the INPP1 gene at nucleotide position given by the RS# and genetic position 972691 and chr2;
191053261,the INPP1 gene at nucleotide position given by the RS# and genetic position 2016037 and chr2;
191042763,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1619120 and chr9;
84531750,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1565445 and chr9;
84846625,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1387923 and chr9;
84870190, andmutations in linkage disequilibrium with any of the aforementioned nucleotides. or combinations thereof, one or more nucleotide positions in a sequence region corresponding to a wildtype genomic DNA sequence; and
correlating any determined mutational burden as a diagnosis of bipolar disorder. - View Dependent Claims (24, 25, 26, 27)
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28. A therapeutic composition comprising:
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antisense or small interfering RNA sequences that are specific to mutant genes drawn from the group of genes consisting essentially of the BNDF gene at nucleotide position given by the RS# and genetic position 2049045 and chr21;
27650817.the IMPA2 gene at nucleotide position given by the RS# and genetic position 971362 and chr18;
11970618,the IMPA2 gene at nucleotide position given by the RS# and genetic position 971363 and chr18;
11970460,the INPP1 gene at nucleotide position given by the RS# and genetic position 972691 and chr2;
191053261,the INPP1 gene at nucleotide position given by the RS# and genetic position 2016037 and chr2;
191042763,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1619120 and chr9;
84531750,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1565445 and chr9;
84846625,the NTRK2 gene at nucleotide position given by the RS# and genetic position 1387923 and chr9;
84870190, andmutations in linkage disequilibrium with any of the aforementioned nucleotides. or combinations thereof, or mutant messenger RNA transcribed therefrom;
wherein the antisense or small interfering RNA sequences are adapted to bind to and inhibit transcription or translation of target genes according to the genes having mutational burden without preventing transcription or translation of wild-type genes of the same type. - View Dependent Claims (29)
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30. A kit comprising
devices and reagents for measuring mutational burden in the genes of a patient; - and
a computer algorithm consisting of executable computer code residing on a memory medium that, in response to the measured mutational burdens of the patient'"'"'s genes, determines in and for that patient a diagnosis for mood disorders, or for treatment outcome should the patient be given medication for mood disorders. - View Dependent Claims (31, 32, 33, 34, 35, 36)
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Specification