Targets, methods, and reagents for diagnosis and treatment of schizophrenia

• US 20040014095A1
• Filed: 03/26/2003
• Published: 01/22/2004
• Est. Priority Date: 03/26/2002
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology, Rockefeller University
• Original Assignee: Massachusetts Institute of Technology, Rockefeller University
• Inventors: Miyakawa, Tsuyoshi, Karayiorgou, Maria, Tonegawa, Susumu, Gerber, David J.
• Granted Patent: US 7,935,500 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

The present invention provides targets, methods, and reagents for the diagnosis and treatment of schizophrenia and related conditions. The invention provides methods for the diagnosis of schizophrenia and susceptibility to schizophrenia by detection of polymorphisms, mutations, variations, alterations in expression, etc., in calcineurin genes or calcineurin interacting genes, or polymorphisms linked to such genes. The invention provides oligonucleotides, arrays, and antibodies for detection of polymorphisms and variants. The invention provides transgenic mice having alterations in such genes. The invention also provides methods of treating schizophrenia by administering compounds that target these genes. The invention further provides screening methods for identifying such compounds and compounds obtained by perfoming the screens.

Claims

1. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:

(i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and

(ii) detecting a polymorphic variant of a polymorphism in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or detecting a polymorphic variant of a polymorphism in a genomic region linked to such a gene, in the sample.

2. The method of claim 1, wherein the gene or a portion thereof is coincident with a schizophrenia susceptibility locus.

3. The method of claim 2, wherein the locus is a genetically identified locus.

4. The method of claim 1, wherein the polymorphism occurs in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule.

5. The method of claim 4, wherein the polymorphism occurs in a coding portion of the gene.

6. The method of claim 5, wherein the polymorphic variant results in an alteration in the amino acid sequence of the calcineurin subunit or calcineurin interacting molecule encoded by the gene.

7. The method of claim 1, wherein the polymorphism occurs in a genomic region linked to a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule.

8. The method of claim 7, wherein the polymorphism is genetically linked to the gene.

9. The method of claim 1, wherein the gene encodes a polypeptide selected from the group consisting of:

CNB;

CNAα

;

CNAβ

;

CNAγ

;

Cabin 1;

calcineurin B homologous protein;

calcipressins;

DSCR-1;

calsarcin-1;

calsarcin-3;

A kinase anchor protein 5;

FK506 binding protein 5;

interleukin enhancer binding factor 2 (ILF2 subunit of nuclear factor of activated T cells);

nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2;

ryanodine receptor type 3;

IP3 (inositol triphosphate) receptor type 1;

pituitary adenylate cyclase activating polypeptide (PACAP); and

calcium-signal modulating cyclophilin ligand.

10. The method of claim 9, wherein the gene encodes CNAγ

.

11. The method of claim 10, wherein the polymorphism is CC-5.

12. The method of claim 1, wherein the method is performed so as to detect, either in individually or in parallel, polymorphic variants of multiple polymorphisms in a coding or noncoding portion of one or more genes encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or in a genomic region linked to such a gene, in the sample.

13. The method of claim 1, wherein the detecting step comprises:

contacting the sample with an oligonucleotide array, wherein the array comprises a plurality of oligonucleotides designed to specifically detect polymorphic variants of multiple polymorphisms in a coding or noncoding portion of one or more genes encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or in a genomic region linked to such a gene, in the sample.

14. The method of claim 12 or 13, wherein the multiple polymorphisms comprise a risk haplotype for schizophrenia.

15. The method of claim 14, wherein the risk haplotype comprises one or more of the CC-21, CC-33, CC-S3;

G, C, A polymorphic variants.

16. The method of claim 15, wherein the risk haplotype comprises one, two, or three of the CC-21, CC-33, CC-S3;

G, C, A polymorphic variants.

17. The method of claim 1, wherein one or more polymorphisms in or linked to a gene encoding CNAγ

is detected.

18. The method of claim 1, wherein the detecting step comprises:

contacting the sample with an oligonucleotide, wherein the oligonucleotide is designed to specifically detect or amplify a polymorphic variant of the polymorphism.

19. The method of claim 1, wherein the detecting step comprises:

contacting the sample with an oligonucleotide array, wherein the array comprises one or more oligonucleotides designed to specifically detect a polymorphic variant of the polymorphism.

20. The method of claim 1, further comprising the step of:

determining that the subject is susceptible to or suffers from schizophrenia if the polymorphic variant is associated with an increased risk of schizophrenia.

73. The method of any of claims 32, 62, 64, 70, or 71, further comprising the step of:

identifying the subject as at risk of or suffering from schizophrenia using the method of claim 1 or any other appropriate method.

123. The method of claim 122, further comprising the step of identifying the subject as at risk of or suffering from schizophrenia according to the method of claim 1.

21. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:

(i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and

(ii) detecting an alteration or variation in expression or activity of a calcineurin subunit or a calcineurin interacting molecule in the sample, relative to the expression or activity of the calcineurin subunit or calcineurin interacting molecule that would be expected in a sample obtained from a normal subject.

22. The method of claim 21, wherein the alteration or variation comprises an increase or decrease in abundance of an mRNA that encodes the calcineurin subunit or calcineurin interacting molecule, or an increase or decrease in abundance of the calcineurin subunit or calcineurin interacting molecule.

23. The method of claim 21, wherein the calcineurin subunit or calcineurin interacting molecule is selected from the group consisting of:

CNB;

CNAα

;

CNAβ

;

CNAγ

;

Cabin 1;

calcineurin B homologous protein;

calcipressins;

DSCR-1;

calsarcin-1;

calsarcin-3;

A kinase anchor protein 5;

FK506 binding protein 5;

interleukin enhancer binding factor 2 (ILF2 subunit of nuclear factor of activated T cells);

nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2;

ryanodine receptor type 3;

IP3 (inositol triphosphate) receptor type 1;

pituitary adenylate cyclase activating polypeptide (PACAP); and

calcium-signal modulating cyclophilin ligand.

24. The method of claim 23, wherein the calcineurin subunit or calcineurin interacting molecule is CNAγ

.

25. The method of claim 21, wherein the alteration or variation comprises an increase or decrease in phosphatase activity.

26. A method for the diagnosis of schizophrenia or schizophrenia susceptibility comprising:

(i) providing a sample obtained from a subject to be tested for schizophrenia or schizophrenia susceptibility; and

(ii) detecting an alteration or variation in a calcineurin subunit or a calcineurin interacting molecule in the sample.

27. The method of claim 26, wherein the alteration or variation comprises an alteration or variation in the amino acid sequence, size, or tissue or subcellular distribution of the calcineurin subunit or calcineurin interacting molecule.

28. The method of claim 26, wherein the calcineurin subunit or calcineurin interacting molecule is selected from the group consisting of:

CNB;

CNAα

;

CNAβ

;

CNAγ

;

Cabin 1;

calcineurin B homologous protein;

calcipressins;

DSCR-1;

calsarcin-1;

calsarcin-3;

A kinase anchor protein 5;

FK506 binding protein 5;

interleukin enhancer binding factor 2 (ILF2 subunit of nuclear factor of activated T cells);

nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2;

ryanodine receptor type 3;

IP3 (inositol triphosphate) receptor type 1;

pituitary adenylate cyclase activating polypeptide (PACAP); and

calcium-signal modulating cyclophilin ligand (CAML).

29. The method of claim 28, wherein the calcineurin subunit or calcineurin interacting molecule is CNAγ

.

30. The method of claim 26, wherein the detecting step comprises employing an antibody that specifically binds to the calcineurin subunit or calcineurin interacting molecule.

31. The method of claim 30, wherein the detecting step comprises employing an antibody that specifically binds to a variant of the calcineurin subunit or calcineurin interacting molecule, the presence of which variant is indicative of susceptibility or presence of schizophrenia.

32. A method for treating schizophrenia or susceptibility to schizophrenia comprising:

providing a subject at risk of or suffering from schizophrenia; and

administering a compound that modulates activity or abundance of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule to the subject.

33. The method of claim 32, wherein the compound enhances activity or abundance of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule.

34. The method of claim 32, wherein the compound reduces activity or abundance of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule.

35. The method of claim 32, wherein the compound modulates activity of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule.

36. The method of claim 35, wherein the compound enhances activity of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule.

37. The method of claim 35, wherein the compound reduces activity of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule.

38. The method of claim 32, wherein the compound modulates expression of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule.

39. The method of claim 38, wherein the compound enhances expression of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule.

40. The method of claim 38, wherein the compound reduces expression of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule.

41. The method of claim 32, wherein the compound binds to calcineurin, a calcineurin subunit, or a calcineurin interacting molecule.

42. The method of claim 32, wherein the compound disrupts binding of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule to a second molecule.

43. The method of claim 42, wherein the second molecule is a calcineurin subunit or a calcineurin interacting molecule.

44. The method of claim 32, wherein the compound modulates binding between calcineurin and calmodulin.

45. The method of claim 32, wherein the compound disrupts binding between calcineurin or a calcineurin subunit and a calcineurin inhibitor.

46. The method of claim 45, wherein the calcineurin inhibitor is Cabin1 or CHP.

47. The method of claim 32, wherein the calcineurin, calcineurin subunit, or calcineurin interacting molecule is selected from the group consisting of:

CNB;

CNAα

;

CNAβ

;

CNAγ

;

Cabin 1;

calcineurin B homologous protein;

calcipressins;

DSCR-1;

calsarcin-1;

calsarcin-3;

A kinase anchor protein 5;

FK506 binding protein 5;

interleukin enhancer binding factor 2 (ILF2 subunit of nuclear factor of activated T cells);

nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2;

ryanodine receptor type 3;

IP3 (inositol triphosphate) receptor type 1;

pituitary adenylate cyclase activating polypeptide (PACAP); and

calcium-signal modulating cyclophilin ligand.

48. The method of claim 47, wherein the calcineurin subunit is CNAγ

.

49. The method of claim 32, wherein the compound acts by a mechanism that involves activation or inhibition of calcineurin.

50. The method of claim 32, wherein the compound acts by a mechanism that does not involve activation or inhibition of calcineurin.

51. The method of claim 32, wherein the compound activates or inhibits a member of the NF-AT transcription factor family.

52. The method of claim 32, wherein the compound inactivates DARPP-32 or inhibitor 1.

53. The method of claim 32, wherein the compound blocks or inhibits binding of DARPP-32 or inhibitor 1 to protein phosphatase 1.

54. The method of claim 32, wherein the compound binds to ryanodine receptor type 3 or modulates activity of ryanodine receptor type 3.

55. The method of claim 54, wherein the compound increases activity of ryanodine receptor type 3.

56. The method of claim 54, wherein the compound decreases activity of ryanodine receptor type 3.

57. The method of claim 32, wherein the compound binds to inositol triphosphate receptor type 1 or modulates activity of inositol triphosphate receptor 1.

58. The method of claim 57, wherein the compound increases activity of inositol triphosphate receptor type 1.

59. The method of claim 57, wherein the compound decreases activity of inositol triphosphate receptor type 1.

60. The method of claim 32, wherein the administering step comprises introducing a gene therapy vector into the subject.

61. The method of claim 60, wherein the gene therapy vector comprises a nucleic acid that encodes a calcineurin subunit or a calcineurin molecule or a substrate or inhibitor of calcineurin.

62. A method for treating schizophrenia or susceptibility to schizophrenia comprising:

providing a subject at risk of or suffering from schizophrenia; and

administering a compound that modulates intracellular calcium levels to the subject.

63. The method of claim 62, wherein the compound binds to or modulates activity of a molecule selected from the group consisting of:

a ryanodine receptor, an IP3 receptor, a PACAP receptor, a receptor that activates phospholipase C, a calcium pump, a calcium channel, phospholipase C, and CAMLG.

65. The method of claim 62 or 64, wherein the compound acts is an agonist or antagonist of a neuropeptide or neuropeptide receptor.

66. The method of claim 62 or 64, wherein the compound modulates an ion channel.

67. The method of claim 66, wherein the ion channel is a calcium channel.

68. The method of claim 66, wherein the calcium channel is an L-type calcium channel.

69. The method of claim 66, wherein the calcium channel is a capacitance-regulated activation channel.

64. A method for treating schizophrenia or susceptibility to schizophrenia comprising:

providing a subject at risk of or suffering from schizophrenia; and

administering a compound that modulates hippocampal or cortical LTD to the subject.

70. A method for treating schizophrenia or susceptibility to schizophrenia comprising:

providing a subject at risk of or suffering from schizophrenia; and

administering a compound that modulates expression or activity of one or more NFAT-regulated proteins.

71. A method for treating an immune system condition in a subject having schizophrenia or susceptibility to schizophrenia comprising:

providing a subject at risk of or suffering from an immune system abnormality and at risk of or suffering from schizophrenia; and

administering a compound that modulates activity or abundance of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule to the subject.

72. The method of claim 71, wherein the immune system abnormality is altered cytokine production, altered T cell subset ratios, or production of autoantibodies, or a combination of these.

74. A method of identifying a polymorphism useful in diagnosis of schizophrenia or susceptibility to schizophrenia comprising steps of:

identifying one or more polymorphisms in or linked to a gene encoding a CN subunit or CN interacting protein;

providing a set of samples including samples obtained from subjects affected with schizophrenia;

testing the samples for linkage or association of one or more variants of the polymorphism with schizophrenia; and

identifying the polymorphism as useful in diagnosis of schizophrenia if linkage of association between one or more variants of the polymorphism and schizophrenia susceptibility.

75. A method of identifying a mutation that contributes to or causes schizophrenia or susceptibility to schizophrenia comprising steps of:

identifying a polymorphism in or linked to a gene encoding a CN subunit or CN interacting protein;

determining that a polymorphic variant of the polymorphism is linked to or associated with susceptibilty to schizophrenia;

sequencing the gene and optionally regulatory regions of the gene in a sample obtained from one or more subjects suffering from schizophrenia;

comparing the sequence obtained with a normal or wild type sequence of the same gene;

identifying the polymorphic variant as representing a mutation that causes or contributes to schizophrenia if the sequence obtained in the sequencing step differs from the normal or wild type sequence.

76. A method for identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:

providing a biological system comprising NF-AT, calcineurin, and an NF-AT reporter;

contacting the biological system with a compound;

comparing the transcriptional response of the reporter in the presence of the compound with the response or expected response in the absence of the compound; and

identifying the compound as a a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the transcriptional response in the presence of the compound is different from the transcriptional response that occurs or would be expected in the absence of the compound.

77. The method of claim 76, wherein the biological system is a cell or population of cells.

78. The method of claim 76, wherein the biological system comprises CNAγ

and lacks CNAα and

CNAβ

.

79. The method of claim 76, wherein the biological system further comprises a calcineurin inhibitor.

80. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:

providing a biological system comprising phosphorylated calcineurin substrate and calcineurin;

contacting the biological system with a compound;

comparing the extent or rate of dephosphorylation of the substrate with the extent or rate of dephosphorylation occurring or expected to occur in the absence of the compound; and

identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of dephosphorylation in the presence of the compound is different from the extent or rate of dephosphorylation that occurs or would be expected in the absence of the compound.

81. The method of claim 80, wherein the biological system comprises CNAγ

and lacks CNAα and

CNAβ

.

82. The method of claim 80, wherein the biological system further comprises a calcineurin inhibitor.

83. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:

providing a biological system comprising a cellular membrane comprising ryanodine receptor type 3;

contacting the biological system with a compound;

contacting the cellular membrane with ryanodine;

comparing the extent or rate of binding of ryanodine to the cellular membrane in the presence of the compound with the extent or rate of binding that occurs or would be expected in the absence of the compound; and

identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of binding in the presence of the compound is different from that occurring or expected to occur in the absence of the compound.

84. The method of claim 83, wherein the biological system comprises CNAα

and lacks CNAα and

CNAβ

.

85. The method of claim 83, wherein the biological system further comprises a calcineurin inhibitor.

86. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:

providing a biological system comprising a cellular membrane comprising IP3 receptor type 1;

contacting the biological system with a compound;

contacting the cellular membrane with IP3;

comparing the extent or rate of binding of IP3 to the cellular membrane in the presence of the compound with the extent or rate of binding that occurs or would be expected in the absence of the compound; and

identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of binding in the presence of the compound is different from that occurring or expected to occur in the absence of the compound.

87. The method of claim 86, wherein the biological system comprises CNAγ

and lacks CNAα and

CNAβ

.

88. The method of claim 86, wherein the biological system further comprises a calcineurin inhibitor.

89. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:

providing a biological system comprising a transcriptional reporter construct, wherein the construct comprises a PP1-responsive regulatory element;

contacting the biological system with the compound;

comparing transcriptional response of the reporter in the presence of the compound with the response or expected response in the absence of the compound; and

identifying the compound as a modulator of PP1 activity if the transcriptional response in the presence of the compound is different from the transcriptional response that occurs or would be expected in the absence of the compound.

90. The method of claim 89, wherein the biological system is a cell or population of cells.

91. The method of claim 89, wherein the biological system comprises CNAγ

and lacks CNAα and

CNAβ

.

92. The method of claim 89, wherein the biological system further comprises a calcineurin inhibitor.

93. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:

providing a biological system comprising calcineurin and an endogenous calcineurin inhibitor;

contacting the biological system with the compound;

comparing extent or rate of binding of calcineurin and the endogenous calcineurin inhibitor in the presence of the compound with the extent or rate of binding that occurs or would be expected to occur in the absence of the compound; and

identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of binding of calcineurin and the endogenous calcineurin inhibitor in the presence of the compound is different from the extent or rate of binding that occurs or would be expected in the absence of the compound.

94. The method of claim 93, wherein the comparing step comprises performing a two or three hybrid screen.

95. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:

providing a biological system comprising calcineurin and calmodulin;

contacting the biological system with the compound;

comparing extent or rate of binding of calcineurin and calmodulin in the presence of the compound with the extent or rate of binding that occurs or would be expected to occur in the absence of the compound; and

identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent or rate of binding of calcineurin and calmodulin in the presence of the compound is different from the extent or rate of binding that occurs or would be expected in the absence of the compound.

96. The method of claim 95, wherein the comparing step comprises performing a two or three hybrid screen.

97. The method of claim 95, wherein different calcium ranges are tested.

98. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:

providing a biological system suitable for measuring LTD;

contacting the biological system with the candidate compound;

measuring LTD in the biological system; and

identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the extent of LTD in the biological system from the extent of LTD that occurs or would be expected to occur in the absence of the compound.

99. The method of claim 98, wherein the biological system comprises a hippocampal slice.

100. A method of identifying a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia comprising steps of:

providing a biological system suitable for measuring intracellular calcium;

contacting the biological system with the candidate compound;

measuring intracellular calcium or calcium flux in the biological system; and

identifying the compound as a candidate compound for treatment of schizophrenia or susceptibility to schizophrenia if the level of intracellular calcium or calcium flux in the biological system differs from the level of intracellular calcium or calcium flux that occurs or would be expected to occur in the absence of the compound.

101. The method of claim 100, wherein the biological system is a cell or population of cells.

102. The method of claim 100, wherein the measuring step comprises measuring level or flux of a calcium sensitive molecule or activity of a calcium sensor protein.

104. The method of any of claims 76, 80, 83, 86, 89, 93, 95, 98, 100, or 103 further comprising the step of testing the compound in an animal model for schizophrenia or in human subjects at risk of or suffering from schizophrenia.

118. A compound identified according to the method of any of claims 76, 80, 83, 86, 89, 93, 95, 98, 100, 103, 117.

119. A derivative of any of the compounds of claim 118.

120. The derivative of claim 119, wherein the derivative displays enhanced bioavailability, enhanced ability to cross the blood-brain barrier, or an improved safety profile.

121. A pharmaceutical composition comprising:

any of the compounds of claim 118 or 119; and

a pharmaceutically acceptable carrier.

122. A method of treating schizophrenia or susceptibility to schizophrenia comprising steps of:

providing a subject at risk of or suffering from schizophrenia; and

administering any of the pharmaceutical compositions of claim 121 to the subject either alone or concurrently with a second compound for treatment of schizophrenia or schizophrenia susceptibility or a compound that reduces side effects of such a compound.

103. A method for identifying a candidate compound for treatment of schizophrenia or schizophrenia susceptibility comprising steps of:

providing a molecular structure of CN or a CN complex;

identifying a structure that is expected to bind to CN or a CN complex or to prevent binding of CN or of a CN subunits either to another CN subunit or to a CN interacting molecule; and

selecting a compound having such a structure as a candidate compound for treatment of schizophrenia or schizophrenia susceptibility.

105. A method of identifying a compound for treatment of schizophrenia comprising steps of:

providing a subject or subjects;

administering a candidate compound to the subject or subjects, wherein the candidate compound modulates activity or abundance of calcineurin, a calcineurin subunit, or a calcineurin interacting molecule;

comparing severity or incidence of the phenotype in the subject or subjects to severity or incidence of the phenotype to that existing or expected to exist in a subject or subjects to which the candidate compound is not administered; and

identifying the candidate compound as a compound for the treatment of schizophrenia or schizophrenia susceptibility if severity or incidence of the phenotype in the subject or subjects is less than that existing or expected to exist in a subject or subjects to which the compound is not administered.

106. A method of identifying a compound for treatment of schizophrenia comprising steps of:

providing a subject or subjects at risk of or exhibiting one or more phenotypes suggestive of schizophrenia, wherein the subject or subjects have an alteration in at least one calcineurin subunit or calcineurin interacting molecule or in a gene encoding such a molecule;

administering a candidate compound to the subject or subjects;

comparing severity or incidence of the phenotype in the subject or subjects to severity or incidence of the phenotype to that existing or expected to exist in a subject or subjects to which the candidate compound is not administered; and

identifying the candidate compound as a compound for the treatment of schizophrenia or schizophrenia susceptibility if severity or incidence of the phenotype in the subject or subjects is less than that existing or expected to exist in a subject or subjects to which the compound is not administered.

107. The method of claim 106, wherein the alteration is an alteration in expression level or expression pattern.

108. The method of claim 106, wherein the alteration is an alteration in amino acid sequence.

109. The method of claim 106, wherein the subject or subjects exhibit a polymorphic variant of a gene encoding a calcineurin subunit or calcineurin interacting molecule, wherein presence of the variant is associated with one or more phenotypes suggestive of schizophrenia.

110. The method of claim 106, wherein the subject or subjects are nonhuman animals and exhibit a polymorphic variant of a gene encoding a calcineurin subunit or calcineurin interacting molecule, wherein presence of such a variant at a homologous site in humans confers susceptibility to schizophrenia or is indicative of the presence of schizophrenia.

111. The method of claim 106, wherein the subject or subjects are mice.

112. The method of claim 106, wherein the subject or subjects are humans.

113. The method of claim 106, wherein the subject or subjects are genetically engineered.

114. The method of claim 106, wherein the subject or subjects have an alteration in at least two molecules selected from the group consisting of calcineurin subunits and calcineurin interacting molecules.

115. The method of claim 106, wherein the subject or subjects are deficient in expression of at least one calcineurin subunit or calcineurin interacting molecule.

116. The method of claim 106 or 115, wherein the calcineurin subunit is CNB.

117. The method of claim 106 or 115, wherein the calcineurin subunit is CNAγ

.

124. An oligonucleotide designed to specifically detect or amplify a naturally occurring polymorphic variant of a polymorphism in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or a polymorphic variant of a polymorphism in a genomic region linked to such a gene, wherein the gene or a portion thereof is coincident with a schizophrenia susceptibility locus.

125. The oligonucleotide of claim 124, wherein the gene is selected from the group consisting of:

CNB;

CNAα

;

CNAβ

;

CNAγ

;

Cabin 1;

calcineurin B homologous protein;

a calcipressins;

DSCR-1;

calsarcin-1;

calsarcin-3;

A kinase anchor protein 5;

FK506 binding protein 5;

interleukin enhancer binding factor 2 (ILF2 subunit of nuclear factor of activated T cells);

nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2;

ryanodine receptor type 3;

IP3 (inositol triphosphate) receptor type 1;

pituitary adenylate cyclase activating polypeptide (PACAP); and

calcium-signal modulating cyclophilin ligand.

126. The oligonucleotide of claim 125, wherein the gene is CNAγ

.

127. The oligonucleotide of claim 126, wherein the polymorphism is the CC-21, CC-33, CC-S3, or CC-5 polymorphism.

133. A pair of oligonucleotides as set forth in claim 124 or 128, wherein the oligonucleotides hybridize to opposite DNA strands on either side of the polymorphic site.

134. A kit comprising the oligonucleotide of claim 124 or 128 and one or more items selected from the group consisting of:

packaging and instructions for use, a buffer, nucleotides, a polymerase, an enzyme, a positive control sample, a negative control sample, and a negative control primer or probe.

135. An oligonucleotide array comprising a plurality of oligonucleotides as set forth in claim 124 or 128.

136. The oligonucleotide array of claim 135, wherein the oligonucleotides detect polymorphic variants at a plurality of different polymorphic sites.

137. A kit comprising the oligonucleotide array of claim 135 and one or more items selected from the group consisting of:

packaging and instructions for use, a buffer, nucleotides, a polymerase, an enzyme, a positive control sample, a negative control sample, and a negative control primer or probe.

128. An oligonucleotide designed to specifically detect or amplify a naturally occurring nucleic acid region comprising a polymorphic site in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or a polymorphic variant of a polymorphism in a genomic region linked to such a gene, wherein the gene or a portion thereof is coincident with a schizophrenia susceptibility locus.

129. The oligonucleotide of claim 128, wherein the schizophrenia susceptibility locus is genetically identified.

130. The oligonucleotide of claim 128, wherein the gene is selected from the group consisting of:

CNB;

CNAα

;

CNAβ

;

CNAγ

;

Cabin 1;

calcineurin B homologous protein;

a calcipressin;

DSCR-1;

calsarcin-1;

calsarcin-3;

A kinase anchor protein 5;

FK506 binding protein 5;

interleukin enhancer binding factor 2 (ILF2 subunit of nuclear factor of activated T cells);

nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2;

ryanodine receptor type 3;

IP3 (inositol triphosphate) receptor type 1;

pituitary adenylate cyclase activating polypeptide (PACAP); and

calcium-signal modulating cyclophilin ligand.

131. The oligonucleotide of claim 130, wherein the gene is CNAγ

.

132. The oligonucleotide of claim 131, wherein the polymorphism is the CC-21, CC-33, CC-S3, or CC-5 polymorphism.

138. A primer that terminates at the nucleotide position immediately adjacent to a naturally occurring polymorphic site on the 3′

side and extends at least 8 and less than 100 nucleotides in the 5′

direction from this site, wherein the polymorphic site is the site of a polymorphism in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or is the site of a polymorphism in a genomic region linked to such a gene.

139. The primer of claim 138, wherein the gene or a portion thereof is coincident with a schizophrenia susceptibility locus.

140. The primer of claim 139, wherein the schizophrenia susceptiblity locus is genetically identified.

141. The primer of claim 139, wherein the gene is selected from the group consisting of:

CNB;

CNAα

;

CNAβ

;

CNAγ

;

Cabin 1;

calcineurin B homologous protein;

a calcipressin;

DSCR-1;

calsarcin-1;

calsarcin-3;

A kinase anchor protein 5;

FK506 binding protein 5;

interleukin enhancer binding factor 2 (ILF2 subunit of nuclear factor of activated T cells);

nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2;

ryanodine receptor type 3;

IP3 (inositol triphosphate) receptor type 1;

pituitary adenylate cyclase activating polypeptide (PACAP); and

calcium-signal modulating cyclophilin ligand.

142. The primer of claim 141, wherein the gene is CNAγ

.

143. The primer of claim 142, wherein the polymorphism is the CC-21, CC-33, CC-S3, or CC-5 polymorphism.

144. A pair of primers as set forth in claim 138, wherein the primers hybridize to opposite DNA strands adjacent to the location of the polymorphic site.

145. A kit comprising the primer of claim 138 and one or more items selected from the group consising of:

packaging and instructions for use, a buffer, nucleotides, a polymerase, an enzyme, a positive control sample, a negative control sample, and a negative control primer or probe.

146. An siRNA molecule targeted to a transcript encoding a calcineurin subunit or calcineurin interacting molecule.

147. The siRNA molecule of claim 146, wherein the calcineurin subunit or calcineurin interacting molecule is encoded by a gene that is coincident with a schizophrenia susceptibility locus.

148. The siRNA molecule of claim 147, wherein the schizophrenia susceptibility locus is genetically identified.

149. The siRNA molecule of claim 146, wherein the siRNA molecule is selectively or specifically targeted to a transcript encoding a polymorphic variant of such a transcript, wherein existence of the polymorphic variant in a subject is indicative of susceptibility to or presence of schizophrenia.

150. The siRNA molecule of claim 146, wherein the transcript encodes a molecule selected from the group consisting of:

CNB;

CNAα

;

CNAβ

;

CNAγ

;

Cabin 1;

calcineurin B homologous protein;

calcipressin;

DSCR-1;

calsarcin-1;

calsarcin-3;

A kinase anchor protein 5;

FK506 binding protein 5;

interleukin enhancer binding factor 2 (ILF2 subunit of nuclear factor of activated T cells);

nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2;

ryanodine receptor type 3;

IP3 (inositol triphosphate) receptor type 1;

pituitary adenylate cyclase activating polypeptide (PACAP); and

calcium-signal modulating cyclophilin ligand.

151. The siRNA molecule of claim 146, wherein the calcineurin subunit is CNAγ

.

152. A kit comprising the siRNA molecule of claim 146 and one or more items selected from the group consisting of:

packaging and instructions for use, a buffer, a positive control sample, and a negative control siRNA.

153. An antibody that specifically binds to a variant of a calcineurin subunit or calcineurin interacting molecule, wherein the calcineurin subunit or calcineurin interacting molecule is encoded by a gene comprising a polymorphic variant, wherein existence of the polymorphic variant in a subject is indicative of susceptibility to or presence of schizophrenia.

154. The antibody of claim 153, wherein the calcineurin subunit or calcineurin interacting molecule is selected from the group consisting of:

CNB;

CNAα

;

CNAβ

;

CNAγ

;

Cabin 1;

calcineurin B homologous protein;

calcipressin;

DSCR-1;

calsarcin-1;

calsarcin-3;

A kinase anchor protein 5;

FK506 binding protein 5;

interleukin enhancer binding factor 2 (ILF2 subunit of nuclear factor of activated T cells);

nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2;

ryanodine receptor type 3;

IP3 (inositol triphosphate) receptor type 1;

pituitary adenylate cyclase activating polypeptide (PACAP); and

calcium-signal modulating cyclophilin ligand.

155. The antibody of claim 153, wherein the calcineurin subunit or calcineurin interacting molecule is CNAγ

.

156. The antibody of claim 155, wherein the polymorphic variant is a variant of the CC-5 polymorphism.

157. The antibody of claim 156, wherein the polymorphic variant results in an arginine to glutamine amino acid change in CNAγ

.

158. A kit comprising the antibody of claim 153 and one or more items selected from the group consisting of:

packaging and instructions for use, a buffer, a substrate, a secondary antibody, an enzyme, a positive control sample, a negative control sample, and a negative control antibody.

159. A transgenic animal having altered expression of CNAγ

.

160. The transgenic animal of claim 159, wherein the animal is a mouse.

161. The transgenic mouse of claim 160, wherein the mouse is a CNAγ

hypomorph.

162. The transgenic mouse of claim 160, wherein the mouse expresses CNAγ

in a tissue specific or tissue restricted manner.

163. The trangenic mouse of claim 160, wherein the mouse overexpresses CNAγ

in one or more cell types, organs, tissues, or regions thereof.

164. The trangenic mouse of claim 160, wherein the mouse underexpresses CNAγ

in one or more cell types, organs, tissues, or regions thereof.

165. The transgenic mouse of claim 160, wherein the mouse lacks detectable expression of CNAγ

.

166. The trangenic mouse of claim 160, wherein the mouse expresses a variant of CNAγ

, which variant differs in sequence from the wild type sequence of CNAγ

as defined in Genbank.

167. The transgenic animal of claim 159, wherein the animal exhibits one or more phenotypes suggestive of schizophrenia.

168. A transgenic mouse, wherein the mouse is a CNB hypomorph.

169. A mouse obtained by crossing a mouse having altered expression of CNAγ

or CNB with a second mouse having altered expression of a CN subunit or CN interacting molecule.

170. A database comprising a list of polymorphic sequences stored on a computer-readable medium, wherein the polymorphic sequences occur in a coding or noncoding portion of a gene encoding a calcineurin subunit or encoding a calcineurin interacting molecule, or in a genomic region linked to such a gene, and wherein the list is largely or entirely limited to polymorphisms have been identified as useful in performing genetic diagnosis of schizophrenia or susceptibility to schizophrenia, or for performing genetic studies of schizophrenia or susceptibility to schizophrenia.