GENETIC MARKERS FOR SCHIZOPHRENIA AND BIPOLAR DISORDER

• US 20100151461A1
• Filed: 12/22/2008
• Published: 06/17/2010
• Est. Priority Date: 12/24/2007
• Status: Active Grant

• Current Assignee: SureGene, LLC
• Original Assignee: SureGene, LLC
• Inventors: Brennan, Mark David
• Granted Patent: US 8,460,868 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/172 Haplotypes
• CPC Class Codes: G06Q 99/00 Subject matter not provided for in other groups of this subclass

Abstract

The invention provides haplotypes and SNPs of the HPCAL1 and SV2C genes which predict the risk for developing schizophrenia or bipolar disorder and predict which patients are likely to respond to a given treatment or are more likely to experience negative side effects.

Claims

1. A method of determining a human subject'"'"'s risk of developing schizophrenia (SZ) or bipolar disorder (BD), the method comprising:

obtaining a test haplotype for the subject by determining the genotype for one or more test markers in the HPCAL1 gene between and including SNPs rs4668676 (SEQ ID NO;

1) and rs12692407 (SEQ ID NO;

11), or in the SV2C gene between and including SNPs rs889189 (SEQ ID NO;

     12) and rs31244 (SEQ ID NO;

19), wherein the one or more test markers are selected from the group consisting of;

rs4668676 (SEQ ID NO;

1) or a marker in linkage disequilibrium therewith;

rs6714483 (SEQ ID NO;

2) or a marker in linkage disequilibrium therewith;

rs17882379 (SEQ ID NO;

3) or a marker in linkage disequilibrium therewith;

rs6755271 (SEQ ID NO;

4) or a marker in linkage disequilibrium therewith;

rs887973 (SEQ ID NO;

5) or a marker in linkage disequilibrium therewith;

rs11893459 (SEQ ID NO;

6) or a marker in linkage disequilibrium therewith;

rs2270299 (SEQ ID NO;

7) or a marker in linkage disequilibrium therewith;

rs1808315 (SEQ ID NO;

8) or a marker in linkage disequilibrium therewith;

rs11694643 (SEQ ID NO;

9) or a marker in linkage disequilibrium therewith;

rs3732120 (SEQ ID NO;

10) or a marker in linkage disequilibrium therewith;

rs12692407 (SEQ ID NO;

10) or a marker in linkage disequilibrium therewith;

rs889189 ((SEQ ID NO;

11) or a marker in linkage disequilibrium therewith;

rs736005 (SEQ ID NO;

12) or a marker in linkage disequilibrium therewith;

rs6453211 (SEQ ID NO;

13) or a marker in linkage disequilibrium therewith;

rs4704298 (SEQ ID NO;

14) or a marker in linkage disequilibrium therewith;

rs1501926 (SEQ ID NO;

15) or a marker in linkage disequilibrium therewith;

rs11960621 (SEQ ID NO;

17) or a marker in linkage disequilibrium therewith;

rs2270927 (SEQ ID NO;

18) or a marker in linkage disequilibrium therewith; and

rs31244 (SEQ ID NO;

19) or a marker in linkage disequilibrium therewith;

wherein the test haplotype indicates the subject'"'"'s risk of developing SZ or BD.

2. The method of claim 1, wherein the test haplotype provides information regarding a subject'"'"'s risk of developing SZ.

3. The method of claim 1, wherein the test haplotype provides information regarding a subject'"'"'s risk of developing BD.

4. The method of claim 1, wherein obtaining a test haplotype comprises:

obtaining a sample comprising DNA from the subject; and

determining the genotype for the test marker.

5. The method of claim 1, further comprising:

obtaining a reference haplotype comprising a reference marker that corresponds to the test marker; and

comparing the test haplotype to the reference haplotype, wherein the presence of a haplotype in both the test haplotype and a reference haplotype is indicative of whether there is an increased likelihood that a subject will develop SZ or BD.

6. The method of claim 5, wherein the reference haplotype is from one or more subjects who have SZ, SPD, SD, or BD and the presence of a haplotype in both the test haplotype and the reference haplotype indicates that there is an increased likelihood that the subject will develop SZ or BD.

7. The method of claim 5, wherein the reference haplotype comprises a haplotype from at least one of the following relatives of the subject:

(a) a parent who has SZ, SD, SPD, or BD;

(b) a sibling who has SZ, SD, SPD, or BD, and an unaffected parent;

(c) or a second degree relative who has SZ, SD, SPD, or BD, and an unaffected parent, and

sharing of a haplotype between the test haplotype and the reference haplotype from the relative who has SZ, SD, SPD or BD, and lack of sharing of a haplotype of a haplotype between the test haplotype and the reference haplotype from the unaffected relative, is indicative of an increased likelihood that the subject will develop broadly defined SZ or BD.

8. The method of claim 1, further comprising determining the genotype of one or more additional markers listed in Table A, or one or more test markers that are in linkage disequilibrium with a marker listed in Table A.

9. The method of claim 1, wherein the subject is a patient having or suspected of having SZ or BD.

10. The method of claim 1, wherein the subject has one or more risk factors associated with SZ or BD.

11. The method of claim 10, wherein the risk factors associated with SZ or BD include one or more of:

a relative afflicted with SZ, SPD, SD or BD and a genetically based phenotypic trait associated with risk for SZ, SPD, SD or BD.

12. The method of claim 1, wherein the subject is a child, fetus, or embryo.

13. The method of claim 1, further comprising administering a pharmacological treatment to a subject identified as being at altered risk for developing SZ or BD.

14. The method of claim 1, wherein the test haplotype further provides information that differentiates patients that are more likely to respond to a treatment from those who are less likely to respond, or patients that are more likely to experience negative side effects from those less likely to experience negative side effects.

15. The method of claim 1, further comprising selecting or excluding a subject for enrollment in a clinical trial based on the test haplotype.

16. The method of claim 1, further comprising stratifying a subject population for analysis of a clinical trial based on the test haplotypes in the subjects.

17. The method of claim 1, further comprising confirming a diagnosis of SZ or BD using a psychometric instrument.

18. The method of claim 1, further comprising stratifying patients into biologically similar groups based on test haplotypes in order to determine a differential diagnosis.

31. The method of claim 1, wherein obtaining a test haplotype comprises obtaining a sample comprising genomic DNA of the subject, and determining the identity of the alleles at the test markers.

32. The method of claim 1, wherein obtaining a test haplotype comprises constructing test haplotypes from previous genotyping results, wherein the previous genotyping results include at least one test marker that is listed in Table A or is in linkage disequilibrium with a marker listed in Table A.

19. An array comprising a substrate having a plurality of addressable areas, wherein one or more of the addressable areas comprises a probe that can be used to detect two or more polymorphisms listed in Table A or Table B.

20. A method of predicting an effect of a haplotype on the outcome of a treatment for schizophrenia (SZ), schizotypal personality disorder (SPD), schizoaffective disorder (SD), or bipolar disorder (BD), the method comprising:

obtaining a test haplotype for the subject by determining the genotype for one or more test markers in the HPCAL1 gene between and including SNPs rs4668676 (SEQ ID NO;

1) and rs12692407 (SEQ ID NO;

11), or in the SV2C gene between and including SNPs rs889189 (SEQ ID NO;

     12) and rs31244 (SEQ ID NO;

19), wherein the one or more test markers are selected from the group consisting of;

rs4668676 (SEQ ID NO;

1) or a marker in linkage disequilibrium therewith;

rs6714483 (SEQ ID NO;

2) or a marker in linkage disequilibrium therewith;

rs17882379 (SEQ ID NO;

3) or a marker in linkage disequilibrium therewith;

rs6755271 (SEQ ID NO;

4) or a marker in linkage disequilibrium therewith;

rs887973 (SEQ ID NO;

5) or a marker in linkage disequilibrium therewith;

rs11893459 (SEQ ID NO;

6) or a marker in linkage disequilibrium therewith;

rs2270299 (SEQ ID NO;

7) or a marker in linkage disequilibrium therewith;

rs1808315 (SEQ ID NO;

8) or a marker in linkage disequilibrium therewith;

rs11694643 (SEQ ID NO;

9) or a marker in linkage disequilibrium therewith;

rs3732120 (SEQ ID NO;

10) or a marker in linkage disequilibrium therewith;

rs12692407 (SEQ ID NO;

10) or a marker in linkage disequilibrium therewith;

rs889189 ((SEQ ID NO;

11) or a marker in linkage disequilibrium therewith;

rs736005 (SEQ ID NO;

12) or a marker in linkage disequilibrium therewith;

rs6453211 (SEQ ID NO;

13) or a marker in linkage disequilibrium therewith;

rs4704298 (SEQ ID NO;

14) or a marker in linkage disequilibrium therewith;

rs1501926 (SEQ ID NO;

15) or a marker in linkage disequilibrium therewith;

rs11960621 (SEQ ID NO;

17) or a marker in linkage disequilibrium therewith;

rs2270927 (SEQ ID NO;

18) or a marker in linkage disequilibrium therewith; and

rs31244 (SEQ ID NO;

19) or a marker in linkage disequilibrium therewith;

wherein the test haplotype indicates the subject'"'"'s likely response to the treatment.

21. A method of selecting a subject for inclusion in a clinical trial, the method comprising:

obtaining a haplotype for the subject comprising at least one marker that is listed in Table A or is in linkage disequilibrium with a marker listed in Table A;

determining whether the haplotype is associated with altered response to a clinical treatment; and

including the subject if the haplotype indicates that the subject has altered response to the clinical treatment in question.

22. The method of claim 21, wherein the clinical trial is of a treatment for SZ, SPD, SD, or BD.

23. A method of selecting a subject for administration of a treatment for schizophrenia (SZ), schizotypal personality disorder (SPD), schizoaffective disorder (SD), or bipolar disorder (BD), the method comprising:

obtaining a haplotype for the subject, wherein the haplotype comprises at least one marker that is listed in Table A or is in linkage disequilibrium with a marker listed in Table A;

determining whether the haplotype is associated with an altered response profile for a clinical treatment; and

selecting the subject if the haplotype indicates that the subject is more likely to have an improved response profile to the clinical treatment in question.

24. A method of selecting a treatment for a subject, the method comprising:

obtaining a haplotype for the subject, wherein the haplotype comprises at least one marker that is listed in Table A or is in linkage disequilibrium with a marker listed in Table A;

determining whether the haplotype is associated with an altered response profile for a clinical treatment; and

selecting the treatment if the haplotype indicates that the subject is more likely to have an improved response profile to the clinical treatment in question.

25. A method of identifying haplotypes associated with altered outcome to a treatment for schizophrenia (SZ), schizotypal personality disorder (SPD), schizoaffective disorder (SD), or bipolar disorder (BD), the method comprising obtaining a haplotype for a subject, wherein the haplotype comprises at least one marker that is listed in Table A or is in linkage disequilibrium with a marker listed in Table A;

obtaining data regarding response to a treatment in the subject; and

correlating the haplotype with a response to the clinical treatment.

26. The method of claim 25, wherein the data regarding response to a treatment comprises at least one parameter selected from the group consisting of efficacy, side-effect profile, treatment maintenance and discontinuation rates, return to work status, hospitalizations, suicidality, total healthcare cost, social functioning scales, response to non-pharmacological treatments, and dose response curves.

27. The method of claim 26, wherein the side-effect profile includes one or more of weight gain, metabolic dysfunction, lipid dysfunction, movement disorders, and extrapyramidal symptoms.

28. The method of claim 26, wherein the information regarding outcome of the treatment is from a completed clinical trial.

29. A method of providing information regarding one or more of the following:

a subject'"'"'s risk of developing schizophrenia (SZ) or bipolar disorder (BD); and

clinical response to antipsychotic medications, the method comprising;

obtaining a sample from the subject at a first site;

transferring the sample to a second site for analysis, wherein the analysis provides data regarding the identity, presence or absence of at least one test marker that is listed in Table A or is in linkage disequilibrium with a marker listed in Table A;

analyzing the data for potential impact on one or more of the following;

a subject'"'"'s risk of developing schizophrenia (SZ) or bipolar disorder (BD); and

clinical response to antipsychotic medications; and

transferring the results of the analysis to one or more of the following;

a health care provider;

the subject;

a healthcare payer;

or a clinical trial sponsor.

30. The method of claim 29, wherein the data is transferred to a healthcare payer and used to decide whether to reimburse a health care provider or subject for medical expenses, including drug costs.