Methods for assessing risk of developing a viral of disease using a genetic test

1. A method of treating a condition in a subject in need of immunosuppressive therapy, comprising: administering a therapeutically effective amount of an immunosuppressive agent to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is associated with the absence of one or more genetic variations in the subject, wherein the subject has been tested for a presence of the one or more genetic variations with a genetic assay and has been identified as not having the one or more genetic variations;

wherein the one or more genetic variations disrupts or modulates SERPINA1 gene, an AIRE gene, a C8B gene, an MCM5 gene, a CFHR2 gene, a DNASE1L3 gene, a FCN2 gene, a LY9 gene, an MDC1 gene or a PRAM1 gene.

2. The method of claim 1 , wherein the condition is multiple sclerosis or a relapsing form of multiple sclerosis.

3. The method of claim 1 , wherein the condition is Crohn's disease.

4. The method of claim 1 , wherein the immunosuppressive agent is interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab, diroximel fumarate, siponimod or any combination thereof.

5. The method of claim 1 , wherein the one or more genetic variations comprises chr21:45708278 G>A, chr14:94847262 T>A, chr1:57409459 C>A, chr22:35806756 G>A, chr1:196918605 A>G, chr3:58191230 G>T, chr9:137779251 G>A, chr1:160769595 AG>A, chr6:30673359 T>G, or chr19:8564523 T>G; wherein chromosome positions of the one or more genetic variations are defined with respect to UCSC hg19.

6. The method of claim 1 , wherein a first genetic variation of the one or more genetic variations comprises chr21:45708278 G>A, chr14:94847262 T>A, chr1:57409459 C>A, chr22:35806756 G>A, chr1:196918605 A>G, chr3:58191230 G>T, chr9:137779251 G>A, chr1:160769595 AG>A, chr6:30673359 T>G, chr19:8564523 T>G; and wherein a second genetic variation of the one or more genetic variations comprises chr2:163136505 C>G, chr11:67818269 G>A, chr22-23915745 G>A, chr16:81942175 A>G, chr19:7712287 G>C, chr1:92946625-G-C, chr1:42047208 C>G, chr22:23915583 T>C, chr1:27699670 AG>A, chr11:108106443 T>A, chr2:230579019 G>A, chr19:48643270 C>T, chr4:151793903 T>C, chr6:3015818 G>A, chr6:32814942 C>T, chr6:32816772 C>A, chr16:81939089 T>C, chr16:81942028 C>G or chr6:51798908 C>T, wherein the chromosome positions are defined with respect to UCSC hg19.

7. The method of claim 1 , wherein the one or more genetic variations have an odds ratio (OR) of 2 or more, and wherein the OR is:

[ D D /D N ]/[ N D /N N ],

wherein:

D D is the number of subjects in a diseased cohort of subjects with the one or more genetic variations;

D N the number of subjects in the diseased cohort without the one or more genetic variations;

N D is the number of subjects in a non-diseased cohort of subjects with the one or more genetic variations; and

N N is the number of subjects in the non-diseased cohort without the one or more genetic variations; and

wherein the diseased cohort of subjects have PML and the non-diseased cohort of subjects do not have PML.

8. The method of claim 1 , wherein a first genetic variation of the one or more genetic variations disrupts or modulates a gene selected from SERPINA1, AIRE, C8B, MCM5, CFHR2, DNASE1L3, FCN2, LY9, MDC1 and PRAM1; and wherein a second genetic variation of the one or more genetic variations disrupts or modulates a gene selected from IFIH1, TCIRG1, IGLL1, PLCG2, STXBP2, GFI1, HIVEP3, PKHD1, ATM, DNER, LIG1, LRBA, TAP1, FCN3 and NQO2.

9. The method of claim 1 , wherein the one or more genetic variations comprise an SNV in a gene selected from the group consisting of SERPINA1, AIRE, C8B, MCM5, CFHR2, DNASE1L3, FCN2, LY9, MDC1, and PRAM1.

10. The method of claim 9 , wherein a first genetic variation of the one or more genetic variations comprise an SNV in a gene selected from the group consisting of SERPINA1, AIRE, C8B, MCM5, CFHR2, DNASE1L3, FCN2, LY9, MDC1, and PRAM1; and wherein a second genetic variation of the one or more genetic variations disrupts or modulates a gene selected from IFIH1, TCIRG1, IGLL1, PLCG2, STXBP2, GFI1, HIVEP3, PKHD1, ATM, DNER, LIG1, LRBA, FCN3, NQO2 and TAP1.

11. The method of claim 7 , wherein the diseased cohort of subjects, the non-diseased cohort of subjects, or both cohorts of subjects are ethnically matched.

12. The method of claim 7 , wherein the one or more genetic variations have an odds ratio (OR) of 6 or more.

13. The method of claim 1 , wherein the subject has been identified as not having one or more other genetic variations that disrupt or modulate a corresponding gene according to Tables 1, 3, 6-10, 28A, 29, 31, 34-36, 47 and 48.

14. The method of claim 1 , wherein the subject is identified as not having one or more other genetic variations that disrupt or modulate a corresponding gene according to Tables 19-24, 40 and 42.

15. The method of claim 1 , wherein the subject has been tested with a JCV-antibody test, a CD62L test, or a CSF IgM oligoclonal bands test.

16. The method of claim 1 , wherein the one or more genetic variations comprise two or more genetic variations.

17. The method of claim 1 , wherein the method further comprises testing the subject for the presence of the one or more genetic variations with the genetic assay prior to the administering.

18. The method of claim 17 , wherein the genetic assay comprises microarray analysis, PCR, sequencing, nucleic acid hybridization, or any combination thereof.

19. The method of claim 17 , wherein the one or more genetic variations disrupt or modulate one or more immune response-related genes or immune pathway related genes.

20. The method of claim 17 , wherein prior to testing the subject for the presence of the one or more genetic variations with the genetic assay the method further comprises obtaining biological samples from subjects with PML and (a) confirming each biological sample is not a duplicate of any other biological sample based on nucleic acid information of the biological samples or (b) determining a sex genotype for each biological sample based on nucleic acid information of the biological samples, and confirming the sex genotype of each biological sample is the same as a sex phenotype of the subject with PML from which the biological sample was obtained.

21. The method of claim 1 , wherein the one or more genetic variations disrupts or modulates a SERPINA1 gene.

22. The method of claim 1 , wherein the one or more genetic variations disrupts or modulates an AIRE gene.

23. The method of claim 1 , wherein the one or more genetic variations disrupts or modulates a C8B gene.

24. The method of claim 1 , wherein the one or more genetic variations disrupts or modulates an MCM5 gene.

25. The method of claim 1 , wherein the one or more genetic variations disrupts or modulates a CFHR2 gene.

26. The method of claim 1 , wherein the one or more genetic variations disrupts or modulates a DNASE1L3 gene.

27. The method of claim 1 , wherein the one or more genetic variations disrupts or modulates a FCN2 gene.

28. The method of claim 1 , wherein the one or more genetic variations disrupts or modulates a LY9 gene.

29. The method of claim 1 , wherein the one or more genetic variations disrupts or modulates an MDC1 gene.

30. The method of claim 1 , wherein the one or more genetic variations disrupts or modulates a PRAM1 gene.