Protein Phosphatase 3 Calcineurin Gamma Isoform Catalytic Subunit PPP3CC and Schizophrenia: An Assoc

1
Protein Phosphatase 3 Calcineurin Gamma Isoform
Catalytic Subunit (PPP3CC) and Schizophrenia An
Association

• Akochi Agunwamba,
• University of Massachusetts, Boston
• Summer Research Program in Genomics,
• Kimberly Aldinger, B.A.
• Pamela Sklar, M.D, Ph.D.
• Neuropsychiatric Genetics Group,
• Program in Medical and Population Genetics,
• Broad Institute of MIT and Harvard, Cambridge, MA

2
Road Map

• Schizophrenia (SCZ) Introduced
• PPP3CC association with SCZ
• Project goals
• Methods
• Results
• Concluding thoughts

3
Schizophrenia A Terrible Disease

• Schizophrenia is a devastating brain
  disorderthe most chronic and disabling of the
  severe mental illnesses.1
• 1. http//www.nimh.nih.gov/publicat/schizsoms.cfm

4
SCZ No Known Cure !

• Affects 1 out of 100 people everywhere
• Symptoms Delusions, hallucinations, incoherent
  speech, severely disorganized and catatonic
  behavior
• Multifactorial Environmental and genetic causes
• There is no known cure! It can only be managed.

5
Pharmacological Studies and Mice Models Implicate
Calcineurin in SCZ

• Pharmacological studies show calcineurin is
  important component of several neurological
  processes in mice and humans1.2
• Calcineurin (a protein) regulatory subunit
  catalytic subunit2
• Mice lacking calcineurin regulatory protein
  showed SCZ-like symptoms1
• PPP3CC a calcineurin catalytic protein shows
  association with SCZ in a study by Gerber et al.2

• Miyakawa, T. et al (2003), Conditional
  calcineurin knockout mice exhibit multiple
  abnormal behaviors related to schizophrenia.
  Proc. Nat. Acad. Sci. 100 8987-8992.
• Gerber, D. J. et al. (2003), Evidence for
  association of schizophrenia with genetic
  variation in the 8p21.3 gene, PPP3CC, encoding
  the calcineurin gamma subunit. Proc. Nat. Acad.
  Sci. 100 8993-8998.

6
Gerber et al. Found Association with One PPP3CC
Haplotype

• US Sample 210 trios South African Afrikaans
  sample 200 trios
• CC1a CC20 CC21
  CCS3
• PPP3CC
• Locus
  
  
  
  
• TDT
• Freq
  T/nT p-value
• 41 C T G A 1.26 0.00121
• Haplotype
• Gerber, D. J. et al. (2003), Evidence for
  association of schizophrenia with genetic
  variation in the 8p21.3 gene, PPP3CC, encoding
  the calcineurin gamma subunit. Proc. Nat. Acad.
  Sci. 100 8993-8998.

7
Goals Of the Project

• Fully capture variation in PPP3CC locus
• Verify Gerber association

8
The Sample

• 111 trios of affected and two parents (one trio
  per pedigree)
• 321 Cases and 242 Controls
• Portuguese ancestry

9
Genotyping and Analysis

• The SNPs we selected for genotyping
• The Gerber SNPs
• Two additional SNPs from the HapMap SNP database
• We genotyped the SNPs using standard methods
• We performed the TDT on the combined sample

10
Gerber et al. SNPs Do not Capture PPP3CC Enough
Variation

• HapMap_SNP1
  HapMap_SNP2
• CC1a
  CC20 CC21 CCS3
• PPP3CC
• Locus
  
  
  
  
• TDT
• Freq p-value
• Gerber Haplotype 39.05 C - T - G
  A 0.12
• 1st sub haplotype 38.93 C A T C G
  A 0.037
• 2nd sub haplotype 0.13 C A T T G
  A 0.45

11
Limits of Study

• Our sample was Caucasian-only
• A larger sample size would be more informative

12
Conclusions

• We achieved our goals
• We fully captured the variation in the PPP3CC
  region in our sample
• We verified the Gerber association
• We also found
• Gerber SNPs do not characterized variation at
  PPP3CC locus
• Significant Gerber haplotype included two
  sub-haplotypes
• A significant sub-haplotype a very insignificant
  sub-haplotype
• The combined significant and insignificant
  sub-haplotypes caused the discrepancy with our
  results

13
Conclusions (contd.)

• Open questions
• Can Gerber et al. replicate our findings in their
  sample?
• Are our results valid in larger and more diverse
  samples?

14
Acknowledgements

• Emily Walsh
• Alejandro Palma
• Whitney Green
• Manuel Rivas
• Elizabeth Rossin
• Angela Gabriel
• Jennifer Meade
• Roy Charles

• The Broad institute
• Program in Population Genetics
• Pamela Sklar
• Kimberly Aldinger
• Skye Waggonner
• Anthony Tahl

• Contact information akochi_at_cs.umb.edu