Schizophrenia associated genes, proteins and biallelic markers

Abstract

The invention concerns the human sbg1, g34665, sbg2, g35017 and g35018 genes, polynucleotides, polypeptides biallelic markers, and human chromosome 13q31-q33 biallelic markers. The invention also concerns the association established between schizophrenia and bipolar disorder and the biallelic markers and the sbg1, g34665, sbg2, g35017 and g35018 genes and nucleotide sequences. The invention provides means to identify compounds useful in the treatment of schizophrenia, bipolar disorder and related diseases, means to determine the predisposition of individuals to said disease as well as means for the disease diagnosis and prognosis.

1 . An isolated polypeptide comprising any one of SEQ ID NO: 27 to 33 or 35. 
     
     
         2 . An isolated nucleic acid comprising:
 a) a nucleic acid sequence encoding a polypeptide according to  claim 1 ;   b) the polynucleotide sequence of nucleotide position 213818 to 243685 of SEQ ID NO: 1, or the complement thereof;   c) any of the polynucleotide sequences of SEQ ID NO: 2 or 3 or the complement thereof;   d) any of the polynucleotide sequences of SEQ ID NO: 4 to 26 or the complement thereof;   e) a polynucleotide encoding any of the polypeptide sequences of SEQ ID NO: 27 to 35;   f) a polynucleotide having at least 70% identity with any of the polynucleotide sequences of SEQ ID NO: 2 to 26 or the complement thereof;   g) a polynucleotide that hybridizes under stringent conditions with any of the polynucleotide sequences of SEQ ID NO: 2 to 26 or the complement thereof;   h) any of the polynucleotide sequences of SEQ ID NO: 44 to 53 or the complement thereof;   i) a fragment of at least 50 nucleotides of the polynucleotide specified in (b) or comprising a fragment of at least 15 nucleotides of any of the polynucleotides specified in (c) or comprising a fragment of at least 12 nucleotides of any of the polynucleotides specified in (d); or   j) a fragment of at least 12 nucleotides of any of the polynucleotides specified in (b) comprising any of the biallelic markers A85 to A219.   
     
     
         3 . An array of polynucleotides comprising a nucleic acid according to  claim 2  attached to a solid support. 
     
     
         4 . A recombinant vector, host cell, or non-human host animal comprising a nucleic acid according to  claim 2 . 
     
     
         5 . A diagnostic kit comprising a polynucleotide according to  claim 2 . 
     
     
         6 . An isolated or purified antibody that selectively binds to a polypeptide according to the polypeptide of any one of SEQ ID NO: 27-35. 
     
     
         7 . A method of genotyping or diagnosis comprising determining the identity of a nucleotide at any one of the biallelic markers shown as A85 to A219, or the complement thereof in a biological sample. 
     
     
         8 . A method of estimating the frequency of an allele of a biallelic marker in a population; detecting an association between a genotype and a trait; estimating the frequency of a haplotype for a set of biallelic markers in a population; detecting an association between a haplotype and a trait; determining whether an individual is at risk of schizophrenia or bipolar disorder; screening of a candidate substance that interacts with a sbg1 polypeptide; or screening molecules that modulate the expression of a sbg1 polypeptide. 
     
     
         9 . The method according to  claim 8 , wherein said method of estimating the frequency of an allele of a biallelic marker in a population comprises:
 a) genotyping individuals from said population for said biallelic marker according to the method of  claim 7 ; and   b) determining the proportional representation of said allele marker in said population.   
     
     
         10 . The method according to  claim 8 , wherein said method of detecting an association between a genotype and a trait comprises:
 a) determining the frequency of at least one biallelic marker in a trait positive population according to the method of  claim 9 ;   b) determining the frequency of at least one biallelic marker in a control population according to the method of  claim 9 ; and   c) determining whether a statistically significant association exists between said genotype and said trait.   
     
     
         11 . The method according to  claim 10 , wherein said trait is schizophrenia or bipolar disorder, predisposition to schizophrenia or bipolar disorder, an early onset of schizophrenia or bipolar disorder, or a beneficial response to or side effects related to treatment against schizophrenia or bipolar disorder, or a symptom of schizophrenia or bipolar disorder. 
     
     
         12 . The method according to  claim 8 , wherein said method of estimating the frequency of a haplotype for a set of biallelic markers in a population comprises:
 a) genotyping at least one biallelic marker according to the method of  claim 7  for each individual in said population;   b) genotyping a second biallelic marker by determining the identity of the nucleotides at said second biallelic marker for both copies of said second biallelic marker present in the genome of each individual in said population; and   c) applying a haplotype determination method to the identities of the nucleotides determined in steps a) and b) to obtain an estimate of said frequency.   
     
     
         13 . The method according to  claim 8 , wherein said method of detecting an association between a haplotype and a trait comprises:
 a) estimating the frequency of at least one haplotype in a trait positive population according to the method of  claim 12 ;   b) estimating the frequency of said haplotype in a control population according to the method of  claim 12 ; and   c) determining whether a statistically significant association exists between said haplotype and said trait.   
     
     
         14 . The method according to  claim 13 , wherein said trait is schizophrenia or bipolar disorder, predisposition to schizophrenia or bipolar disorder, an early onset of schizophrenia or bipolar disorder, or a beneficial response to or side effects related to treatment against schizophrenia or bipolar disorder, or a symptom of schizophrenia or bipolar disorder. 
     
     
         15 . The method according to  claim 8 , wherein said method of determining whether an individual is at risk of schizophrenia or bipolar disorder comprises:
 a) genotyping at least one biallelic marker according to the method of  claim 7 ; and   b) correlating the result of step a) with a risk of developing schizophrenia or bipolar disorder.   
     
     
         16 . The method according to  claim 8 , wherein said method for the screening of a candidate substance that interacts with a sbg1 polypeptide comprises:
 a) providing a polypeptide selected from:
 1) a polypeptide comprising any of the polypeptide sequences of SEQ ID NO: 27 to 35; 
 2) a polypeptide comprising a polypeptide encoded by any of the polynucleotide sequences of SEQ ID NO: 2 to 26; 
 3) a polypeptide comprising a polypeptide encoded by a polynucleotide having at least 70% identity with any of the polynucleotide sequences of SEQ ID NO: 2 to 26; 
 4) a polypeptide comprising a polypeptide encoded by a polynucleotide that hybridizes under stringent conditions with any of the polynucleotide sequences of SEQ ID NO: 2 to 26; or 
 5) a polypeptide comprising a fragment of at least 6 contiguous amino acid residues of any of the polypeptides specified in (1) to (4); 
   b) obtaining a candidate substance;   c) bringing into contact said polypeptide with said candidate substance; and   d) detecting the complexes formed between said polypeptide and said candidate substance.   
     
     
         17 . The method according to  claim 8 , wherein said method for screening molecules that modulate the expression of a sbg1 polypeptide comprises:
 a) cultivating a prokaryotic or eukaryotic cell that has been transfected with a polynucleotide sequence selected from:
 1) an isolated polynucleotide comprising the polynucleotide sequence of nucleotide position 213818 to 243685 of SEQ ID NO: 1, or the complement thereof; 
 2) an isolated polynucleotide comprising any of the polynucleotide sequences of SEQ ID NO: 2 or 3 or the complement thereof; 
 3) an isolated polynucleotide comprising any of the polynucleotide sequences of SEQ ID NO: 4 to 26 or the complement thereof; 
 4) an isolated polynucleotide comprising a polynucleotide encoding any of the polypeptide sequences of SEQ ID NO: 27 to 35; or 
 5) an isolated polynucleotide comprising a polynucleotide having at least 70% identity with any of the polynucleotide sequences of SEQ ID NO: 2 to 26 or the complement thereof; 
   b) bringing into contact the cultivated cell with a molecule to be tested; and   c) quantifying the expression of the protein encoded by said polynucleotide sequence.