Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia.
Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members--alpha, beta, and gamma--which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHalpha enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allele-specific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.
Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York 10461, United States.
Erika
E
Pedrosa
Radu
R
Stefanescu
Benjamin
B
Margolis
Oriana
O
Petruolo
Yungtai
Y
Lo
Karen
K
Nolan
Tomas
T
Novak
Pavla
P
Stopkova
Herbert M
HM
Lachman
D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001714:Bipolar Disorder / Q000175:diagnosis / Q000235:genetics*; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D035061:Control Groups; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*
D015820:Cadherins