Survey of schizophrenia and bipolar disorder candidate genes using chromatin immunoprecipitation and tiled microarrays (ChIP-chip).
It has been difficult to identify disease-causing alleles in schizophrenia (SZ) and bipolar disorder (BD) candidate genes. One reason is that responsible functional variants may exist in unidentified regulatory domains. With the advent of microarray technology and high throughput sequencing, however, it is now feasible to screen genes for such regulatory domains relatively easily by using chromatin immunoprecipitation-based methodologies, such as ChIP-chip and ChIP-seq. In ChIP-chip, regulatory sequences can be captured from chromatin immunoprecipitates prepared with antibodies against covalently modified histones that mark certain regulatory domains; DNA extracted from such immunoprecipitates can then be used as microarray probes. As a first step toward demonstrating the feasibility of this approach in psychiatric genetics, we used ChIP-chip to identify regulatory domains in several candidate genes: NRG1, DTNBP1, DISC1, DAO, DAOA, PDE4B, and COMT. Immunoprecipitates were generated with antibodies to histone H3 acetylated at lysine 9 (H3K9Ac) and histone H3 monomethylated at lysine 4 (H3K4me1), which mark promoters and some enhancers, using fetal brain chromatin as a substrate. Several novel putative regulatory elements, as well as the core and proximal promoters for each gene, were enriched in the immunoprecipitates. Genetic variants within these regions would be of interest to study as potential disease-associated alleles.
Pedrosa
Erika
E
Department of Psychiatry, Division of Basic Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Locker
Joseph
J
Lachman
Herbert M
HM
D001714:Bipolar Disorder / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D002394:Catechol O-Methyltransferase / Q000235:genetics; D047369:Chromatin Immunoprecipitation / Q000379:methods*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics; D003605:D-Amino-Acid Oxidase / Q000235:genetics; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D005333:Fetus; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine / Q000235:genetics; D046228:Microarray Analysis / Q000379:methods*; D009419:Nerve Tissue Proteins / Q000235:genetics; D020890:Neuregulin-1 / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*
D002352:Carrier Proteins; C475071:DAOA protein, human; C412476:DISC1 protein, human; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C417983:DAO protein, human; D003605:D-Amino-Acid Oxidase; D002394:Catechol O-Methyltransferase; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; D008239:Lysine