Mutation screening of the DTNBP1 exonic sequence in 669 schizophrenics and 710 controls using high-resolution melting analysis.
A large number of independent studies have reported evidence for association between the dysbindin gene (DTNBP1) and schizophrenia; however, specific risk alleles have been not been implicated as causal. In this study we set out to perform a comprehensive assessment of DNA variation within the exonic sequence of DTNBP1. To achieve this we optimized a high-resolution melting analysis (HRMA) protocol and applied it to screen all 11 DTNBP1 exons for DNA variants in a sample of 669 cases and 710 controls from the UK. Despite identifying seven exonic variants with a minor allele frequency (MAF) >0.01, none was significantly associated with schizophrenia (minimum P = 0.054), showing that the strong association we previously reported in this sample is not the result of association to a common functional variant located within the exonic sequence of any of the three major DTNBP1 transcripts. We also sought additional support for DTNBP1 as a susceptibility gene for schizophrenia by testing the hypothesis that rare exonic highly penetrant variants exist at the DTNBP1 locus. Our analysis failed to identify an enrichment of rare functional variants in the patients compared to the controls. Taken as a whole, this data demonstrate that if DTNBP1 is a risk gene for schizophrenia then risk is not conferred by mutations that affect the structure of the dysbindin protein.
MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, Cardiff University, Cardiff, UK.
S
S
Dwyer
L
L
Carroll
K K
KK
Mantripragada
M J
MJ
Owen
M C
MC
O'Donovan
N M
NM
Williams
D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis / Q000379:methods*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D005091:Exons / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D009691:Nucleic Acid Denaturation / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D012680:Sensitivity and Specificity
D002352:Carrier Proteins; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins