Recent research suggests that variation in the gene encoding dystrobrevin
binding protein (DTNBP1) confers susceptibility to
schizophrenia. Thus far, no specific risk haplotype has been identified in
more than 1 study.
To confirm DTNBP1 as a schizophrenia susceptibility
gene, to identify and replicate specific risk and protective haplotypes, and
to explore relationships between DTNBP1 and the phenotype.
Genetic association study based on mutation detection and case-control
All subjects were unrelated and ascertained from general (secondary
care) psychiatric inpatient and outpatient services.
The Cardiff, Wales, sample included 708 white subjects from the United
Kingdom and Ireland (221 females) who met DSM-IV criteria
for schizophrenia and were individually matched for age, sex, and ethnicity
to 711 blood donor controls (233 females). Mean ± SD age at first psychiatric
contact for cases was 23.6 ± 7.7 years; mean age at ascertainment was
41.8 ± 13.5 years. The Dublin, Ireland, sample included 219 white subjects
from the Republic of Ireland who met DSM-III-R criteria
for schizophrenia or schizoaffective disorder and 231 controls. The mean age
of the Irish cases was 46.0 ± 8.5 years; mean age at first psychiatric
contact was 25.2 ± 12.4 years.
Main Outcome Measure
Evidence for association between the DTNBP1 locus
In the Cardiff sample, there was no evidence for association with previously
implicated haplotypes but strong evidence for association with multiple novel
haplotypes. Maximum evidence was found for a novel 3-marker haplotype (global P<.001), composed of 1 risk haplotype (P = .01) and 2 protective haplotypes, 1 common (P = .006) and 1 rare (P<.001). Specific
risk and protective haplotypes were replicated in the Dublin sample (P = .02, .047, and .006, respectively). The only phenotypic
variable associated with any haplotype was between the common protective haplotype
and higher educational achievement (P = .02, corrected
for multiple tests).
DTNBP1 is a susceptibility gene for schizophrenia.
Specific risk and protective haplotypes were identified and replicated. Association
with educational achievement may suggest protection mediated by IQ, although
this needs to be confirmed in an independent data set.