Fan et al 2005
have alerted us to the unresolved disparity between ethnicities regarding catechol-O-methyltransferase
(COMT) effect size in family-based association studies of schizophrenia. According
to
Glatt et al 2003
, it would seem that only in Europeans is the effect of the Val allele considerably
stronger (odds ratio [OR] = 2.2) than is observed in population-based association
studies (OR = 1.1). There is reason to doubt this view, because
Glatt et al 2003
re-calculated ORs for the original studies with a model known as the “haplotype relative
risk” model. In this model, fictitious healthy siblings of cases are assumed to carry
the alleles that were not transmitted to affected subjects. However, conceptualizing
siblings of affected subjects as non-diseased is not considered legitimate. In addition,
the model implies that the control subjects can only carry the alleles that the affected
subjects do not receive, thereby leading to an overestimate of the true relative risk
(for a review of related shortcomings, readers are referred to
Ahsan et al 2002
). Several alternatives have been developed to assist with the calculation of effect
size in the case-parent triad, including the method proposed by
Lohmueller et al 2003
. When this is applied to existing family-based studies of the COMT Val/Met variant
in schizophrenia with Comprehensive Meta-Analysis V2.2 (BioStat, Englewood, New Jersey),
pooled ORs in Europeans drop noticeably (OREuropean = 1.46; 95% confidence interval [CI]European = .9–2.3; Table 1). As a result, data are now in better agreement with
Fan et al 2005
and their recent meta-analysis of population-based studies of COMT alleles (OREuropean = 1.06; 95% CIEuropean = .9–1.2). Effect size in the European ethnicity, which had driven the earlier overall
significance of family-based associations in schizophrenia (
Glatt et al 2003
), is no longer significant (pEuropean > .09; ORoverall = 1.19; 95% CIoverall = 1.0–1.4; poverall > .08). Asian populations (ORAsian = 1.13; 95% CIAsian = .9–1.4; pAsian = .27) are only marginally affected by the statistical correction and still exhibit
a lower net effect size when compared with Europeans. An explanation of the remaining
disparity can be provided by a major difference in group size regarding the number
of transmissions counted (1:3 for Europeans/Asians). The present findings are in line
with a limited effect size of the Val/Met variant in schizophrenia both in Asians
and in Europeans.
Egan et al 2001
,
Fan et al 2002
,
Kunugi et al 1997
,
Li et al 2000
,
Lohmueller et al 2003
,
Semwal et al 2001
Table 1Family-Based Association Studies at COMT Val/Met Alleles in Schizophrenia: A Re-Analysis
of Pooled Effect Size
COMT, catechol-O-methyltransferase; OR, odds ratio; CI, confidence interval.
aData set includes two Japanese families.
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References
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Published online: August 10, 2006
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- ReplyBiological PsychiatryVol. 60Issue 6
- PreviewDr. Sand et al (2006) have pointed out the limitation of using “haplotype relative risk” model to calculate the effect size of transmission/disequilibrium test (TDT) studies in a previous study (Glatt et al 2003). They further used the method introduced by Lohmueller et al (2003) to re-analyze the five TDT studies in that study and found no significant overall evidence for association between the catechol-O-methyltransferase (COMT) Val allele and schizophrenia in both European and Asian populations.
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