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Allelic heterogeneity in genetic association meta-analysis: an application to DTNBP1 and schizophrenia.

ABSTRACT: BACKGROUND/AIMS:Meta-analysis of genetic association studies is a useful approach when individual investigations do not yield studywise significant results but the evidence across studies is modest and homogeneous. Current meta-analysis methods account for heterogeneity by down-weighting studies as a function of between-study variance. We contend that current approaches may obscure interesting phenomena in genetic association data. However, an appropriate approach to examining heterogeneity across studies is lacking. METHODS:We develop a novel approach, based on the EM algorithm, to detect allelic heterogeneity, identify subpopulations and assign studies to those subpopulations. We then apply these methods to the association between DTNBP1 and schizophrenia (Scz), one of the most studied relationships in complex disease genetics. We examined 32 published and unpublished population and family-based association studies containing up to 14 SNPs spanning the DTNBP1 locus. RESULTS:We explored heterogeneity in several ways including meta-regression and approaches aimed at exploring the mixture of heterogeneous studies at a particular SNP. We found significant evidence for a mixture of association distributions at multiple loci. CONCLUSION:We propose a novel approach that is broadly applicable and may be useful in large scale genetic association meta-analyses to detect significant allelic heterogeneity.

SUBMITTER: Maher BS

PROVIDER: S-EPMC7077085 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Allelic heterogeneity in genetic association meta-analysis: an application to DTNBP1 and schizophrenia.

Maher Brion S BS Reimers Mark A MA Riley Brien P BP Kendler Kenneth S KS

Human heredity 20091204 2

<h4>Background/aims</h4>Meta-analysis of genetic association studies is a useful approach when individual investigations do not yield studywise significant results but the evidence across studies is modest and homogeneous. Current meta-analysis methods account for heterogeneity by down-weighting studies as a function of between-study variance. We contend that current approaches may obscure interesting phenomena in genetic association data. However, an appropriate approach to examining heterogene ...[more]

PMID: 19996605

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Project description:BACKGROUND:Straub et al. (2002b) located a susceptibility region for schizophrenia at the DTNBP1 locus. At least 40 studies (including one study in US populations) attempted to replicate this original finding, but the reported findings are highly diverse and at least five pathways by which dysbindin protein might be involved in schizophrenia have been proposed. This study aimed to test the association in two common US populations by using powerful analytic methods. METHODS:Six markers at DTNBP1 were genotyped by mass spectroscopy ('MassARRAY' technique) in a sample of 663 individuals, including 346 healthy individuals European-Americans (EAs) and 48 African-Americans (AAs), and 317 individuals with schizophrenia (235 EAs and 82 AAs). Thirty-eight ancestry-informative markers were genotyped in this sample to infer the ancestry proportions. Diplotype, haplotype, genotype, and allele frequency distributions were compared between the cases and controls, controlling for possible population stratification, admixture, and sex-specific effects, and taking interaction effects into account, using a logistic regression analysis (an extended structured association method). RESULTS:Conventional case-control comparisons showed that genotypes of the markers P1578 (rs1018381) and P1583 (rs909706) were nominally associated with schizophrenia in EAs and in AAs, respectively. These associations became less or nonsignificant after controlling for population stratification and admixture effects (using structured association or regression analysis), and became nonsignificant after correction for multiple testing. However, regression analysis showed that the common diplotypes (ACCCTT/GCCGCC or GCCGCC/GCCGCC) and the interaction effects of haplotypes GCCGCC/GCCGCC significantly affected risk for schizophrenia in EAs, effects that were modified by sex. Fine-mapping using d or J statistics located the specific markers (d: P1328; J: P1333) closest to the putative risk sites in EAs. CONCLUSION:This study shows that DTNBP1 is a risk gene for schizophrenia in EAs. Variation at DTNBP1 may modify risk for schizophrenia in this population.

Dataset Information

Allelic heterogeneity in genetic association meta-analysis: an application to DTNBP1 and schizophrenia.

Publications

Allelic heterogeneity in genetic association meta-analysis: an application to DTNBP1 and schizophrenia.

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