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A method for identifying genetic heterogeneity within phenotypically defined disease subgroups.

ABSTRACT: Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic architectures, in which disease-associated variants have different effect sizes in two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximizing power in comparison to standard variant-by-variant subgroup analysis. Where evidence for genetic subgrouping is found, we present methods for post hoc identification of the contributing genetic variants. We demonstrate the method on a range of simulated and test data sets, for which expected results are already known. We investigate subgroups of individuals with type 1 diabetes (T1D) defined by autoantibody positivity, establishing evidence for differential genetic architecture with positivity for thyroid-peroxidase-specific antibody, driven generally by variants in known T1D-associated genomic regions.

SUBMITTER: Liley J

PROVIDER: S-EPMC5357574 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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A method for identifying genetic heterogeneity within phenotypically defined disease subgroups.

Liley James J Todd John A JA Wallace Chris C

Nature genetics 20161226 2

Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic architectures, in which disease-associated variants have different effect sizes in two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximiz ...[more]

PMID: 28024155

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A method for identifying genetic heterogeneity within phenotypically defined disease subgroups.

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A method for identifying genetic heterogeneity within phenotypically defined disease subgroups.

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