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A Bayesian approach to genetic association studies with family-based designs.

ABSTRACT: For genome-wide association studies with family-based designs, we propose a Bayesian approach. We show that standard transmission disequilibrium test and family-based association test statistics can naturally be implemented in a Bayesian framework, allowing flexible specification of the likelihood and prior odds. We construct a Bayes factor conditional on the offspring phenotype and parental genotype data and then use the data we conditioned on to inform the prior odds for each marker. In the construction of the prior odds, the evidence for association for each single marker is obtained at the population-level by estimating its genetic effect size by fitting the conditional mean model. Since such genetic effect size estimates are statistically independent of the effect size estimation within the families, the actual data set can inform the construction of the prior odds without any statistical penalty. In contrast to Bayesian approaches that have recently been proposed for genome-wide association studies, our approach does not require assumptions about the genetic effect size; this makes the proposed method entirely data-driven. The power of the approach was assessed through simulation. We then applied the approach to a genome-wide association scan to search for associations between single nucleotide polymorphisms and body mass index in the Childhood Asthma Management Program data.

SUBMITTER: Naylor MG

PROVIDER: S-EPMC3349938 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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A Bayesian approach to genetic association studies with family-based designs.

Naylor Melissa G MG Weiss Scott T ST Lange Christoph C

Genetic epidemiology 20100901 6

For genome-wide association studies with family-based designs, we propose a Bayesian approach. We show that standard transmission disequilibrium test and family-based association test statistics can naturally be implemented in a Bayesian framework, allowing flexible specification of the likelihood and prior odds. We construct a Bayes factor conditional on the offspring phenotype and parental genotype data and then use the data we conditioned on to inform the prior odds for each marker. In the co ...[more]

PMID: 20818722

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Project description:The cost of next-generation sequencing is now approaching that of early GWAS panels, but is still out of reach for large epidemiologic studies and the millions of rare variants expected poses challenges for distinguishing causal from non-causal variants. We review two types of designs for sequencing studies: two-phase designs for targeted follow-up of genomewide association studies using unrelated individuals; and family-based designs exploiting co-segregation for prioritizing variants and genes. Two-phase designs subsample subjects for sequencing from a larger case-control study jointly on the basis of their disease and carrier status; the discovered variants are then tested for association in the parent study. The analysis combines the full sequence data from the substudy with the more limited SNP data from the main study. We discuss various methods for selecting this subset of variants and describe the expected yield of true positive associations in the context of an on-going study of second breast cancers following radiotherapy. While the sharing of variants within families means that family-based designs are less efficient for discovery than sequencing unrelated individuals, the ability to exploit co-segregation of variants with disease within families helps distinguish causal from non-causal ones. Furthermore, by enriching for family history, the yield of causal variants can be improved and use of identity-by-descent information improves imputation of genotypes for other family members. We compare the relative efficiency of these designs with those using unrelated individuals for discovering and prioritizing variants or genes for testing association in larger studies. While associations can be tested with single variants, power is low for rare ones. Recent generalizations of burden or kernel tests for gene-level associations to family-based data are appealing. These approaches are illustrated in the context of a family-based study of colorectal cancer.

Dataset Information

A Bayesian approach to genetic association studies with family-based designs.

Publications

A Bayesian approach to genetic association studies with family-based designs.

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