Estimating haplotype-disease associations with pooled genotype data.
The genetic dissection of complex human diseases requires large-scale association studies which explore the population associations between genetic variants and disease phenotypes. DNA pooling can substantially reduce the cost of genotyping assays in these studies, and thus enables one to examine a large number of genetic variants on a large number of subjects. The availability of pooled genotype data instead of individual data poses considerable challenges in the statistical inference, especially in the haplotype-based analysis because of increased phase uncertainty. Here we present a general likelihood-based approach to making inferences about haplotype-disease associations based on possibly pooled DNA data. We consider cohort and case-control studies of unrelated subjects, and allow arbitrary and unequal pool sizes. The phenotype can be discrete or continuous, univariate or multivariate. The effects of haplotypes on disease phenotypes are formulated through flexible regression models, which allow a variety of genetic hypotheses and gene-environment interactions. We construct appropriate likelihood functions for various designs and phenotypes, accommodating Hardy-Weinberg disequilibrium. The corresponding maximum likelihood estimators are approximately unbiased, normally distributed, and statistically efficient. We develop simple and efficient numerical algorithms for calculating the maximum likelihood estimators and their variances, and implement these algorithms in a freely available computer program. We assess the performance of the proposed methods through simulation studies, and provide an application to the Finland-United States Investigation of NIDDM Genetics Study. The results show that DNA pooling is highly efficient in studying haplotype-disease associations. As a by-product, this work provides valid and efficient methods for estimating haplotype-disease associations with unpooled DNA samples.
Zeng
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Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599-7420, USA.
Lin
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DY
D000465:Algorithms; D016022:Case-Control Studies; D015331:Cohort Studies; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D030561:Databases, Nucleic Acid; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D010641:Phenotype; D018401:Sample Size