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Am J Hum Genet. 2002 April; 70(4): 920–934.
Published online 2002 March 4.
PMCID: PMC379120
Quantitative-Trait Homozygosity and Association Mapping and Empirical Genomewide Significance in Large, Complex Pedigrees: Fasting Serum-Insulin Level in the Hutterites
Mark Abney,1,2 Carole Ober,1 and Mary Sara McPeek1,2
Departments of 1Human Genetics and 2Statistics, University of Chicago, Chicago
Address for correspondence: Dr. Mark Abney, Department of Human Genetics, University of Chicago, 920 East 58th Street, Chicago, IL 60637. E-mail: abney/at/genetics.uchicago.edu
Received October 24, 2001; Accepted January 10, 2002.
Abstract
We present methods for linkage and association mapping of quantitative traits for a founder population with a large, known genealogy. We detect linkage to quantitative-trait loci (QTLs) through a multipoint homozygosity-mapping method. We propose two association methods, one of which is single point and uses a general two-allele model and the other of which is multipoint and uses homozygosity by descent for a particular allele. In all three methods, we make extensive use of the pedigree and genotype information, while keeping the computations simple and efficient. To assess significance, we have developed a permutation-based test that takes into account the covariance structure due to relatedness of individuals and can be used to determine empirical genomewide and locus-specific P values. In the case of multivariate-normally distributed trait data, the permutation-based test is asymptotically exact. The test is broadly applicable to a variety of mapping methods that fall within the class of linear statistical models (e.g., variance-component methods), under the assumption of random ascertainment with respect to the phenotype. For obtaining genomewide P values, our proposed method is appropriate when positions of markers are independent of the observed linkage signal, under the null hypothesis. We apply our methods to a genome screen for fasting insulin level in the Hutterites. We detect significant genomewide linkage on chromosome 19 and suggestive evidence of QTLs on chromosomes 1 and 16.