Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: fasting serum-insulin level in the Hutterites.
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.
Abney
Mark
M
Department of Human Genetics, University of Chicago, 920 East 85th Street, Chicago, IL 60637, USA. abney@genetics.uchicago.edu
Ober
Carole
C
McPeek
Mary Sara
MS
D000483:Alleles; D002874:Chromosome Mapping / Q000379:methods* / Q000706:statistics & numerical data; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D005006:Ethnicity / Q000235:genetics*; D005215:Fasting / Q000097:blood*; D005260:Female; D018703:Founder Effect; D008040:Genetic Linkage / Q000235:genetics; D015894:Genome, Human; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000097:blood*; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D019655:Quantitative Trait, Heritable; D012067:Religion; D013023:South Dakota
D007328:Insulin