Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: fasting serum-insulin level in the Hutterites

Am J Hum Genet. 2002 Apr;70(4):920-34. doi: 10.1086/339705. Epub 2002 Mar 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Chromosome Mapping / methods*
  • Chromosome Mapping / statistics & numerical data
  • Chromosomes, Human, Pair 1 / genetics
  • Chromosomes, Human, Pair 16 / genetics
  • Chromosomes, Human, Pair 19 / genetics
  • Ethnic Groups / genetics*
  • Fasting / blood*
  • Female
  • Founder Effect
  • Genetic Linkage / genetics
  • Genome, Human
  • Homozygote*
  • Humans
  • Insulin / blood*
  • Male
  • Models, Genetic
  • Pedigree
  • Quantitative Trait, Heritable*
  • Religion
  • South Dakota


  • Insulin