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Using Extended Genealogy to Estimate Components of Heritability for 23 Quantitative and Dichotomous Traits

Author

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  • Noah Zaitlen
  • Peter Kraft
  • Nick Patterson
  • Bogdan Pasaniuc
  • Gaurav Bhatia
  • Samuela Pollack
  • Alkes L Price

Abstract

Important knowledge about the determinants of complex human phenotypes can be obtained from the estimation of heritability, the fraction of phenotypic variation in a population that is determined by genetic factors. Here, we make use of extensive phenotype data in Iceland, long-range phased genotypes, and a population-wide genealogical database to examine the heritability of 11 quantitative and 12 dichotomous phenotypes in a sample of 38,167 individuals. Most previous estimates of heritability are derived from family-based approaches such as twin studies, which may be biased upwards by epistatic interactions or shared environment. Our estimates of heritability, based on both closely and distantly related pairs of individuals, are significantly lower than those from previous studies. We examine phenotypic correlations across a range of relationships, from siblings to first cousins, and find that the excess phenotypic correlation in these related individuals is predominantly due to shared environment as opposed to dominance or epistasis. We also develop a new method to jointly estimate narrow-sense heritability and the heritability explained by genotyped SNPs. Unlike existing methods, this approach permits the use of information from both closely and distantly related pairs of individuals, thereby reducing the variance of estimates of heritability explained by genotyped SNPs while preventing upward bias. Our results show that common SNPs explain a larger proportion of the heritability than previously thought, with SNPs present on Illumina 300K genotyping arrays explaining more than half of the heritability for the 23 phenotypes examined in this study. Much of the remaining heritability is likely to be due to rare alleles that are not captured by standard genotyping arrays.Author Summary: Phenotype is a function of a genome and its environment. Heritability is the fraction of variation in a phenotype determined by genetic factors in a population. Current methods to estimate heritability rely on the phenotypic correlations of closely related individuals and are potentially upwardly biased, due to the impact of epistasis and shared environment. We develop new methods to estimate heritability over both closely and distantly related individuals. By examining the phenotypic correlation among different types of related individuals such as siblings, half-siblings, and first cousins, we show that shared environment is the primary determinant of inflated estimates of heritability. For a large number of phenotypes, it is not known how much of the heritability is explained by SNPs included on current genotyping platforms. Existing methods to estimate this component of heritability are biased in the presence of related individuals. We develop a method that permits the inclusion of both closely and distantly related individuals when estimating heritability explained by genotyped SNPs and use it to make estimates for 23 medically relevant phenotypes. These estimates can be used to increase our understanding of the distribution and frequency of functionally relevant variants and thereby inform the design of future studies.

Suggested Citation

  • Noah Zaitlen & Peter Kraft & Nick Patterson & Bogdan Pasaniuc & Gaurav Bhatia & Samuela Pollack & Alkes L Price, 2013. "Using Extended Genealogy to Estimate Components of Heritability for 23 Quantitative and Dichotomous Traits," PLOS Genetics, Public Library of Science, vol. 9(5), pages 1-11, May.
  • Handle: RePEc:plo:pgen00:1003520
    DOI: 10.1371/journal.pgen.1003520
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    References listed on IDEAS

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    1. Brendan Maher, 2008. "Personal genomes: The case of the missing heritability," Nature, Nature, vol. 456(7218), pages 18-21, November.
    2. Teri A. Manolio & Francis S. Collins & Nancy J. Cox & David B. Goldstein & Lucia A. Hindorff & David J. Hunter & Mark I. McCarthy & Erin M. Ramos & Lon R. Cardon & Aravinda Chakravarti & Judy H. Cho &, 2009. "Finding the missing heritability of complex diseases," Nature, Nature, vol. 461(7265), pages 747-753, October.
    3. Shashaank Vattikuti & Juen Guo & Carson C Chow, 2012. "Heritability and Genetic Correlations Explained by Common SNPs for Metabolic Syndrome Traits," PLOS Genetics, Public Library of Science, vol. 8(3), pages 1-8, March.
    4. Ian J. Deary & Jian Yang & Gail Davies & Sarah E. Harris & Albert Tenesa & David Liewald & Michelle Luciano & Lorna M. Lopez & Alan J. Gow & Janie Corley & Paul Redmond & Helen C. Fox & Suzanne J. Row, 2012. "Genetic contributions to stability and change in intelligence from childhood to old age," Nature, Nature, vol. 482(7384), pages 212-215, February.
    5. Alkes L Price & Agnar Helgason & Gudmar Thorleifsson & Steven A McCarroll & Augustine Kong & Kari Stefansson, 2011. "Single-Tissue and Cross-Tissue Heritability of Gene Expression Via Identity-by-Descent in Related or Unrelated Individuals," PLOS Genetics, Public Library of Science, vol. 7(2), pages 1-9, February.
    6. Peter M Visscher & Sarah E Medland & Manuel A R Ferreira & Katherine I Morley & Gu Zhu & Belinda K Cornes & Grant W Montgomery & Nicholas G Martin, 2006. "Assumption-Free Estimation of Heritability from Genome-Wide Identity-by-Descent Sharing between Full Siblings," PLOS Genetics, Public Library of Science, vol. 2(3), pages 1-10, March.
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