Original Paper

Locus-Specific Heritability Estimation via the Bootstrap in Linkage Scans for Quantitative Trait Loci
Long Yang Wu^a, Lei Sun^{b, c}, Shelley B. Bull<sup>a, b

a</sup>Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto,
^bDepartment of Public Health Sciences, University of Toronto, Toronto,
^cHospital for Sick Children Research Institute, Toronto, Canada

Address of Corresponding Author

Hum Hered 2006;62:84-96 (DOI: 10.1159/000096096)

  Key Words

• Bias reduction
• Genome scan
• Genome-wide
• Resampling
• Variance components
• Linkage analysis
• Effect size estimation
• QTL
• Framingham Heart Study

  Abstract

Background/Aims: In genome-wide linkage analysis ofquantitative trait loci (QTL), locus-specific heritability estimates are biased when the original data are used to both localize linkage and estimate effects, due to maximization of the LOD score over the genome. Positive bias is increased by adoption of stringent significance levels to control genome-wide type I error. We propose multi-locus bootstrap resampling estimators for bias reduction in the situation in which linkage peaks at more than one QTL are of interest. Methods: Bootstrap estimates were based on repeated sample splitting in the original dataset. We conducted simulation studies in nuclear families with 0 to 5 QTLs and applied the methods in a genome-wide analysis of a blood pressure phenotype in extended pedigrees from the Framingham Heart Study (FHS). Results: Compared to naïve estimates in the original simulation samples, bootstrap estimates had reduced bias and smaller mean squared error. In the FHS pedigrees, the bootstrap yielded heritability estimates as much as 70% smaller than in the original sample. Conclusions: Because effect estimates obtained in an initial study are typically inflated relative to those expected in an independent replication study, successful replication will be more likely when sample size requirements are based on bias-reduced estimates.

Copyright © 2006 S. Karger AG, Basel

  Author Contacts

Dr. Shelley B. Bull, Samuel Lunenfeld Research Institute of
Mount Sinai Hospital, Prosserman Centre for Health Research
Lebovic Building 5th floor, 60 Murray Street, Box # 18
Toronto, Ont. M5T 3L9 (Canada)
Tel. +1 416 586 8245, Fax +1 416 586 8404, E-Mail bull@mshri.on.ca

  Article Information

The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI, Contract No. N01-HC-25195), in collaboration with Boston University School of Medicine. This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Conditions for use of the Framingham Heart Study data were approved by the Research Ethics Board of Mount Sinai Hospital, Toronto, Canada. We gratefully acknowledge the contribution of Boston University staff (Framingham Heart Study) and the Investigators within the Framingham Heart Study who have collected and analysed these data.

Received: April 24, 2006
Accepted after revision: August 1, 2006
Published online: October 12, 2006
Number of Print Pages : 13
Number of Figures : 6, Number of Tables : 4, Number of References : 23