Abstract
BackgroundUsing the longitudinal Framingham Heart Study data on blood pressure, we analyzed the reproducibility of linkage measures from serial cross-sectional surveys of a defined population by performing genome-wide model-free linkage analyses to systolic blood pressure (SBP) and history of hypertension (HTN) measured at five separate time points.ResultsThe heritability of SBP was relatively stable over time, ranging from 11.6 to 23.5% (coefficient of variation = 25.7%). However, the variability in linkage results was much greater. The average correlation in LOD scores at any pair of time points was 0.46 for HTN (NPL All LOD) and 0.17 for SBP (Variance Components LOD). No evidence of reproducible linkage results was found, with a mean κ of 0.02 for linkage to HTN and -0.03 for SBP linkage. At loci with potential evidence for linkage (LOD > 1.0 at one or more time points), the correlation was even lower. The coefficient of variation at loci with potential evidence of linkage was 126% for HTN and 135% for SBP. None of 15 chromosomal regions for HTN and only one of 28 regions for SBP with potential evidence for linkage had a LOD > 1.0 at more than two of the five time points.ConclusionThese data suggest that, although heritability estimates at different time points are relatively robust, the reproducibility of linkage results in serial cross-sectional samples of a geographically defined population at successive time points is poor. This may explain in part the difficulty encountered in replicating linkage studies of complex phenotypes.
Highlights
Using the longitudinal Framingham Heart Study data on blood pressure, we analyzed the reproducibility of linkage measures from serial cross-sectional surveys of a defined population by performing genome-wide model-free linkage analyses to systolic blood pressure (SBP) and history of hypertension (HTN) measured at five separate time points
The study of complex disease genetics has far almost exclusively relied on the use of phenotypic data obtained at a single time point by a cross-sectional study, it is reasonable to hypothesize that longitudinally collected data may provide more insight into genetic susceptibilities for disease
An understanding of the reproducibility of linkage results using phenotypic data measured at different time points in serial cross-sectional surveys of a defined population will be important both to our understanding of the potential importance of sampling variation between studies and in developing robust methods for analyzing longitudinal data
Summary
Using the longitudinal Framingham Heart Study data on blood pressure, we analyzed the reproducibility of linkage measures from serial cross-sectional surveys of a defined population by performing genome-wide model-free linkage analyses to systolic blood pressure (SBP) and history of hypertension (HTN) measured at five separate time points. The inability to replicate linkage findings has been a significant limitation in the advancement of understanding the genetics of complex human diseases [1]. This problem in reproducibility has been attributed to high false-positive rates due to the large number of simultaneous hypotheses being tested in genome screens, to differences in study design and phenotype definition, genetic heterogeneity, or to differences in environmental exposures affecting gene × environment interactions [2]. An understanding of the reproducibility of linkage results using phenotypic data measured at different time points in serial cross-sectional surveys of a defined population will be important both to our understanding of the potential importance of sampling variation between studies and in developing robust methods for analyzing longitudinal data. We have explored the stability of linkage results to both a dichotomous and a quantitative trait in serial crosssectional samples of a population-based sample in order to better understand the dependence of analytic results on sampling error and the particular time at which a sample is phenotypically assessed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
