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Comprehensive multi-stage linkage analyses identify a locus for adult height on chromosome 3p in a healthy Caucasian population

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Abstract

There have been a number of genome-wide linkage studies for adult height in recent years. These studies have yielded few well-replicated loci, and none have been further confirmed by the identification of associated gene variants. The inconsistent results may be attributable to the fact that few studies have combined accurate phenotype measures with informative statistical modelling in healthy populations. We have performed a multi-stage genome-wide linkage analysis for height in 275 adult sibling pairs drawn randomly from the Victorian Family Heart Study (VFHS), a healthy population-based Caucasian cohort. Height was carefully measured in a standardised fashion on regularly calibrated equipment. Following genome-wide identification of a peak Z-score of 3.14 on chromosome 3 at 69 cM, we performed a fine-mapping analysis of this region in an extended sample of 392 two-generation families. We used a number of variance components models that incorporated assortative mating and shared environment effects, and we observed a peak LOD score of approximately 3.5 at 78 cM in four of the five models tested. We also demonstrated that the most prevalent model in the literature gave the worst fit, and the lowest LOD score (2.9) demonstrating the importance of appropriate modelling. The region identified in this study replicates the results of other genome-wide scans of height and bone-related phenotypes, strongly suggesting the presence of a gene important in bone growth on chromosome 3p. Association analyses of relevant candidate genes should identify the genetic variants responsible for the chromosome 3p linkage signal in our population.

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Acknowledgments

We thank Professor John Hopper for thoughtful and useful suggestions regarding statistical analyses. We also thank Ms Margaret Stebbing, Professor John Hopper, Professor Graham Giles, the general practitioners and research nurses for their contributions to recruitment of VFHS study participants, and Dr Zilla Wong for sample management and preliminary statistical analyses. We gratefully acknowledge support from an Australian Research Council Discovery Project Grant (DP0450426), which includes a Postdoctoral fellowship for JAE. KJS is funded by NHMRC (Project Grant 400255).

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Correspondence to Justine A. Ellis.

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Ellis, J.A., Scurrah, K.J., Duncan, A.E. et al. Comprehensive multi-stage linkage analyses identify a locus for adult height on chromosome 3p in a healthy Caucasian population. Hum Genet 121, 213–222 (2007). https://doi.org/10.1007/s00439-006-0305-z

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