Confirmation linkage study in support of the X chromosome harbouring a QTL underlying human height variation

Liu, Y. Z.; Xu, Fusheng; Shen, Hui; Liu, Y. J.; Zhao, Liang; Dvornyk, Volodymyr; Conway, Theresa; Li, J. L.; Huang, Qihua; Davies, K. Michael; Recker, Robert R.; Deng, Hong Wen

doi:10.1136/jmg.40.11.825

Cited by 22 publications

(8 citation statements)

References 43 publications

(38 reference statements)

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“…However, this is similar to a frequently used model for a wide variety of traits (including height, e.g. Hirschhorn et al 2001;Liu et al 2003;Perola et al 2001;Wu et al 2003) in the literature, and the effect of the assumption is likely to be less for a trait such as height which is known to be controlled mostly by genes, than for traits such as pulse pressure which are influenced by shared diet and lifestyle factors. The covariance for this second Model, model 1b,…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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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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Section: Discussionmentioning

confidence: 99%

“…Hirschhorn et al 2001;Liu et al 2003;Perola et al 2001;Wu et al 2003) again assumes that there are no shared environmental effects and in addition that there is no covariance between spouses so r C 2 = q SP = 0. We also considered models which allow for assortative mating, as described previously (Harrap et al 2000).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…Eight of the regions demonstrating statistically significant linkage have been included in OMIM as quantitative trait locus (QTL) for stature (STQTL). They were localized on 1p21 (Sammalisto et al 2005;Wu et al 2003), 3p26 (Ellis et al 2007;Wiltshire et al 2002), 6q24 (Hirschhorn et al 2001;Willemsen et al 2004;Xu et al 2002), 7q31-q36 (Hirschhorn et al 2001;Perola et al 2001;Wu et al 2003), 9q22 (Liu et al 2006b;Liu et al 2004), 12q11-q14 (Dempfle et al 2006;Hirschhorn et al 2001;Xu et al 2002), 13q32-q33 (Hirschhorn et al 2001), Xq24 (Liu et al 2006b;Liu et al 2003;Liu et al 2004), Xp22 and Xq25 (Deng et al 2002). Notably, four strong candidate genes are located in these regions: the estrogen receptor a gene (ESR1) on 6q24-q25, the vitamin D receptor (VDR) on 12q12-q14, the tyrosin kinase-like orphan receptor 2 (ROR2) on 9q22, and the homeobox gene, SHOX, whose mutations or haploinsuffiency are associated with idiopathic short stature, on pseudoautosomic region of Xp22.…”

Section: Introductionmentioning

confidence: 99%

Linkage analysis of adult height in a large pedigree from a Dutch genetically isolated population

et al. 2009

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Despite extensive research of genetic determinants of human adult height, the genes identified up until now allow to predict only a small proportion of the trait's variance. To identify new genes we analyzed 2,486 genotyped and phenotyped individuals in a large pedigree including 23,612 members in 18 generations. The pedigree was derived from a young genetically isolated Dutch population, where genetic heterogeneity is expected to be low and linkage disequilibrium has been shown to be increased. Complex segregation analysis confirmed high heritability of adult height, and suggested mixed model of height inheritance in this population. The estimates of the model parameters obtained from complex segregation analysis were used in parametric linkage analysis, which highlighted three genome-wide significant and additionally at least four suggestive loci involved in height. Significant peaks were located at the chromosomal regions 1p32 (LOD score = 3.35), 2p16 (LOD score = 3.29) and 16q24 (LOD score = 3.94). For the latter region, a strong association signal (FDR q < 0.05) was obtained for 19 SNPs, 17 of them were located in the CDH13 (cadherin 13) gene of which one (rs1035569) explained 1.5% of the total height variance.

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“…In linkage studies, height data from families was combined with genetic data from hundreds of genetic markers spread across the genome to identify chromosomal regions that were more often co-inherited in pairs of relatives with similar heights than in pairs of relatives with divergent heights. A number of studies identified several regions where the statistical evidence of linkage surpassed genome-wide thresholds of significance [15,16,17,18,19], defined as a statistical result strong enough that it is unlikely to be observed by chance even when examining the entire genome. However, no one region was clearly reproducible; even a large meta-analysis that combined data from multiple linkage studies did not point overwhelmingly to a single region [4].…”

Section: Genetics Of Heightmentioning

confidence: 99%

Progress in Genome-Wide Association Studies of Human Height

Hirschhorn¹,

Lettre

2009

Horm Res Paediatr

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Human height (stature) is a strongly genetic trait, with up to 90% of the variation in height within a population determined by a combination of multiple inherited factors. Recent advances in genetics and genomics now permit comprehensive genome-wide surveys of common genetic variations in those variants that are associated with stature. The first such studies have borne fruit, identifying over 40 genetic loci that can be reproducibly shown to have an influence on adult height. These unbiased searches throughout the genome identified several loci that also harbour rare mutations responsible for more severe alterations in height or skeletal growth. Although the predictive value of the common variants thus far discovered remains low, the identification of these loci has led to new insights into the biology of human growth, and may help identify genes that underlie previously uncharacterized syndromes of abnormal skeletal growth.

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Confirmation linkage study in support of the X chromosome harbouring a QTL underlying human height variation

Cited by 22 publications

References 43 publications

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

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

Linkage analysis of adult height in a large pedigree from a Dutch genetically isolated population

Progress in Genome-Wide Association Studies of Human Height

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