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

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.

Combined Genome Scans for Body Stature in 6,602 European Twins: Evidence for Common Caucasian Loci

“…The second-highest male signal was observed at 20q21.2 at 21 cM with a suggestive MLOD of 2.70. The same region was previously linked with stature in a study sample of both Finnish and Australian families [15,19]. …”

Combined genome scans for body stature in 6602 European twins: evidence for common Caucasian loci

“…To date, about 20 genome scans have been published that investigate human adult body height [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Since height and various phenotypic characters are recorded in most studies, it is expected that this field will expand even more in the future.…”

“…Human adult stature (body height) has been the target of numerous genetic quantitative trait linkage studies in the past few years [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Despite high heritability estimates for all populations, based on either twin comparison [18][19][20][21] or on actual genetic resemblance in siblings [22], the results have been disappointing and inconsistent, with reports of quantitative trait loci (QTLs) scattered across the genome and rarely replicated.…”

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

“…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.…”