A male-specific quantitative trait locus on 1p21 controlling human stature

Abstract

Background: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. Objective: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. Methods: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. Results: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. Conclusions: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sexspecific locus affecting human stature.

Genetic linkage of human height is confirmed to 9q22 and Xq24

“…Typically as shown in all of the genome-wide linkage scans for height so far, among all the regions reported, only very few reached the significance threshold for linkage (LOD>3.0) (for review see Willemsen et al 2004), implicating the difficulty to detect height genes of ''major effects''. Although our study had achieved the largest sample size and most (Sammalisto et al 2005) likely, the highest statistical power in all the genomewide linkage scans for height, we only detected three regions, 9q22, Xq24, and Xp22, of statistically significant linkage to height. Based on the ''major gene model'' for height, it is reasonable to hypothesize that the three regions detected in our study may harbor genes of relatively large effects on height variation and the effects of other potential loci for height may be too small to be detected with linkage approach, at least in our study population.…”

“…Genetic studies using association or whole genome linkage approaches have suggested quite a few genes and genomic regions associated with or linked to human height (Beck et al 2003;Geller et al 2003;Sammalisto et al 2005;Garnero et al 1998;Hasegawa et al 2000;Perola et al 2001;Hirschhorn et al 2001;Deng et al 2002;Liu et al 2004). However, few such genes and genomic regions Electronic Supplementary Material Supplementary material is available for this article at http://dx.doi.org/10.1007/s00439-006-0136-y and is accessible for authorized users.…”

Genetics of Maximal Walking Speed and Skeletal Muscle Characteristics in Older Women

“…In-house scripts were used to identify any females homozygous for all Xchromosomal markers. The female-specific genetic map in Kosambi cM was constructed using an inhouse developed web-based program, Cartographer (Sammalisto et al, 2005), which uses marker's physical location for the ordering of the markers and then obtains the genetic distances from deCODE genetic map locations (Kong et al, 2002). LOD score results are presented per 1 cM.…”

Common genetic variation in eight genes of the GH/IGF1 axis does not contribute to adult height variation

“…Estimates of heritability for stature are high (h 2 » 0.76-0.90) (Carmichael and McGue 1995;Silventoinen et al 2003;Visscher et al 2006), and previous genome-wide linkage scans have established that adult height is a complex polygenic trait (Deng et al 2002;Hirschhorn et al 2001;Liu et al 2004;Perola et al 2001;Sammalisto et al 2005;Wiltshire et al 2002;Wu et al 2003). Notably, however, few genes, if any, have been robustly associated with height variation in the general population.…”