Extended haplotypes in the growth hormone releasing hormone receptor gene (GHRHR) are associated with normal variation in height

Abstract

Mutations in the gene for growth hormone releasing hormone receptor (GHRHR) cause isolated growth hormone deficiency (IGHD) but this gene has not been found to affect normal variation in height. We performed a whole genome linkage analysis for height in a population from northern Sweden and identified a region on chromosome 7 with a lod-score of 4.7. The GHRHR gene is located in this region and typing of tagSNPs identified a haplotype that is associated with height (p = 0.00077) in the original study population. Analysis of a sample from an independent population from the most northern part of Sweden also showed an association with height (p = 0.0039) but with another haplotype in the GHRHR gene. Both haplotypes span the 3' part of the GHRHR gene, including the region in which most of the mutations in IGHD have been located. The effect size of these haplotypes are larger than that of any gene previously associated with height, which indicates that GHRHR might be one of the most important genes so far identified affecting normal variation in human height.

Figure 1. QTLs for height in the VB population.

A) Multipoint LOD scores across the genome from the initial microsatellite scan. B) Multipoint LOD scores in the chromosome 7 and C) in the chromosome 9 region both including additional markers for fine-mapping. The location of the GHRHR gene is indicated by “X” in figure B.

Figure 2. LD plot of the GHRHR gene region.

Heat-map of the LD (r²) in the HapMap CEU population. The pairwise LD between SNPs and the location of the GHRHR gene.

Figure 3. Effect of the haplotype on height.

Average and standard error in height for individuals not carrying the haplotype associated with short stature (a) and individuals carrying the haplotype associated with short stature (b). The number of individuals in the group (a∶b) are in VB females 37∶230, VB males: 36∶218, NB females: 33∶338, NB males 30∶299.