Stature Quantitative Trait Locus 14

For a discussion of genetic heterogeneity of quantitative trait loci for stature (STQTL), see STQTL1 (606255).

Mapping

Sanna et al. (2008) reported extensive genomewide association studies of individuals in Finland and Sardinia that showed that common variants in the osteoarthritis-associated locus GDF5 (601146)-UQCC (611797) contribute to variation in height with an estimated additive effect of 0.44 cm. The results indicated that there may be a link between the genetic basis of height and osteoarthritis, potentially mediated through alterations in bone growth and development.

To identify genetic variants influencing adult human height, Weedon et al. (2008) used genomewide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. They identified association with a SNP in the UQCC gene, rs6060373 (overall P = 1.7 x 10(-17)). In all, Weedon et al. (2008) identified 20 variants associated with adult height (p less than 5 x 10(-7), with 10 reaching p less than 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with an approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. Each of the robustly associated variants identified in the study altered height by between approximately 0.2 and 0.6 centimeters per allele. Weedon et al. (2008) noted that the rs6060373 SNP in UQCC is highly correlated (r(2) = 0.89) with a functional SNP in GDF5 (rs143383; 601146.0015) shown to alter the risk of osteoarthritis (Miyamoto et al., 2007). Weedon et al. (2008) listed GDF5 as the nearby candidate gene implicated by this SNP, based on the knockout mouse phenotype, associated monogenic human syndromes caused by mutations, and its role in bone formation.

Lettre et al. (2008) carried out a metaanalysis of genomewide association study data of height for 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in greater than 10,000 subjects. A SNP in the UQCC gene, rs6060369, showed strong association (P = 1.4 x 10(-16)). Lettre et al. (2008) identified 12 loci in all that were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)) and that together accounted for approximately 2% of the population variation in height. Individuals with 8 or fewer height-increasing alleles and 16 or more height-increasing alleles differed in height by approximately 3.5 cm. The combined effect size of the rs6060369 C allele was 0.435 cm.

Sanna et al. (2008) identified the rs6060369 allele in their genomewide association analysis and noted it to be in strong linkage disequilibrium with the SNP rs143383 identified by Miyamoto et al. (2007) associated with osteoarthritis (see OS5; 612400). The rs143383 A allele, associated with increased risk of osteoarthritis, was associated with a decrease in height in their studies (P = 5.01 x 10(-12)), and is also associated with decreased transcriptional activity of GDF5 in chondrogenic cells.

Soranzo et al. (2009) performed a genomewide scan in 12,611 participants followed by replication in an additional 7,187 individuals. All participants were of British or Dutch descent. Soranzo et al. (2009) identified 2 SNPs in the 20q11.22 region associated with stature, rs4911494 (combined P = 1.2 x 10(-13)) and rs6088813 (combined P = 9.8 x 10(-14)).