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

Abstract

Human height is an important and heritable trait. Our previous two genome-wide linkage studies using 630 (WG1 study) and an extended sample of 1,816 Caucasians (WG2 study) identified 9q22 [maximum LOD score (MLS)=2.74 in the WG2 study] and preliminarily confirmed Xq24 (two-point LOD score=1.91 in the WG1 study, 2.64 in the WG2 study) linked to height. Here, with a much further extended large sample containing 3,726 Caucasians, we performed a new genome-wide linkage scan and confirmed, in high significance, the two regions' linkage to height. An MLS of 4.34 was detected on 9q22 and a two-point LOD score of 5.63 was attained for Xq24. In an independent sub-sample (i.e., the subjects not involved in the WG1 and WG2 studies), the two regions also achieved significant empirical P values (0.002 and 0.004, respectively) for "region-wise" linkage confirmation. Importantly, the two regions were replicated on a genotyping platform different from the WG1 and WG2 studies (i.e., a different set of markers and different genotyping instruments). Interestingly, 9q22 harbors the ROR2 gene, which is required for growth plate development, and Xq24 was linked to short stature. With the largest sample from a single population of the same ethnicity in the field of linkage studies for complex traits, our current study, together with two previous ones, provided overwhelming evidence substantiating 9q22 and Xq24 for height variation. In particular, our three consecutive whole genome studies are uniquely valuable as they represent the first practical (rather than simulated) example of how significant increase in sample size may improve linkage detection for human complex traits.

Applying Novel Genome-Wide Linkage Strategies to Search for Loci Influencing Type 2 Diabetes and Adult Height in American Samoa

“…Furthermore, they detected a second peak (LOD score 2.22, p = 0.001) on 9q33 and a third peak (LOD score 2.66, p = 0.0004) on 9q34. In addition, Liu et al (2006) confirmed the QTL for height on chromosome 9q22 in an extended data set. Based on our results and on those of the studies previously discussed, we suggest that chromosome region 9q22-qtel hosts at least one, possibly more, QTLs that are of importance for variation in adult height in populations of various ethnicities.…”

“…These fairly low power estimates suggest that additional chromosome regions not detected in the current study might be of great importance for variation in adult height in the studied population. Since the first genome-wide linkage scans for height were performed in 2001 (Hirschhorn et al 2001;Perola et al 2001), several susceptibility loci for height have been reported [for a recent overview see Perola et al (2007)], but, as for most complex phenotypes, only some have been successfully replicated by further studies (Liu et al 2004(Liu et al , 2006Willemsen et al 2004;Sale et al 2005;Shmulewitz et al 2006). The most promising susceptibility loci for height (Score.Max p = 0.005) detected in our current study of sib-pairs from American Samoa was located on chromosome 9q31 at marker D9S1690.…”

Genetics of growth in the normal child

“…Regions identified here attain high significance levels and can be replicated in various populations (28,30). Among the regions with the highest significance are chromosomes 9q22, Xq24 and Xp22 (see Table 3).…”

“…A number of 'second generation' linkage analyses on growth, which mainly involved larger sample sizes (up to 434 pedigrees and 4130 individuals (30)) are narrowing down on a smaller number of genetic regions that are associated with body height. Regions identified here attain high significance levels and can be replicated in various populations (28,30).…”

“…The second generation studies cited here contained O200 pedigrees (434 pedigrees in the publication by (30). No logorithmic odds ratio-scores are given because they differed considerably between the different studies due to sample size and the statistical approach used.…”