Why do men and women have different heights? Why do people have different predispositions to BMI, blood pressure and lipid levels?

Chromosome X is one of the two sex-determining chromosomes and researchers from the University of Helsinki set out to analyze the commonly occurring genetic variation in chromosome X  to find genetic factors that could explain individual differences in various traits.

Hundreds of genetic variants having an effect on these traits have already been identified but the X chromosome has not been studied in most of  previous studies. 25,000 Northern European individuals later, the researchers say they have some answers. 

The study showed that a genetic variant close to ITM2A, a gene that has a role in cartilage development, is frequent among the people being shorter than average. The identified variant, which is present in more than a third of Europeans, was also shown to increase the expression of ITM2A, suggesting that the more the gene is expressed the shorter the person will be. Interestingly, the effect of this variant on height was shown to be much stronger in women.

Estimates of the explained variances in the twelve quantitative phenotypes attributable to chromosome X SNPs and autosomal SNPs separately using equal variance (EV) model. 
DOI: 10.1371/journal.pgen.1004127

 "Studying the X chromosome has some particular challenges. The fact that women have two copies of this chromosome and men only one has to be taken into account in the analysis. We nevertheless wanted to take up the challenge since we had a strong belief that opening 'the X files' for research would reveal new, interesting biological insights," says lead author Dr. Taru Tukiainen of Massachusetts General Hospital in Boston. 

"The double dose of X-chromosomal genes in women could cause problems during the development. To prevent this, there is a process by which one of the two copies of the X chromosome present in the cell is silenced. When we realized that the height associated variant we identified was nearby a gene that is able to escape the silencing we were particularly excited," explains Professor Samuli Ripatti, the principal investigator. "Because both copies of ITM2A remain active, the gene is expressed in higher levels in women. Identifying associations in regions like this where X-chromosomal gene doses are not balanced between men and women can be particularly valuable in helping us to understand why some characteristics differ between sexes.

"Based on our calculations, this variant accounts for a significant, though small proportion, 1-2% of the current difference in mean height between men and women in the Finnish population.

Also two other new X-chromosomal regions, one associating with fasting insulin levels and the other with height, were identified in this study. Neither of these showed any evidence of sex difference in the strength of the genetic effect.

Citation: Taru Tukiainen, Matti Pirinen, Antti-Pekka Sarin, Claes Ladenvall, Johannes Kettunen, Terho Lehtim√§ki, Marja-Liisa Lokki, Markus Perola, Juha Sinisalo, Efthymia Vlachopoulou, Johan G. Eriksson, Leif Groop, Antti Jula, Marjo-Riitta J√§rvelin, Olli T. Raitakari, Veikko Salomaa, Samuli Ripatti, 'Chromosome X-Wide Association Study Identifies Loci for Fasting Insulin and Height and Evidence for Incomplete Dosage Compensation', 06 Feb 2014 PLOS Genetics 
DOI: 10.1371/journal.pgen.1004127. Source: University of Helsinki