Chromosome X-wide association study identifies Loci for fasting insulin and height and evidence for incomplete dosage compensation

PLoS Genet. 2014 Feb 6;10(2):e1004127. doi: 10.1371/journal.pgen.1004127. eCollection 2014 Feb.

Abstract

The X chromosome (chrX) represents one potential source for the "missing heritability" for complex phenotypes, which thus far has remained underanalyzed in genome-wide association studies (GWAS). Here we demonstrate the benefits of including chrX in GWAS by assessing the contribution of 404,862 chrX SNPs to levels of twelve commonly studied cardiometabolic and anthropometric traits in 19,697 Finnish and Swedish individuals with replication data on 5,032 additional Finns. By using a linear mixed model, we estimate that on average 2.6% of the additive genetic variance in these twelve traits is attributable to chrX, this being in proportion to the number of SNPs in the chromosome. In a chrX-wide association analysis, we identify three novel loci: two for height (rs182838724 near FGF16/ATRX/MAGT1, joint P-value = 2.71×10(-9), and rs1751138 near ITM2A, P-value = 3.03×10(-10)) and one for fasting insulin (rs139163435 in Xq23, P-value = 5.18×10(-9)). Further, we find that effect sizes for variants near ITM2A, a gene implicated in cartilage development, show evidence for a lack of dosage compensation. This observation is further supported by a sex-difference in ITM2A expression in whole blood (P-value = 0.00251), and is also in agreement with a previous report showing ITM2A escapes from X chromosome inactivation (XCI) in the majority of women. Hence, our results show one of the first links between phenotypic variation in a population sample and an XCI-escaping locus and pinpoint ITM2A as a potential contributor to the sexual dimorphism in height. In conclusion, our study provides a clear motivation for including chrX in large-scale genetic studies of complex diseases and traits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Body Height / genetics*
  • Cation Transport Proteins / genetics
  • Chromosomes, Human, X / genetics*
  • DNA Helicases / genetics
  • Dosage Compensation, Genetic
  • European Continental Ancestry Group
  • Fasting
  • Female
  • Fibroblast Growth Factors / genetics
  • Genome-Wide Association Study
  • Humans
  • Insulin / blood
  • Insulin / genetics*
  • Male
  • Membrane Proteins / blood
  • Membrane Proteins / genetics*
  • Nuclear Proteins / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Sex Characteristics
  • X Chromosome Inactivation / genetics
  • X-linked Nuclear Protein

Substances

  • Cation Transport Proteins
  • FGF16 protein, human
  • ITM2A protein, human
  • Insulin
  • MagT1 protein, human
  • Membrane Proteins
  • Nuclear Proteins
  • Fibroblast Growth Factors
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein

Grant support

This research was supported through funds from The European Community's Seventh Framework Programme (FP7/2007-2013), EU-BioSHaRE Consortium (grant agreement 261433) (https://www.bioshare.eu). SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (no.s 213506 and 129680) (http://www.aka.fi/eng), Academy of Finland (no. 251217) (http://www.aka.fi/eng), the Finnish foundation for Cardiovascular Research (http://www.sydantutkimussaatio.fi) and the Sigrid Juselius Foundation (http://www.sigridjuselius.fi/foundation). MPi was funded by the Academy of Finland (257654) (http://www.aka.fi/eng). VS was supported by the Academy of Finland (139635) (http://www.aka.fi/eng), and the Finnish Foundation for Cardiovascular Research (http://www.sydantutkimussaatio.fi). TT received funding from Emil Aaltonen Foundation (http://www.emilaaltonen.fi). MPe is partly financially supported for this work by the Finnish Academy SALVE program “Pubgensense” 129322 (http://www.aka.fi/eng) and by grants from Finnish Foundation for Cardiovascular Research (http://www.sydantutkimussaatio.fi). The Young Finns Study has been financially supported by the Academy of Finland (http://www.aka.fi/eng): grants 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi), the Social Insurance Institution of Finland (http://www.kela.fi/web/en), Kuopio, Tampere and Turku University Hospital Medical Funds (grant 9N035 for TL), Juho Vainio Foundation (http://www.juhovainionsaatio.fi/pages/in-english/home.php), Paavo Nurmi Foundation (http://www.paavonurmensaatio.fi/saatio_e3.htm), Finnish Foundation of Cardiovascular Research (http://www.sydantutkimussaatio.fi) and Finnish Cultural Foundation (http://www.skr.fi/en), Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (http://www.emilaaltonen.fi). The Helsinki Birth Cohort Study (HBCS) has been supported by grants from the Academy of Finland (http://www.aka.fi/eng), the Finnish Diabetes Research Society (http://www.diabetes.fi/en/finnish_diabetes_association), Folkhälsan Research Foundation (http://www.folkhalsan.fi/en/startsida/About-Folkhalsan/), Novo Nordisk Foundation (http://www.novonordiskfonden.dk/en), Liv och Hälsa (http://www.livochhalsa.fi), Finska Läkaresällskapet (http://www.fls.fi/sallskapet/), Signe and Ane Gyllenberg Foundation (http://gyllenbergs.fi/en/signe-och-ane-gyllenbergs-stiftelse-en/), Ahokas Foundation and Juho Vainio Foundation (http://www.juhovainionsaatio.fi/pages/in-english/home.php). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.