Opening the X files - Chromosome X-wide association study reveals new loci for fasting insulin and height and evidence for incomplete dosage compensation. T. Tukiainen1,2,3, M. Pirinen2, A.-P. Sarin2,4, C. Ladenvall5, J. Kettunen2,4, T. Lehtimäki6, M.-L. Lokki7, M. Perola2,8,9, J. Sinisalo10, E. Vlachopoulou7, J. G. Eriksson8,11,12,13,14, L. Groop2,5, A. Jula15, M.-R. Järvelin16,17,18,19,20, O. T. Raitakari21,22, V. Salomaa8, S. Ripatti2,4,23,24 1) Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA; 2) Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland; 3) Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, USA; 4) Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland; 5) Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, CRC at Skåne University Hospital, Malmö, Sweden; 6) Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere, Finland; 7) Transplantation Laboratory, Haartman Institute, University of Helsinki, Finland; 8) Department of Chronic Disease Prevention, National Institute for Health and Welfare, Finland; 9) Estonian Genome Center, University of Tartu, Tartu, Estonia; 10) Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; 11) Department of General Practice and Primary Healthcare, University of Helsinki, Finland; 12) Unit of General Practice, Helsinki University Central Hospital, Finland; 13) Folkhälsan Research Center, Helsinki, Finland; 14) Vaasa Central Hospital, Vaasa, Finland; 15) Population Studies Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Turku, Finland; 16) Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, United Kingdom; 17) Institute of Health Sciences, University of Oulu, Finland; 18) Biocenter Oulu, University of Oulu, Finland; 19) Unit of Primary Care, Oulu University Hospital, Finland; 20) Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland; 21) Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland; 22) Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland; 23) Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; 24) Hjelt Institute, University of Helsinki, Helsinki, Finland.

   Thus far chromosome X SNPs have been largely neglected in genome-wide association studies. ChrX, however, contains approximately 5% of genomic DNA and 3% of known SNPs and thus represents one potential source for the missing heritability for complex phenotypes. Here we demonstrate the benefits of including chromosome X in large-scale genetic studies. In order to comprehensively survey the contribution of chrX to common quantitative phenotypes we imputed >400,000 good-quality non-pseudoautosomal chrX SNPs in 19,697 Finnish and Swedish individuals utilizing the imputation reference from the 1000 Genomes Project. We focused our screen on twelve anthropometric and cardiometabolic phenotypes for which tens of autosomal loci have been identified: height, body-mass-index, waist-hip-ratio, systolic and diastolic blood pressure, C-reactive protein, insulin, glucose, total, LDL and HDL cholesterol and triglycerides. Using a linear mixed model we estimate that common and low frequency SNPs in chrX contribute up to 1.4% of the total variance of the twelve phenotypes. The highest estimate was observed for height. Additionally, more than 0.5% of the variance in systolic blood pressure, HDL-C, fasting glucose and insulin appear to be due to X chromosome variation. In a chromosome X-wide association analysis we identify three novel loci: one for fasting insulin (rs139163435 in Xq23, P-value = 2.87×10-8) and two for height (rs182838724 near ATRX and rs1751138 near ITM2A, P-values 4.69×10-8 and 5.97×10-10, respectively). ITM2A is a likely functional candidate in the latter height locus: it has been implicated in cartilage development and is an eQTL in whole blood (P-value = 6.23×10-14, N = 513). Evaluation of the different models of dosage compensation in the three loci shows that there is a lack of dosage compensation in females near ITM2A. This observation is supported by gene expression data and a previous cellular study, which showed that ITM2A escapes from X chromosome inactivation in the majority of women. Our findings provide a clear motivation to assess chrX associations in larger sample sizes to identify further loci for complex traits. In addition, linking phenotype information to loci that escape from the X chromosome inactivation can bring insights into the biological bases of sexually dimorphic traits and sex chromosome aneuploidies.

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