title: Chromosome X-wide association study identifies Loci for fasting insulin and height and evidence for incomplete dosage compensation.
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.
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Taru
authors: T
authors: Tukiainen
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: Matti
authors: M
authors: Pirinen
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland.
authors: Antti-Pekka
authors: AP
authors: Sarin
authors: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, CRC at Skåne University Hospital, Malmö, Sweden.
authors: Claes
authors: C
authors: Ladenvall
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland.
authors: Johannes
authors: J
authors: Kettunen
authors: Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere School of Medicine, Tampere, Finland.
authors: Terho
authors: T
authors: Lehtimäki
authors: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Marja-Liisa
authors: ML
authors: Lokki
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland ; Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: Markus
authors: M
authors: Perola
authors: Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors: Juha
authors: J
authors: Sinisalo
authors: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Efthymia
authors: E
authors: Vlachopoulou
authors: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland ; Department of General Practice and Primary Healthcare, University of Helsinki, Helsinki, Finland ; Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland ; Folkhälsan Research Center, Helsinki, Finland ; Vaasa Central Hospital, Vaasa, Finland.
authors: Johan G
authors: JG
authors: Eriksson
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Department of Clinical Sciences, Diabetes and Endocrinology, Lund University and Lund University Diabetes Centre, CRC at Skåne University Hospital, Malmö, Sweden.
authors: Leif
authors: L
authors: Groop
authors: Population Studies Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Turku, Finland.
authors: Antti
authors: A
authors: Jula
authors: Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom ; Institute of Health Sciences, University of Oulu, Oulu, Finland ; Biocenter Oulu, University of Oulu, Oulu, Finland ; Unit of Primary Care, Oulu University Hospital, Oulu, Finland ; Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.
authors: Marjo-Riitta
authors: MR
authors: Järvelin
authors: Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland ; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
authors: Olli T
authors: OT
authors: Raitakari
authors: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors: Veikko
authors: V
authors: Salomaa
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland ; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom ; Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors: Samuli
authors: S
authors: Ripatti
mesh_terms: D000328:Adult; D001827:Body Height / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics; D004303:Dosage Compensation, Genetic; D005215:Fasting; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012727:Sex Characteristics; D044465:White People; D049951:X Chromosome Inactivation / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D027682:Cation Transport Proteins; C512705:FGF16 protein, human; C485527:ITM2A protein, human; D007328:Insulin; C509698:MagT1 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D005346:Fibroblast Growth Factors; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein