The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes

• Published in: Nature genetics Vol. 42; no. 1; pp. 68 - 71
• Main Authors: Wallace, Chris, Smyth, Deborah J, Maisuria-Armer, Meeta, Walker, Neil M, Todd, John A, Clayton, David G
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2010; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Calcium-Binding Proteins; Cancer Research; Chromosomes, Human, Pair 14 - genetics; Colleges & universities; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Expected values; Families & family life; Family Health; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic susceptibility; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomic Imprinting; Genotype; Human Genetics; Humans; Intercellular Signaling Peptides and Proteins - genetics; letter; Linkage Disequilibrium; Lupus; Male; Medical sciences; Membrane Proteins - genetics; Mental health; Meta-Analysis as Topic; Physiological aspects; Polymorphism, Single Nucleotide; Proteins - genetics; Risk factors; RNA, Long Noncoding; Sample size; Single nucleotide polymorphisms; Thyroid diseases; Type 1 diabetes; United Kingdom; Endocrinopathy; Immunopathology; Autoimmune disease; Chromosome; Type 1 diabetes; Genomic imprinting
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.493

Chris Wallace and colleagues report the identification of a new locus on chromosome 14q32.3 that alters susceptibility to type 1 diabetes with a parent-of-origin effect. The region contains imprinted genes including DLK1 and MEG3 . Genome-wide association (GWA) studies to map common disease susceptibility loci have been hugely successful, with over 300 reproducibly associated loci reported to date 1 . However, these studies have not yet provided convincing evidence for any susceptibility locus subject to parent-of-origin effects. Using imputation to extend existing GWA datasets 2 , 3 , 4 , we have obtained robust evidence at rs941576 for paternally inherited risk of type 1 diabetes (T1D; ratio of allelic effects for paternal versus maternal transmissions = 0.75; 95% confidence interval (CI) = 0.71–0.79). This marker is in the imprinted region of chromosome 14q32.2, which contains the functional candidate gene DLK1 . Our meta-analysis also provided support at genome-wide significance for a T1D locus at chromosome 19p13.2. The highest association was at marker rs2304256 (odds ratio (OR) = 0.86; 95%CI = 0.82–0.90) in the TYK2 gene, which has previously been associated with systemic lupus erythematosus 5 and multiple sclerosis 6 .