title: Targeted Deep Sequencing in Multiple-Affected Sibships of European Ancestry Identifies Rare Deleterious Variants in PTPN22 That Confer Risk for Type 1 Diabetes.
abstract: Despite finding more than 40 risk loci for type 1 diabetes (T1D), the causative variants and genes remain largely unknown. Here, we sought to identify rare deleterious variants of moderate-to-large effects contributing to T1D. We deeply sequenced 301 protein-coding genes located in 49 previously reported T1D risk loci in 70 T1D cases of European ancestry. These cases were selected from putatively high-risk families that had three or more siblings diagnosed with T1D at early ages. A cluster of rare deleterious variants in PTPN22 was identified, including two novel frameshift mutations (ss538819444 and rs371865329) and two missense variants (rs74163663 and rs56048322). Genotyping in 3,609 T1D families showed that rs56048322 was significantly associated with T1D and that this association was independent of the T1D-associated common variant rs2476601. The risk allele at rs56048322 affects splicing of PTPN22, resulting in the production of two alternative PTPN22 transcripts and a novel isoform of LYP (the protein encoded by PTPN22). This isoform competes with the wild-type LYP for binding to CSK and results in hyporesponsiveness of CD4(+) T cells to antigen stimulation in T1D subjects. These findings demonstrate that in addition to common variants, rare deleterious variants in PTPN22 exist and can affect T1D risk.
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT Department of Biomedical Informatics, University of Utah, Salt Lake City, UT.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Quinlan
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Mackey
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
authors.forename: Jocyndra A
authors.initials: JA
authors.lastname: Wright
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA.
authors.forename: Jane H
authors.initials: JH
authors.lastname: Buckner
authors.affiliation: Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA.
authors.forename: Tania
authors.initials: T
authors.lastname: Habib
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL Genetics Institute, University of Florida, Gainesville, FL patcon@ufl.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
mesh_terms: D000293:Adolescent; D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000081247:CSK Tyrosine-Protein Kinase; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007223:Infant; D008297:Male; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D035781:Siblings; D044465:White People / Q000235:genetics*; D055815:Young Adult; D019061:src-Family Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22