title: A cautionary tale: the non-causal association between type 2 diabetes risk SNP, rs7756992, and levels of non-coding RNA, CDKAL1-v1.
abstract: OBJECTIVE
  Intronic single nucleotide polymorphisms (SNPs) in the CDKAL1 gene are associated with risk of developing type 2 diabetes. A strong correlation between risk alleles and lower levels of the non-coding RNA, CDKAL1-v1, has recently been reported in whole blood extracted from Japanese individuals. We sought to replicate this association in two independent cohorts: one using whole blood from white UK-resident individuals, and one using a collection of human pancreatic islets, a more relevant tissue type to study with respect to the aetiology of diabetes.
  
  
  METHODS
  Levels of CDKAL1-v1 were measured by real-time PCR using RNA extracted from human whole blood (n = 70) and human pancreatic islets (n = 48). Expression with respect to genotype was then determined.
  
  
  RESULTS
  In a simple linear regression model, expression of CDKAL1-v1 was associated with the lead type 2 diabetes-associated SNP, rs7756992, in whole blood and islets. However, these associations were abolished or substantially reduced in multiple regression models taking into account rs9366357 genotype: a moderately linked SNP explaining a much larger amount of the variation in CDKAL1-v1 levels, but not strongly associated with risk of type 2 diabetes.
  
  
  CONCLUSIONS
  Contrary to previous findings, we provide evidence against a role for dysregulated expression of CDKAL1-v1 in mediating the association between intronic SNPs in CDKAL1 and susceptibility to type 2 diabetes. The results of this study illustrate how caution should be exercised when inferring causality from an association between disease-risk genotype and non-coding RNA expression.
authors: Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW, UK.
authors: Jonathan M
authors: JM
authors: Locke
authors: Fan-Yan
authors: FY
authors: Wei
authors: Kazuhito
authors: K
authors: Tomizawa
authors: Michael N
authors: MN
authors: Weedon
authors: Lorna W
authors: LW
authors: Harries
mesh_terms: D016022:Case-Control Studies; D051360:Cyclin-Dependent Kinase 5 / Q000097:blood / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns; D007515:Islets of Langerhans / Q000737:chemistry; D016014:Linear Models; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D022661:RNA, Untranslated / Q000097:blood / Q000235:genetics*; D012307:Risk Factors; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000235:genetics; D012359:tRNA Methyltransferases
chemical_list: D022661:RNA, Untranslated; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Nucleic Acids Res. 2003 Jul 1;31(13):3568-71
references: 12824367
references: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):775-80
references: 20080751
references: J Biol Chem. 2010 Sep 10;285(37):28425-33
references: 20584901
references: Hum Mol Genet. 2014 Sep 1;23(17):4639-50
references: 24760768
references: Genome Res. 2013 Sep;23(9):1554-62
references: 23716500
references: Am J Hum Genet. 2013 Dec 5;93(6):1015-26
references: 24268656
references: Nat Genet. 2014 Mar;46(3):234-44
references: 24509480
references: Diabetes. 2014 Jun;63(6):2158-71
references: 24296717
references: J Clin Invest. 2011 Sep;121(9):3598-608
references: 21841312