title: Haplotype synthesis analysis reveals functional variants underlying known genome-wide associated susceptibility loci.
abstract: The functional mechanisms underlying disease association remain unknown for Genome-wide Association Studies (GWAS) susceptibility variants located outside coding regions. Synthesis of effects from multiple surrounding functional variants has been suggested as an explanation of hard-to-interpret findings. We define filter criteria based on linkage disequilibrium measures and allele frequencies which reflect expected properties of synthesizing variant sets. For eligible candidate sets, we search for haplotype markers that are highly correlated with associated variants.
  
  
  
  Via simulations we assess the performance of our approach and suggest parameter settings which guarantee 95% sensitivity at 20-fold reduced computational cost. We apply our method to 1000 Genomes data and confirmed Crohn's Disease (CD) and Type 2 Diabetes (T2D) variants. A proportion of 36.9% allowed explanation by three-variant-haplotypes carrying at least two functional variants, as compared to 16.4% for random variants ([Formula: see text]). Association could be explained by missense variants for MUC19, PER3 (CD) and HMG20A (T2D). In a CD GWAS-imputed using haplotype reference consortium data (64 976 haplotypes)-we could confirm the syntheses of MUC19 and PER3 and identified synthesis by missense variants for 6 further genes (ZGPAZ, GPR65, CLN3/NPIPB8, LOC102723878, rs2872507, GCKR). In all instances, the odds ratios of the synthesizing haplotypes were virtually identical to that of the index SNP. In summary, we demonstrate the potential of synthesis analysis to guide functional follow-up of GWAS findings.
  
  
  
  All methods are implemented in the C/C ++ toolkit GetSynth, available at http://sourceforge.net/projects/getsynth/
  
  
  
  tim.becker@uni-greifswald.de
  
  
  
  Supplementary data are available at Bioinformatics online.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lacour
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald 17475, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
mesh_terms: D019295:Computational Biology / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide