title: Functional Genomics Analysis of Big Data Identifies Novel Peroxisome Proliferator-Activated Receptor γ Target Single Nucleotide Polymorphisms Showing Association With Cardiometabolic Outcomes.
abstract: BACKGROUND
  Cardiovascular disease and type 2 diabetes mellitus represent overlapping diseases where a large portion of the variation attributable to genetics remains unexplained. An important player in their pathogenesis is peroxisome proliferator-activated receptor γ (PPARγ) that is involved in lipid and glucose metabolism and maintenance of metabolic homeostasis. We used a functional genomics methodology to interrogate human chromatin immunoprecipitation-sequencing, genome-wide association studies, and expression quantitative trait locus data to inform selection of candidate functional single nucleotide polymorphisms (SNPs) falling in PPARγ motifs.
  
  
  RESULTS
  We derived 27 328 chromatin immunoprecipitation-sequencing peaks for PPARγ in human adipocytes through meta-analysis of 3 data sets. The PPARγ consensus motif showed greatest enrichment and mapped to 8637 peaks. We identified 146 SNPs in these motifs. This number was significantly less than would be expected by chance, and Inference of Natural Selection from Interspersed Genomically coHerent elemenTs analysis indicated that these motifs are under weak negative selection. A screen of these SNPs against genome-wide association studies for cardiometabolic traits revealed significant enrichment with 16 SNPs. A screen against the MuTHER expression quantitative trait locus data revealed 8 of these were significantly associated with altered gene expression in human adipose, more than would be expected by chance. Several SNPs fall close, or are linked by expression quantitative trait locus to lipid-metabolism loci including CYP26A1.
  
  
  CONCLUSIONS
  We demonstrated the use of functional genomics to identify SNPs of potential function. Specifically, that SNPs within PPARγ motifs that bind PPARγ in adipocytes are significantly associated with cardiometabolic disease and with the regulation of transcription in adipose. This method may be used to uncover functional SNPs that do not reach significance thresholds in the agnostic approach of genome-wide association studies.
authors.affiliation: From the Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA (K.R., C.-Q.L., J.M.O.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (G.R.S.); Department of Clinical Investigation, Centro Nacional Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.M.O.); and Department of Nutritional Genomics, Instituto Madrileno de Estudios Avanzados en Alimentacion, Madrid, Spain (J.M.O). kris.richardson@tufts.edu.
authors.forename: Kris
authors.initials: K
authors.lastname: Richardson
authors.affiliation: From the Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA (K.R., C.-Q.L., J.M.O.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (G.R.S.); Department of Clinical Investigation, Centro Nacional Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.M.O.); and Department of Nutritional Genomics, Instituto Madrileno de Estudios Avanzados en Alimentacion, Madrid, Spain (J.M.O).
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Schnitzler
authors.affiliation: From the Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA (K.R., C.-Q.L., J.M.O.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (G.R.S.); Department of Clinical Investigation, Centro Nacional Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.M.O.); and Department of Nutritional Genomics, Instituto Madrileno de Estudios Avanzados en Alimentacion, Madrid, Spain (J.M.O).
authors.forename: Chao-Qiang
authors.initials: CQ
authors.lastname: Lai
authors.affiliation: From the Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA (K.R., C.-Q.L., J.M.O.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (G.R.S.); Department of Clinical Investigation, Centro Nacional Investigaciones Cardiovasculares (CNIC), Madrid, Spain (J.M.O.); and Department of Nutritional Genomics, Instituto Madrileno de Estudios Avanzados en Alimentacion, Madrid, Spain (J.M.O).
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D020816:Amino Acid Motifs; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D000072516:Retinoic Acid 4-Hydroxylase
chemical_list: D047495:PPAR gamma; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase
keywords: adipocytes; cardiovascular disease; genetic polymorphism; genetics; genomics; type 2 diabetes mellitus