title: Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy.
abstract: OBJECTIVE
  Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM.
  
  
  RESULTS
  116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here.
  
  
  CONCLUSIONS
  We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Esslinger
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Garnier
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Korniat
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Proust
authors.affiliation: Institute of Gender in Medicine and Center for Cardiovascular Research, Charite University Hospital, and DZHK, Berlin, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kararigas
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Partnersite Munich Heart Alliance, Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller-Nurasyid
authors.affiliation: INSERM, UMR-S970, Department of Epidemiology, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Empana
authors.affiliation: Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Morley
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Perret
authors.affiliation: Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Stark
authors.affiliation: Department of Medecine and Genetics Harvard Medical School, Boston, MA, United States of America.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bick
authors.affiliation: Royal Brompton Hospital, London, United Kingdom.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Prasad
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research, Neuherberg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kriebel
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Tiret
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Declan P
authors.initials: DP
authors.lastname: O'Regan
authors.affiliation: Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Marguiles
authors.affiliation: Department of Medecine and Genetics Harvard Medical School, Boston, MA, United States of America.|Howard Hughes Medical Institute, Chevy Chase, MD, United States of America.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: INSERM, UMR-S970, Department of Epidemiology, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.|AP-HP, Georges Pompidou European Hospital, Pharmacology Department, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Boutouyrie
authors.affiliation: INSERM U1116, Université de Lorraine, Nancy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacolley
authors.affiliation: INSERM, UMR-S970, Department of Epidemiology, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.|AP-HP, Georges Pompidou European Hospital, Cardiology Department, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jouven
authors.affiliation: DZHK (German Centre for Cardiovascular Research), Partnersite Munich Heart Alliance, Munich, Germany.|Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.|AP-HP, Pitié-Salpêtrière Hospital, Cardiology Department, Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Centre de Référence des Maladies Cardiaques Héréditaires, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.|AP-HP, Pitié-Salpêtrière Hospital, Cardiology Department, Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Centre de Référence des Maladies Cardiaques Héréditaires, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Isnard
authors.affiliation: IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.
authors.forename: Eloisa
authors.initials: E
authors.lastname: Arbustini
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research, Neuherberg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.affiliation: National Heart Centre Singapore, Singapore.|National Heart and Lung Institute, Imperial College London, London, United Kingdom.|Duke-NUS, Singapore.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.affiliation: Department of Medecine and Genetics Harvard Medical School, Boston, MA, United States of America.|Howard Hughes Medical Institute, Chevy Chase, MD, United States of America.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.affiliation: Institute of Gender in Medicine and Center for Cardiovascular Research, Charite University Hospital, and DZHK, Berlin, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.affiliation: Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.|AP-HP, Pitié-Salpêtrière Hospital, Cardiology Department, Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Centre de Référence des Maladies Cardiaques Héréditaires, Paris, France.|Université de Versailles-Saint Quentin, AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.|AP-HP, Pitié-Salpêtrière Hospital, Cardiology Department, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Villard
mesh_terms: D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D059472:Exome; D020022:Genetic Predisposition to Disease; D006801:Humans; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide