RT Journal
A1 Friedrichs, Frauke
A1 Zugck, Christian
A1 Rauch, Gerd-Jörg
A1 Ivandic, Boris
A1 Weichenhan, Dieter
A1 Müller-Bardorff, Margit
A1 Meder, Benjamin
A1 El Mokhtari, Nour Eddine
A1 Regitz-Zagrosek, Vera
A1 Hetzer, Roland
A1 Schäfer, Arne
A1 Schreiber, Stefan
A1 Chen, Jian
A1 Neuhaus, Isaac
A1 Ji, Ruiru
A1 Siemers, Nathan O.
A1 Frey, Norbert
A1 Rottbauer, Wolfgang
A1 Katus, Hugo A.
A1 Stoll, Monika
T1 HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy
JF Genome Research 
JO Genome Research 
YR 2009 
FD March 01 
VO 19 
IS 3 
SP 395 
OP 403 
DO 10.1101/gr.076653.108 
UL http://genome.cshlp.org/content/19/3/395.abstract 
AB Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the etiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the etiology of DCM. We show that a 600-kb region of linkage disequilibrium (LD) on 5q31.2-3, harboring multiple genes, is associated with cardiomyopathy in three independent Caucasian populations (combined P-value = 0.00087). Functional assessment in zebrafish demonstrates that at least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. Evolutionary analysis across multiple vertebrate genomes suggests that this heart failure-associated LD block emerged by a series of genomic rearrangements across amphibian, avian, and mammalian genomes and is maintained as a cluster in mammals. Taken together, these observations challenge the simple notion that disease phenotypes can be traced to altered function of a single locus within a haplotype and suggest that a more detailed assessment of causality can be necessary.