title: Genome-wide linkage scan identifies two novel genetic loci for coronary artery disease: in GeneQuest families.
abstract: Coronary artery disease (CAD) is the leading cause of death worldwide. Recent genome-wide association studies (GWAS) identified >50 common variants associated with CAD or its complication myocardial infarction (MI), but collectively they account for <20% of heritability, generating a phenomena of "missing heritability". Rare variants with large effects may account for a large portion of missing heritability. Genome-wide linkage studies of large families and follow-up fine mapping and deep sequencing are particularly effective in identifying rare variants with large effects. Here we show results from a genome-wide linkage scan for CAD in multiplex GeneQuest families with early onset CAD and MI. Whole genome genotyping was carried out with 408 markers that span the human genome by every 10 cM and linkage analyses were performed using the affected relative pair analysis implemented in GENEHUNTER. Affected only nonparametric linkage (NPL) analysis identified two novel CAD loci with highly significant evidence of linkage on chromosome 3p25.1 (peak NPL  = 5.49) and 3q29 (NPL  = 6.84). We also identified four loci with suggestive linkage on 9q22.33, 9q34.11, 17p12, and 21q22.3 (NPL  = 3.18-4.07). These results identify novel loci for CAD and provide a framework for fine mapping and deep sequencing to identify new susceptibility genes and novel variants associated with risk of CAD.
authors.affiliation: Heart Center, the First Affiliated Hospital, Lanzhou University, Lanzhou, Gansu 730000, P. R. China; Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America.
authors.forename: Hanxiang
authors.initials: H
authors.lastname: Gao
authors.affiliation: Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America; Institute of Medical Systems Biology and School of Public Health, Guangdong Medical College, Dongguan, Guangdong, 523808, P. R. China.
authors.forename: Shaoqi
authors.initials: S
authors.lastname: Rao
authors.affiliation: Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America.
authors.forename: Gongqing
authors.initials: G
authors.lastname: Shen
authors.affiliation: Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Xi
authors.affiliation: Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America.
authors.forename: Shenghan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Heart Center, the First Affiliated Hospital, Lanzhou University, Lanzhou, Gansu 730000, P. R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ellis
authors.affiliation: Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America.
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Scripps Translational Science Institute, Scripps Research Institute, Scripps Clinic, La Jolla, California, 92037, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
authors.affiliation: Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America; Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America; Center for Sleep Medicine, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, Ohio, United States of America; Department of Genetics and Genome Sciences, Case Western Reserve University, 9500 Euclid Ave., Cleveland, Ohio, 44195, United States of America; Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Qing K
authors.initials: QK
authors.lastname: Wang
mesh_terms: D000328:Adult; D017668:Age of Onset; D002874:Chromosome Mapping; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics*; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance; D014481:United States / Q000453:epidemiology