title: Genome-wide linkage and positional association analyses identify associations of novel AFF3 and NTM genes with triglycerides: the GenSalt study.
abstract: We conducted a genome-wide linkage scan and positional association study to identify genes and variants influencing blood lipid levels among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1906 participants from 633 Han Chinese families. Lipids were measured from overnight fasting blood samples using standard methods. Multipoint quantitative trait genome-wide linkage scans were performed on the high-density lipoprotein, low-density lipoprotein, and log-transformed triglyceride phenotypes. Using dense panels of single nucleotide polymorphisms (SNPs), single-marker and gene-based association analyses were conducted to follow-up on promising linkage signals. Additive associations between each SNP and lipid phenotypes were tested using mixed linear regression models. Gene-based analyses were performed by combining P-values from single-marker analyses within each gene using the truncated product method (TPM). Significant associations were assessed for replication among 777 Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). Bonferroni correction was used to adjust for multiple testing. In the GenSalt study, suggestive linkage signals were identified at 2p11.2‒2q12.1 [maximum multipoint LOD score (MML) = 2.18 at 2q11.2] and 11q24.3‒11q25 (MML = 2.29 at 11q25) for the log-transformed triglyceride phenotype. Follow-up analyses of these two regions revealed gene-based associations of charged multivesicular body protein 3 (CHMP3), ring finger protein 103 (RNF103), AF4/FMR2 family, member 3 (AFF3), and neurotrimin (NTM) with triglycerides (P = 4 × 10(-4), 1.00 × 10(-5), 2.00 × 10(-5), and 1.00 × 10(-7), respectively). Both the AFF3 and NTM triglyceride associations were replicated among MESA study participants (P = 1.00 × 10(-7) and 8.00 × 10(-5), respectively). Furthermore, NTM explained the linkage signal on chromosome 11. In conclusion, we identified novel genes associated with lipid phenotypes in linkage regions on chromosomes 2 and 11.
authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
authors.forename: Changwei
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Lydia A L
authors.initials: LA
authors.lastname: Bazzano
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
authors.forename: Dabeeru C
authors.initials: DC
authors.lastname: Rao
authors.affiliation: Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX 77030, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Hixson
authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: He
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Gu
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Gu
authors.affiliation: Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX 77030, USA.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Shimmin
authors.affiliation: Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD 20892-7936, USA.
authors.forename: Cashell E
authors.initials: CE
authors.lastname: Jaquish
authors.affiliation: Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Schwander
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Huang
authors.affiliation: Institute of Basic Medicine, Shandong Academy of Medical Sciences, Ji'nan 250062, China.
authors.forename: Fanghong
authors.initials: F
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Epidemiology and Biostatistics, Nanjing Medical University School of Public Health, Nanjing 210029, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Chong
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
authors.forename: Xiangfeng
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA. Electronic address: tkelly@tulane.edu.
authors.forename: Tanika N
authors.initials: TN
authors.lastname: Kelly
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D055012:Chromosomal Position Effects; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D008040:Genetic Linkage; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D019006:Neural Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: C097738:AFF3 protein, human; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D058851:GPI-Linked Proteins; D005819:Genetic Markers; D019006:Neural Cell Adhesion Molecules; D009687:Nuclear Proteins; D014280:Triglycerides; C092530:neurotrimin
keywords: Gene-based analysis; Linkage analysis; Lipids; Positional association analysis
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