TY - JOUR
T1 - Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits
AU - Middelberg, Rita P.S.
AU - Ferreira, Manuel A.R.
AU - Henders, Anjali K.
AU - Heath, Andrew C.
AU - Madden, Pamela A.F.
AU - Montgomery, Grant W.
AU - Martin, Nicholas G.
AU - Whitfield, John B.
N1 - Funding Information:
We are grateful to the twins and their families for their generous participation in these studies. We would like to thank Ann Eldridge and Marlene Grace for the collection of data; Leanne Wallace for sample handling and preparation for the serum biochemistry and genotyping; Lisa Bowdler, Steven Crooks, Melinda Richter and Sara Smith for sample processing and preparation for the GWAS genotyping; Harry Beeby for IT support; and the following people in the QIMR GWAS group: Scott Gordon, Dale Nyholt, Stuart Macgregor and Naomi Wray for generating and checking of integrated genome-wide typing data and Sarah Medland for imputing the data. Financial support was provided from the National Health and Medical Research Council (241944, 389875), NIH (AA07535, AA13320, AA13321, AA14041, AA11998, AA17688, DA012854, DA019951) and Wellcome Trust for funding (WT084766/Z/08/Z). GWM is supported by an NHMRC Fellowship (619667) and RPSM is supported by NHMRC Training Fellowship (611512).
PY - 2011/9/24
Y1 - 2011/9/24
N2 - Background: Genome-wide association studies (GWAS) have become a major strategy for genetic dissection of human complex diseases. Analysing multiple phenotypes jointly may improve both our ability to detect genetic variants with multiple effects and our understanding of their common features. Allelic associations for multiple biochemical traits (serum alanine aminotransferase, aspartate aminotransferase, butrylycholinesterase (BCHE), C-reactive protein (CRP), ferritin, gamma glutamyltransferase (GGT), glucose, high-density lipoprotein cholesterol (HDL), insulin, low-density lipoprotein cholesterol (LDL), triglycerides and uric acid), and body-mass index, were examined.Methods: We aimed to identify common genetic variants affecting more than one of these traits using genome-wide association analysis in 2548 adolescents and 9145 adults from 4986 Australian twin families. Multivariate and univariate associations were performed.Results: Multivariate analyses identified eight loci, and univariate association analyses confirmed two loci influencing more than one trait at p < 5 × 10-8. These are located on chromosome 8 (LPL gene affecting HDL and triglycerides) and chromosome 19 (TOMM40/APOE-C1-C2-C4 gene cluster affecting LDL and CRP). A locus on chromosome 12 (OASL gene) showed effects on GGT, LDL and CRP. The loci on chromosomes 12 and 19 unexpectedly affected LDL cholesterol and CRP in opposite directions.Conclusions: We identified three possible loci that may affect multiple traits and validated 17 previously-reported loci. Our study demonstrated the usefulness of examining multiple phenotypes jointly and highlights an anomalous effect on CRP, which is increasingly recognised as a marker of cardiovascular risk as well as of inflammation.
AB - Background: Genome-wide association studies (GWAS) have become a major strategy for genetic dissection of human complex diseases. Analysing multiple phenotypes jointly may improve both our ability to detect genetic variants with multiple effects and our understanding of their common features. Allelic associations for multiple biochemical traits (serum alanine aminotransferase, aspartate aminotransferase, butrylycholinesterase (BCHE), C-reactive protein (CRP), ferritin, gamma glutamyltransferase (GGT), glucose, high-density lipoprotein cholesterol (HDL), insulin, low-density lipoprotein cholesterol (LDL), triglycerides and uric acid), and body-mass index, were examined.Methods: We aimed to identify common genetic variants affecting more than one of these traits using genome-wide association analysis in 2548 adolescents and 9145 adults from 4986 Australian twin families. Multivariate and univariate associations were performed.Results: Multivariate analyses identified eight loci, and univariate association analyses confirmed two loci influencing more than one trait at p < 5 × 10-8. These are located on chromosome 8 (LPL gene affecting HDL and triglycerides) and chromosome 19 (TOMM40/APOE-C1-C2-C4 gene cluster affecting LDL and CRP). A locus on chromosome 12 (OASL gene) showed effects on GGT, LDL and CRP. The loci on chromosomes 12 and 19 unexpectedly affected LDL cholesterol and CRP in opposite directions.Conclusions: We identified three possible loci that may affect multiple traits and validated 17 previously-reported loci. Our study demonstrated the usefulness of examining multiple phenotypes jointly and highlights an anomalous effect on CRP, which is increasingly recognised as a marker of cardiovascular risk as well as of inflammation.
UR - http://www.scopus.com/inward/record.url?scp=80053173074&partnerID=8YFLogxK
U2 - 10.1186/1471-2350-12-123
DO - 10.1186/1471-2350-12-123
M3 - Article
C2 - 21943158
AN - SCOPUS:80053173074
SN - 1471-2350
VL - 12
JO - BMC Medical Genetics
JF - BMC Medical Genetics
M1 - 123
ER -