A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy
Abstract Background Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them....
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doaj-e3b1be3abc284364a6e4e9a65f29e6972021-04-02T10:52:04ZengBMCBMC Medical Genomics1755-87942018-03-0111111010.1186/s12920-018-0339-9A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophyClaudia Tamar Silva0Irina V. Zorkoltseva1Maartje N. Niemeijer2Marten E. van den Berg3Najaf Amin4Ayşe Demirkan5Elisa van Leeuwen6Adriana I. Iglesias7Laura B. Piñeros-Hernández8Carlos M. Restrepo9Jan A. Kors10Anatoly V. Kirichenko11Rob Willemsen12Ben A. Oostra13Bruno H. Stricker14André G. Uitterlinden15Tatiana I. Axenovich16Cornelia M. van Duijn17Aaron Isaacs18Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterInstitute of Cytology and Genetics SD RASDepartment of Epidemiology, Erasmus University Medical CenterDepartment of Epidemiology, Erasmus University Medical CenterGenetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterGenetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterGenetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterGenetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterCenter for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), GENIUROS Research group, School of Medicine and Health Science, Universidad del RosarioCenter for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), GENIUROS Research group, School of Medicine and Health Science, Universidad del RosarioDepartment of Medical Informatics, Erasmus University Medical CenterInstitute of Cytology and Genetics SD RASDepartment of Clinical Genetics, Erasmus University Medical CenterGenetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterDepartment of Epidemiology, Erasmus University Medical CenterDepartment of Epidemiology, Erasmus University Medical CenterInstitute of Cytology and Genetics SD RASGenetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterGenetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical CenterAbstract Background Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. Methods The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. Results We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. Conclusions We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH.http://link.springer.com/article/10.1186/s12920-018-0339-9 |
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language |
English |
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Article |
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DOAJ |
author |
Claudia Tamar Silva Irina V. Zorkoltseva Maartje N. Niemeijer Marten E. van den Berg Najaf Amin Ayşe Demirkan Elisa van Leeuwen Adriana I. Iglesias Laura B. Piñeros-Hernández Carlos M. Restrepo Jan A. Kors Anatoly V. Kirichenko Rob Willemsen Ben A. Oostra Bruno H. Stricker André G. Uitterlinden Tatiana I. Axenovich Cornelia M. van Duijn Aaron Isaacs |
spellingShingle |
Claudia Tamar Silva Irina V. Zorkoltseva Maartje N. Niemeijer Marten E. van den Berg Najaf Amin Ayşe Demirkan Elisa van Leeuwen Adriana I. Iglesias Laura B. Piñeros-Hernández Carlos M. Restrepo Jan A. Kors Anatoly V. Kirichenko Rob Willemsen Ben A. Oostra Bruno H. Stricker André G. Uitterlinden Tatiana I. Axenovich Cornelia M. van Duijn Aaron Isaacs A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy BMC Medical Genomics |
author_facet |
Claudia Tamar Silva Irina V. Zorkoltseva Maartje N. Niemeijer Marten E. van den Berg Najaf Amin Ayşe Demirkan Elisa van Leeuwen Adriana I. Iglesias Laura B. Piñeros-Hernández Carlos M. Restrepo Jan A. Kors Anatoly V. Kirichenko Rob Willemsen Ben A. Oostra Bruno H. Stricker André G. Uitterlinden Tatiana I. Axenovich Cornelia M. van Duijn Aaron Isaacs |
author_sort |
Claudia Tamar Silva |
title |
A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy |
title_short |
A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy |
title_full |
A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy |
title_fullStr |
A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy |
title_full_unstemmed |
A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy |
title_sort |
combined linkage, microarray and exome analysis suggests map3k11 as a candidate gene for left ventricular hypertrophy |
publisher |
BMC |
series |
BMC Medical Genomics |
issn |
1755-8794 |
publishDate |
2018-03-01 |
description |
Abstract Background Electrocardiographic measures of left ventricular hypertrophy (LVH) are used as predictors of cardiovascular risk. We combined linkage and association analyses to discover novel rare genetic variants involved in three such measures and two principal components derived from them. Methods The study was conducted among participants from the Erasmus Rucphen Family Study (ERF), a Dutch family-based sample from the southwestern Netherlands. Variance components linkage analyses were performed using Merlin. Regions of interest (LOD > 1.9) were fine-mapped using microarray and exome sequence data. Results We observed one significant LOD score for the second principal component on chromosome 15 (LOD score = 3.01) and 12 suggestive LOD scores. Several loci contained variants identified in GWAS for these traits; however, these did not explain the linkage peaks, nor did other common variants. Exome sequence data identified two associated variants after multiple testing corrections were applied. Conclusions We did not find common SNPs explaining these linkage signals. Exome sequencing uncovered a relatively rare variant in MAPK3K11 on chromosome 11 (MAF = 0.01) that helped account for the suggestive linkage peak observed for the first principal component. Conditional analysis revealed a drop in LOD from 2.01 to 0.88 for MAP3K11, suggesting that this variant may partially explain the linkage signal at this chromosomal location. MAP3K11 is related to the JNK pathway and is a pro-apoptotic kinase that plays an important role in the induction of cardiomyocyte apoptosis in various pathologies, including LVH. |
url |
http://link.springer.com/article/10.1186/s12920-018-0339-9 |
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