TY - JOUR
T1 - A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy
AU - Silva, Claudia Tamar
AU - Zorkoltseva, Irina V.
AU - Niemeijer, Maartje N.
AU - Van Den Berg, Marten E.
AU - Amin, Najaf
AU - Demirkan, Ayşe
AU - Van Leeuwen, Elisa
AU - Iglesias, Adriana I.
AU - Piñeros-Hernández, Laura B.
AU - Restrepo, Carlos M.
AU - Kors, Jan A.
AU - Kirichenko, Anatoly V.
AU - Willemsen, Rob
AU - Oostra, Ben A.
AU - Stricker, Bruno H.
AU - Uitterlinden, André G.
AU - Axenovich, Tatiana I.
AU - Van Duijn, Cornelia M.
AU - Isaacs, Aaron
N1 - Funding Information:
The Erasmus Rucphen Family (ERF) study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP Grant No. 018947 (LSHG-CT-2006-01947) and also received funding from the European Community’s Seventh Framework Programme (FP7/2007– 2013)/Grant Agreement HEALTH-F4–2007-201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (No. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043), and Russian Federal Agency of Scientific Organizations projects VI.53.2.2 and 0324–2015-0003. Exome sequencing analysis in ERF was supported by the Netherlands Organization for the Health Research and Development grant for Project No. 91111025. This work was also supported by the Federal Agency of Scientific Organizations #0324–2015-0003 (IZ, AK and TA). Finally, this work was further funded by the European Union's Horizon 2020 research and innovation programme as part of the Common mechanisms and pathways in Stroke and Alzheimer's disease (CoSTREAM) project (www.costrea-m.eu, grant agreement No 667375) and the European Union’s Horizon 2020 research and innovation programme Marie Skłodowska-Curie Research and Innovation Staff Exchange (RISE) under the grant agreement No 645740 as part of the Personalized pREvention of Chronic DIseases (PRECeDI) project. The Rotterdam Study is funded by Erasmus Medical Center (MC) and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission; and the Municipality of Rotterdam. The Exome-Sequencing dataset was funded by the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) sponsored Netherlands Consortium for Healthy Aging (NCHA; Project No. 050–060-810), by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the and by a Complementation Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl; Project Number CP2010–41).
Funding Information:
We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. Najaf Amin is supported by the Hersenstichting Nederland (the Netherlands Brain Foundation) (Project Number F2013(1)-28). Rotterdam study: We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Mr. Pascal Arp, Ms. Mila Jhamai and Mr. Marijn Verkerk for their help in creating the RS-Exome-Sequencing database.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/3/5
Y1 - 2018/3/5
N2 - 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.
AB - 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.
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U2 - 10.1186/s12920-018-0339-9
DO - 10.1186/s12920-018-0339-9
M3 - Article
C2 - 29506515
AN - SCOPUS:85042935618
SN - 1755-8794
VL - 11
JO - BMC Medical Genomics
JF - BMC Medical Genomics
IS - 1
M1 - 22
ER -