A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy

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

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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.

Translated title of the contributionUn análisis combinado de enlaces, microarrays y exomas sugiere que el MAP3K11 es un gen candidato para la hipertrofia ventricular izquierda.
Original languageEnglish (US)
Article number22
JournalBMC Medical Genomics
Volume11
Issue number1
DOIs
StatePublished - Mar 5 2018

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Silva, C. T., Zorkoltseva, I. V., Niemeijer, M. N., Van Den Berg, M. E., Amin, N., Demirkan, A., Van Leeuwen, E., Iglesias, A. I., Piñeros-Hernández, L. B., Restrepo, C. M., Kors, J. A., Kirichenko, A. V., Willemsen, R., Oostra, B. A., Stricker, B. H., Uitterlinden, A. G., Axenovich, T. I., Van Duijn, C. M., & Isaacs, A. (2018). A combined linkage, microarray and exome analysis suggests MAP3K11 as a candidate gene for left ventricular hypertrophy. BMC Medical Genomics, 11(1), [22]. https://doi.org/10.1186/s12920-018-0339-9