Investigation of gene-gene interactions in cardiac traits and serum fatty acid levels in the LURIC Health Study

PLoS One. 2020 Sep 11;15(9):e0238304. doi: 10.1371/journal.pone.0238304. eCollection 2020.

Abstract

Epistasis analysis elucidates the effects of gene-gene interactions (G×G) between multiple loci for complex traits. However, the large computational demands and the high multiple testing burden impede their discoveries. Here, we illustrate the utilization of two methods, main effect filtering based on individual GWAS results and biological knowledge-based modeling through Biofilter software, to reduce the number of interactions tested among single nucleotide polymorphisms (SNPs) for 15 cardiac-related traits and 14 fatty acids. We performed interaction analyses using the two filtering methods, adjusting for age, sex, body mass index (BMI), waist-hip ratio, and the first three principal components from genetic data, among 2,824 samples from the Ludwigshafen Risk and Cardiovascular (LURIC) Health Study. Using Biofilter, one interaction nearly met Bonferroni significance: an interaction between rs7735781 in XRCC4 and rs10804247 in XRCC5 was identified for venous thrombosis with a Bonferroni-adjusted likelihood ratio test (LRT) p: 0.0627. A total of 57 interactions were identified from main effect filtering for the cardiac traits G×G (10) and fatty acids G×G (47) at Bonferroni-adjusted LRT p < 0.05. For cardiac traits, the top interaction involved SNPs rs1383819 in SNTG1 and rs1493939 (138kb from 5' of SAMD12) with Bonferroni-adjusted LRT p: 0.0228 which was significantly associated with history of arterial hypertension. For fatty acids, the top interaction between rs4839193 in KCND3 and rs10829717 in LOC107984002 with Bonferroni-adjusted LRT p: 2.28×10-5 was associated with 9-trans 12-trans octadecanoic acid, an omega-6 trans fatty acid. The model inflation factor for the interactions under different filtering methods was evaluated from the standard median and the linear regression approach. Here, we applied filtering approaches to identify numerous genetic interactions related to cardiac-related outcomes as potential targets for therapy. The approaches described offer ways to detect epistasis in the complex traits and to improve precision medicine capability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Algorithms
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / epidemiology*
  • Cardiovascular Diseases / genetics
  • Case-Control Studies
  • Computational Biology / methods*
  • Epistasis, Genetic*
  • Fatty Acids / blood*
  • Female
  • Follow-Up Studies
  • Genetic Markers*
  • Genome-Wide Association Study
  • Germany / epidemiology
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Prospective Studies
  • Quantitative Trait Loci*
  • Young Adult

Substances

  • Fatty Acids
  • Genetic Markers

Grants and funding

This work is supported by the USDA National Institute of Food and Agriculture and Hatch Appropriations under Project #PEN04275 and Accession #1018544. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Genotyping of the LURIC study participants was supported by the 7th Framework Program AtheroRemo (grant agreement #201668) of the European Union. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Synlab Holding Deutschland GmbH provided support in the form of the salaries for author W.Z. and M.E.K. but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.