An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism

Abstract

Venous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its fatal form, pulmonary embolism (PE). While PE is observed in ~40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (p = 5.3x10-7) at the PLXNA4 locus, with lead SNP rs1424597 at which the minor A allele was further shown to associate with an increased risk of PE (OR = 1.49 [1.12 − 1.98], p = 6.1x10-3). Further association analysis in EOVT revealed that, in the combined MARTHA and EOVT samples, the rs1424597-A allele was associated with increased PE risk (OR = 1.74 [1.27 − 2.38, p = 5.42x10-4) in patients over 37 years of age but not in younger patients (OR = 0.96 [0.65 − 1.41], p = 0.848). Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.

Testing for association with rare variants in the coding and non-coding genome: RAVA-FIRST, a new approach based on CADD deleteriousness score

“…There exists a huge heterogeneity between patients in the age at first VTE event. To study the role of rare variants on VTE age of onset, WGS data were used from 200 individuals from the MARTHA cohort (32). These individuals were selected among patients with unprovoked VTE event who were previously genotyped for a genome-wide association study (33) and present no known genetic predisposing factor.…”

“…A similar trend (p = 4.6•10 -3 ) was observed with red blood cell count. We also investigated the association of the identified region with 376 plasma protein antibodies that were selected to be involved in thrombosis-related processes and that have been previously profiled in MARTHA (32,35). Regression analysis were conducted on log transformed values of antibodies and were adjusted for age, sex, and three internal control antibodies.…”