A phenome-wide approach to identify causal risk factors for deep vein thrombosis

Abstract

Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein. DVT can lead to a venous thromboembolism (VTE), the combined term for DVT and pulmonary embolism, a leading cause of death and disability worldwide. Despite the prevalence and associated morbidity of DVT, the underlying causes are not well understood. Our aim was to leverage publicly available genetic summary association statistics to identify causal risk factors for DVT. We conducted a Mendelian randomization phenome-wide association study (MR-PheWAS) using genetic summary association statistics for 973 exposures and DVT (6,767 cases and 330,392 controls in UK Biobank). There was evidence for a causal effect of 57 exposures on DVT risk, including previously reported risk factors (e.g. body mass index-BMI and height) and novel risk factors (e.g. hyperthyroidism and varicose veins). As the majority of identified risk factors were adiposity-related, we explored the molecular link with DVT by undertaking a two-sample MR mediation analysis of BMI-associated circulating proteins on DVT risk. Our results indicate that circulating neurogenic locus notch homolog protein 1 (NOTCH1), inhibin beta C chain (INHBC) and plasminogen activator inhibitor 1 (PAI-1) influence DVT risk, with PAI-1 mediating the BMI-DVT relationship. Using a phenome-wide approach, we provide putative causal evidence that hyperthyroidism, varicose veins and BMI enhance the risk of DVT. Furthermore, the circulating protein PAI-1 has a causal role in DVT aetiology and is involved in mediating the BMI-DVT relationship.

Keywords: ALSPAC; Deep vein thrombosis; Genome-wide association study; Mendelian randomization; Protein quantitative trait loci.

Fig. 1

Overview of the study. First, a MR-PheWAS analysis to find risk factors for DVT was done using the MR-Base database and identified many of these to be associated with adiposity (N=24/57). This was followed by a two-sample mediation MR between BMI-associated pQTL data on DVT risk. MR = mendelian randomization; GWAS = genome-wide association study; VTE = venous thromboembolism; DVT = deep vein thrombosis; SNP = single-nucleotide polymorphism; pQTL = protein quantitative trait loci; PAI-1 = Plasminogen activator inhibitor-1; NOTCH1 = Neurogenic locus notch homolog protein 1; INHBC = Inhibin Subunit Beta C; S Table = Supplementary Table

Fig. 2

A many-to-one forest plot of the exposures which passed the P-value threshold following multiple testing correction (5.43e-5). Each trait is accompanied by two additional descriptive columns (No. SNPs and P -value), while log risk ratio (RR) is displayed to the right, alongside with the confidence intervals. MR methods: Inverse variance weighted (SNP > 1) and Wald ratio (SNP = 1)

Fig. 3

A many-to-one forest plot of the three BMI-associated proteins which passed the multiple-testing corrected P-value threshold (0.003) in the MR analysis. Each protein is accompanied by two additional descriptive columns (type of analysis conducted and P-value), while the effect is displayed to the right, alongside with the confidence intervals (Beta coefficient/Log RR ± 95% CI). Effect sizes of BMI on proteins taken from Goudswaard et al. [18] and Zaghlool et al. [19]

Fig. 4

LocusZoom plots in a 1Mb region of the SNP used to proxy each PAI-1 in both exposure (A) and outcome (DVT, B) data. The x-axis represents the position within the chromosome, while the y-axis is the -log₁₀ of the P-value. Each dot is a SNP, and the colours indicate how much LD there is between the reference SNP and the other genetic variants