In this issue of CHEST (see page 607), Wei and colleagues8 use an innovative approach to identify a novel genetic variant linked to platelets, which is associated with ARDS risk. Several investigators have identified genetic variants in genes implicated in alveolar-capillary barrier integrity,9 inflammation,10 and coagulation as risk factors for ARDS11; however, variants resulting in platelet heterogeneity have not previously been linked to ARDS. Working with the knowledge that thrombocytopenia during critical illness is associated with poor outcomes,12 and that genome-wide association studies have identified several genetic variants linked to platelet count in the noncritically ill,13 Wei and colleagues8 set out to answer several questions. First, they determined the association of single nucleotide polymorphisms (SNPs) in candidate genes with platelet count in a cohort of critically ill patients at risk for ARDS. They selected candidate genes based on previous associations with platelet count in relatively healthy populations and identified an intronic SNP in LRRC16A as also associated with platelet count among the critically ill. Next, the same SNP in LRRC16A was determined to be associated with altered risk of ARDS. Lastly, they used sophisticated statistical methods to determine whether platelet count was a causal mediator linking the LRRC16A genotype to ARDS risk. Decreased platelet count, measured at ICU admission, was associated with increased ARDS risk in their cohort and functioned as a partial mediator of the association between LRRC16A genotype and ARDS. While not proving causation, this approach not only identified a novel genetic risk factor for ARDS, but also provided evidence for a potential mechanism resulting in the altered risk.