Red Blood Cell Distribution Width: genetic evidence for aging pathways in 116,666 volunteers

Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers. A large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%, <50 year olds, 28.4%). RDW was associated with 194 independent genetic signals; 71 are known for conditions including autoimmune disease, certain cancers, BMI, Alzheimer’s disease, longevity, age at menopause, bone density, myositis, Parkinson’s disease, and age-related macular degeneration. Pathways analysis showed enrichment for telomere maintenance, ribosomal RNA and apoptosis. The majority of RDW-associated signals were intronic (119 of 194), including SNP rs6602909 located in an intron of oncogene GAS6 ; the SNP is also an eQTL for this gene in whole blood. RDW-associated exonic genetic signals included a missense variant in PNPLA3 , which codes for a triacylglycerol lipase, and a rare (1% frequency) deletion in SMIM1 , involved in red blood cell formation. Although increased RDW is predictive of cardiovascular outcomes, this was not explained by known CVD or related lipid genetic risks. The predictive value of RDW for a range of negative health outcomes may in part be due to variants influencing fundamental pathways of aging.