Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers

<div><p>Introduction</p><p>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.</p><p>Results</p><p>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. Exclusion of anemic participants did not affect the overall findings. 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 <i>GAS6</i>, an eQTL in whole blood.</p><p>Conclusions</p><p>Although increased RDW is predictive of cardiovascular outcomes, this was not explained by known CVD or related lipid genetic risks, and a RDW genetic score was not predictive of incident disease. The predictive value of RDW for a range of negative health outcomes may in part be due to variants influencing fundamental pathways of aging.</p></div

MAGENTA results: Biological pathways enriched in RDW genetics signals.

<p>MAGENTA results: Biological pathways enriched in RDW genetics signals.</p

Four RDW-associated conditional genetic variants may have damaging effects on proteins.

<p>Four RDW-associated conditional genetic variants may have damaging effects on proteins.</p

Genetic Risk Score associations with RDW.

<p>* FDR = false-discovery rate adjusted significant association. Genetic Risk Scores (GRS) were z-transformed prior to analysis. Linear regression model against RDW (z-transformed) including 116,666 participants, adjusted for age, sex, assessment center and population structure (genetic PCs 1–5). LDL (low-density lipoprotein), HDL (high-density lipoprotein), TG (triglycerides), SBP (systolic blood pressure), CAD (coronary artery disease), T1D (type-1 diabetes), T2D (type-2 diabetes), AMD (age-related macular degeneration), AD (Alzheimer’s disease), FVC (forced vital capacity), BMI (body mass index), IBD (inflammatory bowel disease). Full results in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185083#pone.0185083.s006" target="_blank">S6 Table</a></b>.</p

Genetic variants associated with RDW in GWAS of 116,666 UK Biobank participants.

<p>The variants are grouped into 194 independent signals, colored blue if a variant in the signal is associated with any trait in the NHGRI-EBI GWAS catalog of known associations, otherwise colored in red. The y-axis (–log₁₀ <i>p</i>-values) is limited to 30 for clarity, as the max value is 200. See <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185083#pone.0185083.s001" target="_blank">S1 Table</a></b> for RDW associations for each signal, and <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185083#pone.0185083.s004" target="_blank">S4 Table</a></b> for mapping to the catalog. Horizontal line <i>p</i> = 5x10^-8.</p

Summary statistics for 116,666 UK Biobank participants.

<p>Summary statistics for 116,666 UK Biobank participants.</p

Cumulative risks and the proportion of cases identified for 1 or more islet autoantibodies, multiple islet autoantibodies, and type 1 diabetes in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype according to increasing thresholds of the merged genetic score.

<p>Cumulative risk for developing islet autoantibodies by age 6 years and diabetes by age 10 years (A) and the proportion of cases positive for islet autoantibodies by age 6 years and diabetes by age 10 years (sensitivity; B) in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype stratified by their merged genetic score. The risk and sensitivity are shown for each increment in the genetic score by the 5th percentile of scores in the TEDDY children, ranging from >12.1 (the 5th percentile of children) to >15.4 (the 95th percentile of children). The risk and sensitivity are shown for the development of 1 or more islet autoantibodies (left panels), multiple islet autoantibodies (middle panels), and type 1 diabetes (right panels). Error bars indicate 95% confidence intervals.</p

Merged genetic score in TEDDY children according to their islet autoantibody outcome, geographic location, and sex.

<p>Islet autoantibody outcome (A); geographic location (B); sex (C). Red horizontal lines indicate the median genetic score value in each group.</p

Cumulative risks of 1 or more islet autoantibody, multiple islet autoantibody, and type 1 diabetes in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype.

<p>The cumulative risk for 1 or more islet autoantibodies (A), multiple islet autoantibodies (B), and type 1 diabetes (C) for TEDDY children (<i>y-</i>axis) is shown relative to the age of the children (<i>x-</i>axis) and was calculated using the Kaplan–Meier method. The shaded area represents the 95% confidence interval of the cumulative risk. The numbers at risk indicate the number of children included in the analysis at each age.</p

Cumulative risks of 1 or more islet autoantibody, multiple islet autoantibody, and type 1 diabetes development in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype stratified by their merged score.

<p>The cumulative risk of developing 1 or more islet autoantibodies (A), multiple islet autoantibodies (B), and type 1 diabetes (C) (<i>y-</i>axis) is shown relative to age in years (<i>x-</i>axis) and was calculated using the Kaplan–Meier method. Curves are shown for children with genetic scores in the upper (orange line), lower (green line), and 2 middle (blue line) quartiles. The shaded areas represent the 95% confidence interval of the cumulative risk. The numbers at risk indicate the number of children included in the analysis at each age.</p