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

Summary of L5-midpoint timing by PER2 loss-of-function carrier status in the UK Biobank.

(DOCX)</p

Summary statistics of sleep-midpoint estimated from accelerometer data in UK Biobank and MESA across genotype groups for variants previously reported as causal for delayed sleep phase.

(DOCX)</p

Summary statistics of L5-midpoint timing estimated from accelerometer data in UK Biobank across genotype groups for variants previously reported as causal for familial advanced sleep phase.

(DOCX)</p

P-values from burden testing of rare (MAF < 0.01%) loss-of-function and missense variants in genes outlined in this paper on self-reported sleep duration in UK Biobank.

(DOCX)</p

Summary statistics of L5-midpoint timing estimated from accelerometer data in UK Biobank a across genotype groups for variants previously reported as causal for delayed sleep phase.

(DOCX)</p

Proportion of individuals self-reporting as being “definitely a morning person”, average L5 timing, and average of sleep-midpoint across all nights for each genotype group of variants previously reported to be causal for familial advanced sleep phase in the UK Biobank (UKB), Finnish and MESA studies.

Accelerometer-based estimates of sleep timing unavailable in the Finnish studies. Self-reported “morningness” and accelerometer estimates of L5-timing unavailable in MESA.</p

Summary of average accelerometer derived sleep duration (hours) (all nights) in the subset of exome-sequenced unrelated Europeans in UK Biobank, split by carriers and non-carriers for variants previously reported to be causal for familial natural short sleep.

Summary of average accelerometer derived sleep duration (hours) (all nights) in the subset of exome-sequenced unrelated Europeans in UK Biobank, split by carriers and non-carriers for variants previously reported to be causal for familial natural short sleep.</p

Summary of chronotype by PER2 loss-of-function carrier status in the UK Biobank.

(DOCX)</p

P-values from burden testing of rare (MAF < 0.01%) loss-of-function and missense variants in genes previously reported to harbour variants causal for disruptive sleep duration or timing on accelerometer estimates of sleep duration in UK Biobank.

There were no remaining loss-of-function carriers for GRM1, ADRB1 and CRY2 within the subset of individuals from UK Biobank who wore an accelerometer. (DOCX)</p