Telomere length is greater in ALS than in controls: a whole genome sequencing study.

Author: Al Khleifat A1, Iacoangeli A1,2, Shatunov A1, Fang T1, Sproviero W1, Jones AR1, Opie-Martin S1, Morrison KE3, Shaw PJ4, Shaw CE1,5,6, Powell JF1, Dobson R2,7, Newhouse SJ2,7, Al-Chalabi A1,5
1a Department of Basic and Clinical Neuroscience , King's College London, Maurice Wohl Clinical Neuroscience Institute , London , UK.
2b Department of Biostatistics and Health Informatics , King's College London , London , UK.
3c Faculty of Medicine , University of Southampton, University Hospital Southampton NHS Foundation Trust , Southampton , UK.
4d Sheffield Institute for Translational Neuroscience, University of Sheffield , Sheffield , UK.
5e King's College Hospital , London , UK.
6f Psychology and Neuroscience , United Kingdom Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, King's College London , London , UK, and.
7g Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London , London , UK.
Conference/Journal: Amyotroph Lateral Scler Frontotemporal Degener.
Date published: 2019 Apr 1
Other: Volume ID: 1-6 , Special Notes: doi: 10.1080/21678421.2019.1586951. [Epub ahead of print] , Word Count: 227

BACKGROUND: Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons resulting in progressive paralysis and death, typically within 3-5 years. Although the heritability of ALS is about 60%, only about 11% is explained by common gene variants, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication and shorten naturally with age. Gender and age are risk factors for ALS and also associated with telomere length. We therefore investigated telomere length in ALS.

METHODS: We estimated telomere length by applying a bioinformatics analysis to whole genome sequence data of leukocyte-derived DNA from people with ALS and age and gender-matched matched controls in a UK population. We tested the association of telomere length with ALS and ALS survival.

RESULTS: There were 1241 people with ALS and 335 controls. The median age for ALS was 62.5 years and for controls, 60.1 years, with a male-female ratio of 62:38. Accounting for age and sex, there was a 9% increase of telomere length in ALS compared to matched controls. Those with longer telomeres had a 16% increase in median survival. Of nine SNPs associated with telomere length, two were also associated with ALS: rs8105767 near the ZNF208 gene (p = 1.29 × 10-4) and rs6772228 (p = 0.001), which is in an intron for the PXK gene.

CONCLUSIONS: Longer telomeres in leukocyte-derived DNA are associated with ALS, and with increased survival in those with ALS.


PMID: 30931641 DOI: 10.1080/21678421.2019.1586951