TY - JOUR
T1 - The polygenic nature of telomere length and the anti-ageing properties of lithium
AU - Coutts, Fiona
AU - Palmos, Alish
AU - Duarte, Rodrigo R. R.
AU - de Jong, Simone
AU - Lewis, Cathryn M.
AU - Dima, Danai
AU - Powell, Timothy R.
PY - 2018/12/18
Y1 - 2018/12/18
N2 - Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the
genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression
applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.29%,
with polygenic risk scoring capturing 4.4% of the variance in telomere length in an independent cohort (p = 6.17 × 10−5
). Geneenrichment analysis identified 13 genes associated with telomere length, with the most significant being the leucine rich repeat
gene, LRRC34 (p = 3.69 × 10−18). In the context of lithium, we confirm that chronic use in a sample of 384 bipolar disorder patients is
associated with longer telomeres (p = 0.03). As complementary evidence, we studied three orthologs of telomere length regulators
in a Caenorhabditis elegans model of lithium-induced extended longevity and found all transcripts to be affected post-treatment (p
< 0.05). Lithium may therefore confer its anti-ageing effects by moderating the expression of genes responsible for normal telomere
length regulation. This is supported by our bipolar disorder sample, which shows that polygenic risk scores explain a higher
proportion of the variance in telomere length amongst chronic lifetime lithium users (variance explained = 8.9%, p = 0.01),
compared to non-users (p > 0.05). Consequently, this suggests that lithium may be catalysing the activity of endogenous
mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual’s inherent
telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere
length and consequently lithium’s anti-ageing efficacy.
AB - Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the
genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression
applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.29%,
with polygenic risk scoring capturing 4.4% of the variance in telomere length in an independent cohort (p = 6.17 × 10−5
). Geneenrichment analysis identified 13 genes associated with telomere length, with the most significant being the leucine rich repeat
gene, LRRC34 (p = 3.69 × 10−18). In the context of lithium, we confirm that chronic use in a sample of 384 bipolar disorder patients is
associated with longer telomeres (p = 0.03). As complementary evidence, we studied three orthologs of telomere length regulators
in a Caenorhabditis elegans model of lithium-induced extended longevity and found all transcripts to be affected post-treatment (p
< 0.05). Lithium may therefore confer its anti-ageing effects by moderating the expression of genes responsible for normal telomere
length regulation. This is supported by our bipolar disorder sample, which shows that polygenic risk scores explain a higher
proportion of the variance in telomere length amongst chronic lifetime lithium users (variance explained = 8.9%, p = 0.01),
compared to non-users (p > 0.05). Consequently, this suggests that lithium may be catalysing the activity of endogenous
mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual’s inherent
telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere
length and consequently lithium’s anti-ageing efficacy.
U2 - 10.1038/s41386-018-0289-0
DO - 10.1038/s41386-018-0289-0
M3 - Article
SN - 0893-133X
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
ER -
