Genetically predicted telomere length is associated with clonal somatic copy number alterations in peripheral leukocytes

Abstract

Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Observational studies have identified associations between telomeres and elevated cancer risk, including hematologic malignancies; but biologic mechanisms relating telomere length to cancer etiology remain unclear. Our study sought to better understand the relationship between telomere length and cancer risk by evaluating genetically-predicted telomere length (gTL) in relation to the presence of clonal somatic copy number alterations (SCNAs) in peripheral blood leukocytes. Genotyping array data were acquired from 431,507 participants in the UK Biobank and used to detect SCNAs from intensity information and infer telomere length using a polygenic risk score (PRS) of variants previously associated with leukocyte telomere length. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, higher gTL value was positively associated with the presence of an autosomal SCNA (OR = 1.07, 95% CI = 1.05-1.09, P = 1.61×10 −15). There was high consistency in effect estimates across strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; P het = 0.37) and strata of copy number state (e.g., gain, loss, or neutral events; P het = 0.05). Higher gTL value was associated with a greater cellular fraction of clones carrying autosomal SCNAs (β = 0.004, 95% CI = 0.002-0.007, P = 6.61×10 −4). Our population-based examination of gTL and SCNAs suggests inherited components of telomere length do not preferentially impact autosomal SCNA event location or copy number status, but rather likely influence cellular replicative potential.

Polygenic basis and biomedical consequences of telomere length variation

“…5 ), which may represent different stages of the disease process within individuals before diagnosis. Hematopoietic stem cells with a longer TL are more likely to accrue somatic mutations that potentially lead to leukemic transformation 40 , whereas subsequent high proliferation rates during clonal expansion and the resulting telomere attrition are consistent with the shorter TL in tumors noted in other observational studies 41 . For hypertension, it was probably due to residual bias in the observational analysis (Supplementary Fig.…”

Shared and distinct genetic etiologies for different types of clonal hematopoiesis

“…22 Based on MR-IVW models, we observed positive associations between the TL IV and autosomal mCAs (Z filtered = 5.65, P= 1.21×10 −7 ), CHIP (Z filtered = 4.05, P= 9.68×10 −5 ), and MPNs (Z filtered = 5.61, P= 1.88×10 −7 ), and observed a negative association between the TL IV and LOY (Z filtered = -5.41, P= 5.60×10 −7 ) and did not identify evidence for a genetic relationship between telomere length and LOX ( Supplemental Figure 11, Supplemental Table 14 ), providing additional support to previous reports of associations between inherited telomere length and select CH traits. 17,23,24 The intercept from MR-Egger regression was significant (p< 0.05) for both autosomal mCAs and MPN ( Supplemental Table 14 ), so we performed additional MR weighted median (MR-WM) analyses which displayed the same positive association between the TL IV and autosomal mCAs (Z filtered = 4.16, P= 6.19×10 −5 ), and MPNs (Z filtered = 4.34, P= 3.53×10 −5 ) ( Supplemental Table 14 ). These MR associations are supported by our pathway analyses, which demonstrate telomere pathways are significantly associated with LOY, autosomal mCAs, CHIP, and MPN ( Supplemental Tables 7, 9-11 ); based on these data it is plausible that inherited variation in telomere length maintenance contributes to clonal expansion of mutated hematopoietic stem cells, or alternatively confers greater risk for mutation acquisition in hematopoietic stem cells.…”

“…22 Based on MR-IVW models, we observed positive associations between the TL IV and autosomal mCAs (Z filtered = 5.65, P= 1.21×10 -7 ), CHIP (Z filtered = 4.05, P= 9.68×10 -5 ), and MPNs (Z filtered = 5.61, P= 1.88×10 -7 ), and observed a negative association between the TL IV and LOY (Z filtered = -5.41, P= 5.60×10 -7 ) and did not identify evidence for a genetic relationship between telomere length and LOX (Supplemental Figure 11, Supplemental Table 14), providing additional support to previous reports of associations between inherited telomere length and select CH traits. 17,23,24 The intercept from MR-Egger regression was significant (p< 0.05) for both autosomal mCAs and MPN (Supplemental Table 14), so we performed additional MR weighted median (MR-WM)…”

Germline risk of clonal haematopoiesis

“… 160 ) (the lead variant for increased risk for CHIP 27 and global mCA events 17 ) and rs2853677 (ref. 161 ) (associated with 14q CN-LOH 26 ) associate with longer telomeres and greater telomere length, as predicted by germline variation, is positively associated with mCA events 162 . Recent work using Mendelian randomization has suggested that the telomere–CH relationship is actually bidirectional: longer telomeres may partly cause CHIP (perhaps through an increased propensity for mutation) whereas CHIP, once acquired, may contribute to telomere shortening (possibly via increased rates of cell cycling) 163 .…”