Polygenic modifiers impact penetrance and expressivity in telomere biology disorders

Michael Poeschla; Uma P. Arora; Amanda Walne; Lisa J. McReynolds; Marena R. Niewisch; Neelam Giri; Logan P. Zeigler; Alexander Gusev; Mitchell J. Machiela; Hemanth Tummala; Sharon A. Savage; Vijay G. Sankaran

doi:10.1172/JCI191107

Polygenic modifiers impact penetrance and expressivity in telomere biology disorders

Michael Poeschla,¹ Uma P. Arora,¹ Amanda Walne,² Lisa J. McReynolds,³ Marena R. Niewisch,³ Neelam Giri,³ Logan P. Zeigler,³ Alexander Gusev,⁵ Mitchell J. Machiela,³ Hemanth Tummala,² Sharon A. Savage,³ and Vijay G. Sankaran¹

Published June 3, 2025 - More info

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Abstract

BACKGROUND. Telomere biology disorders (TBDs) exhibit incomplete penetrance and variable expressivity, even among individuals harboring the same pathogenic variant. We assessed whether common genetic variants associated with telomere length combine with large-effect variants to impact penetrance and expressivity in TBDs. METHODS. We constructed polygenic scores (PGS) for telomere length in the UK Biobank to quantify common variant burden, and assessed the PGS distribution across patient cohorts and biobanks to determine whether individuals with severe TBD presentations have increased polygenic burden causing short telomeres. We also characterized rare TBD variant carriers in the UK Biobank. RESULTS. Individuals with TBDs in cohorts enriched for severe pediatric presentations have polygenic scores predictive of short telomeres. In the UK Biobank, we identify carriers of pathogenic TBD variants who are enriched for adult-onset manifestations of TBDs. Unlike individuals in disease cohorts, the PGS of adult carriers do not show a common variant burden for shorter telomeres, consistent with the absence of childhood-onset disease. Notably, TBD variant carriers are enriched for idiopathic pulmonary fibrosis diagnoses, and telomere length PGS stratifies pulmonary fibrosis risk. Finally, common variants affecting telomere length were enriched in enhancers regulating known TBD genes. CONCLUSION. Common genetic variants combine with large-effect causal variants to impact clinical manifestations in rare TBDs. These findings offer a framework for understanding phenotypic variability in other presumed monogenic disorders. FUNDING. This work was supported by National Institutes of Health grants R01DK103794, R01HL146500, R01CA265726, R01CA292941, and the Howard Hughes Medical Institute.

Polygenic modifiers impact penetrance and expressivity in telomere biology disorders

Michael Poeschla,¹ Uma P. Arora,¹ Amanda Walne,² Lisa J. McReynolds,³ Marena R. Niewisch,³ Neelam Giri,³ Logan P. Zeigler,³ Alexander Gusev,⁵ Mitchell J. Machiela,³ Hemanth Tummala,² Sharon A. Savage,³ and Vijay G. Sankaran¹

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Polygenic modifiers impact penetrance and expressivity in telomere biology disorders

Michael Poeschla,1 Uma P. Arora,1 Amanda Walne,2 Lisa J. McReynolds,3 Marena R. Niewisch,3 Neelam Giri,3 Logan P. Zeigler,3 Alexander Gusev,5 Mitchell J. Machiela,3 Hemanth Tummala,2 Sharon A. Savage,3 and Vijay G. Sankaran1

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Michael Poeschla,¹ Uma P. Arora,¹ Amanda Walne,² Lisa J. McReynolds,³ Marena R. Niewisch,³ Neelam Giri,³ Logan P. Zeigler,³ Alexander Gusev,⁵ Mitchell J. Machiela,³ Hemanth Tummala,² Sharon A. Savage,³ and Vijay G. Sankaran¹