@article {840, title = {Determinants of telomere length across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.

}, keywords = {Aging, Genetic Markers, Genetic Variation, Humans, Organ Specificity, Telomere, Telomere Homeostasis, Telomere Shortening}, issn = {1095-9203}, doi = {10.1126/science.aaz6876}, author = {Demanelis, Kathryn and Jasmine, Farzana and Chen, Lin S and Chernoff, Meytal and Tong, Lin and Delgado, Dayana and Zhang, Chenan and Shinkle, Justin and Sabarinathan, Mekala and Lin, Hannah and Ramirez, Eduardo and Oliva, Meritxell and Kim-Hellmuth, Sarah and Stranger, Barbara E and Lai, Tsung-Po and Aviv, Abraham and Ardlie, Kristin G and Aguet, Francois and Ahsan, Habibul and Doherty, Jennifer A and Kibriya, Muhammad G and Pierce, Brandon L} } @article {180, title = {Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 May}, pages = {512-7}, abstract = {

Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 {\texttimes} 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 {\texttimes} 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7\% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.

}, keywords = {Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Case-Control Studies, Cells, Cultured, DNA Helicases, DNA Mutational Analysis, Exome, Exoribonucleases, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Idiopathic Pulmonary Fibrosis, Leukocytes, Lod Score, Male, Middle Aged, Molecular Sequence Data, Pedigree, Telomere, Telomere Shortening}, issn = {1546-1718}, doi = {10.1038/ng.3278}, author = {Stuart, Bridget D and Choi, Jungmin and Zaidi, Samir and Xing, Chao and Holohan, Brody and Chen, Rui and Choi, Mihwa and Dharwadkar, Pooja and Torres, Fernando and Girod, Carlos E and Weissler, Jonathan and Fitzgerald, John and Kershaw, Corey and Klesney-Tait, Julia and Mageto, Yolanda and Shay, Jerry W and Ji, Weizhen and Bilguvar, Kaya and Mane, Shrikant and Lifton, Richard P and Garcia, Christine Kim} } @article {195, title = {Rare variants in RTEL1 are associated with familial interstitial pneumonia.}, journal = {Am J Respir Crit Care Med}, volume = {191}, year = {2015}, month = {2015 Mar 15}, pages = {646-55}, abstract = {

RATIONALE: Up to 20\% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families.

OBJECTIVES: To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis.

METHODS: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds.

MEASUREMENTS AND MAIN RESULTS: We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7\%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10\% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function.

CONCLUSIONS: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.

}, keywords = {Aged, Aged, 80 and over, DNA Helicases, Female, Genetic Variation, Heterozygote, Humans, Lung, Lung Diseases, Interstitial, Male, Middle Aged, Pedigree, Telomere}, issn = {1535-4970}, doi = {10.1164/rccm.201408-1510OC}, author = {Cogan, Joy D and Kropski, Jonathan A and Zhao, Min and Mitchell, Daphne B and Rives, Lynette and Markin, Cheryl and Garnett, Errine T and Montgomery, Keri H and Mason, Wendi R and McKean, David F and Powers, Julia and Murphy, Elissa and Olson, Lana M and Choi, Leena and Cheng, Dong-Sheng and Blue, Elizabeth Marchani and Young, Lisa R and Lancaster, Lisa H and Steele, Mark P and Brown, Kevin K and Schwarz, Marvin I and Fingerlin, Tasha E and Schwartz, David A and Lawson, William E and Loyd, James E and Zhao, Zhongming and Phillips, John A and Blackwell, Timothy S} }