Massive US Study Maps How Telomere Length Varies by Ancestry, Location and Lifestyle
Analysis of 242,000+ Americans reveals who has shorter telomeres, where they live, and 37 newly discovered genetic loci driving telomere biology.
Summary
Researchers estimated leukocyte telomere length (LTL) from whole-genome sequences in 242,494 diverse Americans enrolled in the All of Us program. LTL was shorter with age, smoking, heavy alcohol use, higher BMI, and neighborhood deprivation, and longer with physical activity and moderate alcohol use. Striking geographic patterns emerged: longer LTL clustered on the West Coast and Central Midwest, while shorter LTL clustered in the Southeast. African-like ancestry participants showed faster age-related LTL attrition than European-like participants. A genome-wide association meta-analysis with UK Biobank (total n=679,972) identified 234 loci, including 37 novel ones—six exclusive to non-European populations and one specific to women. Rare variant analysis uncovered nine novel genes, deepening understanding of telomere biology across ancestrally diverse populations.
Detailed Summary
Leukocyte telomere length (LTL) is one of the most-studied markers of biological aging, linked to cardiovascular disease, cancer risk, and longevity. Despite this, most large genomic studies have been conducted predominantly in European-ancestry populations, limiting understanding of how telomere biology varies across diverse groups. This study addresses that gap head-on using the All of Us (AoU) research program, one of the most ancestrally diverse biobanks in the United States.
The team estimated LTL from blood-derived whole-genome sequencing in 242,494 AoU participants, adjusting for sequencing batch effects using principal components of sequencing depth. The cohort was 60.9% female, mean age 51.6 years, and 54.3% European-like ancestry, with substantial representation of African-like, Latino/Admixed American, and other ancestries. LTL associations were examined across anthropometrics, biomarkers, lifestyle factors, socioeconomic status, and clinical diagnoses.
Key phenomic findings confirmed and extended prior work: shorter LTL was linked to higher BMI, smoking, heavy alcohol consumption (≥3 drinks/day), elevated blood pressure, and neighborhood deprivation. Conversely, longer LTL was associated with physical activity, ever (but not heavy) alcohol use, and higher socioeconomic indicators. Critically, 15 of 24 tested traits showed statistically significant heterogeneity in LTL associations by genetic ancestry, and 9 showed heterogeneity by sex—including socioeconomic factors showing the strongest ancestry-dependent variation. African-like ancestry participants exhibited a steeper age-related LTL attrition rate than European-like participants, particularly in males.
Geographic mapping across US states revealed a striking spatial pattern: significantly longer LTL clustered on the West Coast and Central Midwest, while significantly shorter LTL concentrated in the Southeastern United States—a region also characterized by higher cardiovascular disease burden and socioeconomic deprivation.
On the genomic side, a GWAS of common variants in AoU followed by meta-analysis with UK Biobank (combined n=679,972) identified 234 independent loci, of which 37 were novel. Six of these novel loci were identified exclusively in non-European-like populations, and one was women-specific, underscoring the value of diverse cohort inclusion. Rare variant association analysis identified nine novel genes influencing LTL, providing new mechanistic insight into telomere maintenance pathways. These results substantially expand the catalog of genetic determinants of telomere length and highlight how prior European-centric studies missed ancestry-specific signals.
Key Findings
- 234 genomic loci linked to LTL identified, including 37 novel; 6 exclusive to non-European ancestries.
- African-like ancestry individuals show faster age-related telomere shortening, especially in males.
- Longer LTL clusters on the US West Coast and Midwest; shorter LTL concentrated in the Southeast.
- Heavy alcohol (≥3 drinks/day), smoking, high BMI, and neighborhood deprivation all independently associate with shorter LTL.
- Nine novel genes discovered via rare variant analysis, expanding mechanistic understanding of telomere biology.
Methodology
LTL was estimated from blood-derived whole-genome sequencing in 242,494 All of Us participants using modified TelSeq, adjusted for sequencing heterogeneity via principal components of sequencing depth. Common variant GWAS was meta-analyzed with UK Biobank (total n=679,972); rare variant association analysis and phenome-wide association studies were conducted across ancestry and sex strata.
Study Limitations
Observational associations between LTL and traits cannot establish causality; geographic clustering may reflect confounding by ancestry or unmeasured environmental factors. LTL measured from blood may not fully capture tissue-specific telomere dynamics relevant to specific diseases.
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