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Background <p>Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer’s disease (AD) remains unclear.</p> Methods <p>We estimated TL in whole-genome sequencing data from 35,014 Alzheimer’s Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA), 4,188 African Americans (AA), 4,005 Caribbean Hispanics (CH), and 4,170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long (TL &gt; 0) and short (TL ≤ 0) groups. An AD GWAS for the interaction of TL with variants having a minor allele count &gt; 20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNP × TL interaction term.</p> Results <p>AD risk was associated with shorter TL (β = -0.48, <i>P</i> &lt; 2 × 10<sup>–16</sup>). Longer and shorter TL were associated with dosages of <i>APOE</i> ε2 (<i>P</i> = 3.40 × 10<sup>–4</sup>) and ε4 (<i>P</i> = 7.05 × 10<sup>–3</sup>), respectively. In the EA group, genome-wide significant (GWS) TL × SNP interactions were identified for variants in <i>SEMA6A (P</i> = 1.42 × 10<sup>–8</sup>) and <i>LOC105378654 (P</i> = 4.17 × 10<sup>–8</sup>), between <i>IL15</i> and <i>INPP4B (P</i> = 1.77 × 10<sup>–8</sup>) and upstream of <i>RP11-2N5.2</i> (<i>P</i> = 4.60 × 10<sup>–8</sup>). In the NAH group, GWS interactions were observed with an intronic variant in <i>BSN</i> (<i>P</i> = 3.26 × 10<sup>–8</sup>) and missense variant in <i>MST1</i> (<i>P</i> = 3.26 × 10<sup>–8</sup>). In the total sample, interactions with variants between <i>CTD-2160D9.1</i> and <i>EEF1A1P20</i> (<i>P</i> &lt; 1.19 × 10<sup>–8</sup>), in <i>TBC1D22A</i> (<i>P</i> = 1.06 × 10<sup>–8</sup>) and in <i>PLK1</i> (<i>P</i> = 3.28 × 10<sup>–8</sup>) were GWS.</p> Conclusion <p>We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis.</p>

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Interactive effects of telomere length and genetic variants on Alzheimer disease risk across multiple ancestral populations

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  • 发表日期：

    2026年3月20日

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  • Zainab Khurshid,
  • Tong Tong,
  • Oluwatosin Olayinka,
  • John J. Farrell,
  • Congcong Zhu,
  • Eden R. Martin,
  • William S. Bush,
  • Margaret A. Pericak-Vance,
  • Li-San Wang,
  • Gerard D. Schellenberg,
  • Jonathan L. Haines,
  • Kathryn L. Lunetta,
  • Xiaoling Zhang,
  • Lindsay A. Farrer

摘要

Background

Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer’s disease (AD) remains unclear.

Methods

We estimated TL in whole-genome sequencing data from 35,014 Alzheimer’s Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA), 4,188 African Americans (AA), 4,005 Caribbean Hispanics (CH), and 4,170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long (TL > 0) and short (TL ≤ 0) groups. An AD GWAS for the interaction of TL with variants having a minor allele count > 20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNP × TL interaction term.

Results

AD risk was associated with shorter TL (β = -0.48, P < 2 × 10–16). Longer and shorter TL were associated with dosages of APOE ε2 (P = 3.40 × 10–4) and ε4 (P = 7.05 × 10–3), respectively. In the EA group, genome-wide significant (GWS) TL × SNP interactions were identified for variants in SEMA6A (P = 1.42 × 10–8) and LOC105378654 (P = 4.17 × 10–8), between IL15 and INPP4B (P = 1.77 × 10–8) and upstream of RP11-2N5.2 (P = 4.60 × 10–8). In the NAH group, GWS interactions were observed with an intronic variant in BSN (P = 3.26 × 10–8) and missense variant in MST1 (P = 3.26 × 10–8). In the total sample, interactions with variants between CTD-2160D9.1 and EEF1A1P20 (P < 1.19 × 10–8), in TBC1D22A (P = 1.06 × 10–8) and in PLK1 (P = 3.28 × 10–8) were GWS.

Conclusion

We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis.