Abstract
Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear.
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 and short groups according to the median. 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.
AD risk was associated with shorter TL (β = -0.18,
< 2×10
). Longer TL was associated with dosages of
ε2 (
<5.08×10
) and
ε4 (
=2.10×10
). In the EA group, genome-wide significant (GWS) TLxSNP interactions were identified for variants in
=1.42×10
) and
=4.17×10
), between
and
=1.77×10
) and upstream of
(
=4.60×10
). In the NAH group, GWS interactions were observed with an intronic variant in
(
=3.26×10
) and missense variant in
(
=3.26×10
). In the total sample, interactions with variants between
and
(
<1.19×10
), in
(
=1.06×10
) and in
(
=3.28×10
) were GWS.
We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis.