Interactive Effects of Telomere Length and Genetic Variants on Alzheimer Disease Risk Across Multiple Ancestral...

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, P < 2×10 ^-16 ). Longer TL was associated with dosages of APOE ε2 ( P <5.08×10 ^-8 ) and APOE ε4 ( P =2.10×10 ^-2 ). In the EA group, genome-wide significant (GWS) TLxSNP 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.

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