Genetic variants associated with Alzheimer's disease and telomere length

Abstract Background Telomere length (TL), a marker of biological aging, has been implicated in multiple age‐related diseases, but its association with Alzheimer's disease (AD) remains unclear. We analyzed whole genome sequence data from the Alzheimer's Disease Sequencing Project (release 4) to identify genetic variants associated with both AD and TL. Method We estimated TL for 35,014 participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA; 3,701 AD cases, 3,273 controls), 4,188 African Americans (AA; 1,329 AD cases, 2,859 controls), 4,008 Caribbean Hispanics (CH; 1,588 AD cases, 2,420 controls), and 4,170 Native American Hispanics (NAH; 754 AD cases, 3,416 controls). The association of AD with TL was tested using a linear regression model including covariates for age, sex, and dosage of the APOE e2 and e4 alleles. The interaction of TL with SNPs having a minor allele count >20 was evaluated for its association with AD in each ancestry group by logistic regression models using GENESIS including SNP, TL, an interaction term for SNPxTL, and covariates for age, sex, sequencing center, genetic relationship matrix, and principal components of ancestry. Results were combined across groups using METASOFT. Result AD ( p = 5.32x10 ‐12 ), age ( p = 2.00x10 ‐16 ), sex ( p = 2.00x10 ‐16 ), and APOE e2 ( p = 5.35x10 ‐6 ) were significantly associated with TL. In the EA sample, interaction of TL with CRTC3‐AS1 intronic SNP rs533691286 was associated with AD at the genome‐wide significance (GWS) level ( p = 1.13x10 ‐8 ). Suggestive associations were found with rs537146885 located between RP5‐884C9.2 and LINC01343 ( p = 8.95x10 ‐8 ). In the NAH group, GWS associations were observed for interactions of TL with MIR548XHG intronic variants rs117856971 ( p = 2.06x10 ‐9 ) and rs18578882 ( p = 3.70x10 ‐8 ). No TLxSNP interactions were GWS in the CH and AA groups. In the total sample, GWS associations were identified for interactions of TL with intronic variants in SLC23A2 ( rs184956772, p = 3.19x10 ‐9 ) and CFAP61 (rs769676169, p = 3.64x10 ‐9 ), rs1037982496 upstream of DEFB123 ( p = 2.96x10 ‐9 ), and several intergenic variants including DEFB115‐DKKL1P1 (rs968020553, p = 2.96X10 ‐9 ), RP5‐884C9.2‐LINC01343 (rs537146885, p = 4.98x10 ‐9 ), MIR3193‐COX4I2 (rs921951239, p = 2.70x10 ‐9 ), AC010091.1 (rs552422184, p = 5.86x10 ‐9 ), and CTA‐109P11.1‐RP11‐328K15.1 ( rs77699417, p = 6.51x10 ‐9 ). 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.