Introduction Our understanding of the genetic predisposition for age‐at‐onset (AAO) of Alzheimer's disease (AD) is limited. Here, we sought to identify genes modifying AAO and examined whether any have sex‐specific effects. Methods Genome‐wide association analysis were performed on imputed genetic data of 9219 AD cases and 10,345 controls from 20 cohorts of the Alzheimer's Disease Genetics Consortium. AAO was modeled from cases directly and as a survival outcome. Results We identified 11 genome‐wide significant loci (P < 5 × 10−8), including six known AD‐risk genes and five novel loci, UMAD1, LUZP2, ARFGEF2, DSCAM, and 4q25, affecting AAO of AD. Additionally, 39 suggestive loci showed strong association. Twelve loci showed sex‐specific effects on AAO including CD300LG and MLX/TUBG2 for females and MIR4445 for males. Discussion Genes that influence AAO of AD are excellent therapeutic targets for delaying onset of AD. Several loci identified include genes with promising functional implications for AD.
BackgroundAlzheimer’s disease (AD) has high genetic heritability for both disease risk and age‐at‐onset (AAO) of AD. However, our understanding of genetics of AAO of AD lags behind AD risk. Here, we utilized two statistical approaches to identify genes modifying AAO of AD globally or in a sex‐specific manner.MethodPooled data from 9,219 AD cases and 10,345 controls from 20 cohorts from the Alzheimer Disease Genetic Consortium were analyzed using a linear mixed model (LMM) for AAO from cases only, and a Cox proportional hazard frailty model (CoxFM) from all subjects with AAO observed in cases and censored at age‐at‐exam in controls. Both methods modeled outcome on SNP, sex, APOE‐e4, and 10 principal components (PCs), and incorporated random intercept by cohort. Fisher’s method was used to combine results of LMM and CoxFM. Genome‐wide significant variants were determined based on p < 5×10−8 in individual or combined tests. Multiple secondary analyses were performed including sex‐specific association tests for top SNPs (p< 10−6). Two gene‐expression datasets of prefrontal cortex tissues from NCBI/GEO were analyzed by sex to evaluate the sex‐specific AAO genes.ResultWe identified 34 genome‐wide significant loci. We confirmed 6 known AD risk genes (APOE, CR1, BIN1, TREM2, PICALM, and FERMT2) also regulating AAO as AD. Twenty‐eight potential novel loci were identified including ARFGEF2, MAPK9, and the MLX region harboring functional related genes for AD. Sex‐specific analyses showed the effects of PICALM, MLX, and CDH2 on AAO were solely from females, and ATP2C1 from males. Particularly, the MLX region harboring 10 genes in strong LD, including variants in COASY and HSD17B1 previously reported to associate with earlier AAO of AD in female AD patients with Down Syndrome. Gene expression further supported higher differential expression of AD over controls for HSD17B1, COASY, PLEKHH3, and MLX in females than males.ConclusionUsing two statistical methods to model AAO of AD, we identified six known AD risk genes and 28 novel loci associated with AAO of AD, and further narrowed down four loci with sex‐specific effects. Notably, HSD17B1, involved in estrogen activation, has strong functional implications warrant for further investigation.
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