Abstract
Background
Alzheimer’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.
Method
Pooled 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.
Result
We 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.
Conclusion
Using 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.