Common and rare variants of EGF increase the genetic risk of Alzheimer's disease as revealed by targeted sequencing of growth factors in Han Chinese.

ABSTRACT

Alzheimer's disease (AD) is the most common neurodegenerative disease with high heritability. Growth factors (GFs) might contribute to the development of AD due to their broad effects on neuronal system. We herein aimed to investigate the role of rare and common variants of GFs in genetic susceptibility of AD. We screened 23 GFs in 6324 individuals using targeted sequencing. A rare-variant-based burden test and common-variant-based single-site association analyses were performed to identify AD-associated GF genes and variants. The burden test showed an enrichment of rare missense variants (p = 6.08 × 10-4) in GF gene-set in AD patients. Among the GFs, EGF showed the strongest signal of enrichment, especially for loss-of-function variants (p = 0.0019). A common variant rs4698800 of EGF showed significant associations with AD risk (p = 3.24 × 10-5, OR = 1.26). The risk allele of rs4698800 was associated with an increased EGF expression, whereas EGF was indeed upregulated in AD brain. These findings suggested EGF as a novel risk gene for AD.