Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. Genetic and environmental factors mutually contribute to the pathogenesis of AD. Genetics studies of AD have elucidated key disease mechanisms including the amyloid precursor protein (APP) processing and immune-associated pathways. However, most studies were conducted on Caucasian populations and were based on the single nucleotide polymorphism array technique, resulting in an incomplete profiling of genetic signatures. Here, a whole-genome sequencing study of AD was conducted in the Chinese population. Two genes marked by common variants—GCH1 and KCNJ15—as well as AD-risk haplotypes located near the APOE region were identified. Integration of genetic information with transcriptome information, protein bio...[ Read more ]

Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. Genetic and environmental factors mutually contribute to the pathogenesis of AD. Genetics studies of AD have elucidated key disease mechanisms including the amyloid precursor protein (APP) processing and immune-associated pathways. However, most studies were conducted on Caucasian populations and were based on the single nucleotide polymorphism array technique, resulting in an incomplete profiling of genetic signatures. Here, a whole-genome sequencing study of AD was conducted in the Chinese population. Two genes marked by common variants—GCH1 and KCNJ15—as well as AD-risk haplotypes located near the APOE region were identified. Integration of genetic information with transcriptome information, protein biomarkers in plasma and cerebrospinal fluid, brain volumetric data, and clinical indexes further demonstrated the biological impacts of these identified risk factors. Specifically, the results show that KCNJ15 variant rs928771 is associated with the onset age of AD and that the identified risk factors might be associated with local gene expression in specific tissues. Moreover, gene expression analysis of risk variants suggested that they have possible modulatory roles in the immune-associated pathway, which is further evidenced by the observed associations with plasma biomarkers levels. Furthermore, chromatin interaction analysis suggested a novel regulatory mechanism of APOE expression in the human brain. Thus, the present study identified novel AD-associated genetic signatures with putative biological implications, namely KCNJ15, GCH1, and haplotypes in the region near APOE, which might contribute to AD pathogenesis in the Chinese population.