Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis.

Abstract

Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the <i>APOE</i> locus (sentinel variant rs73052335, <i>P</i> = 1.44 × 10^-14), two common variants, <i>GCH1</i> (rs72713460, <i>P</i> = 4.36 × 10^-5) and <i>KCNJ15</i> (rs928771, <i>P</i> = 3.60 × 10^-6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that <i>KCNJ15</i> variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the <i>KCNJ15</i> transcript can be observed in the blood of AD subjects. Moreover, the risk variants of <i>GCH1</i> and <i>KCNJ15</i> are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the <i>APOE</i>, <i>GCH1</i>, and <i>KCNJ15</i> loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of <i>GCH1</i> and <i>KCNJ15</i> in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.