A whole‐genome‐sequencing study to identify genetic variants associated with Alzheimer’s disease progression

Abstract

BackgroundAlzheimer’s disease (AD) is an irreversible neurodegenerative brain disease with varying disease progression rates among individuals. This study aims to identify possible underlying genetic variants associated with AD progression using a whole‐genome sequencing approach.MethodWhole‐genome sequencing at 30x coverage was performed on 416 late‐onset AD patients (mean baseline age ± sd) = 76.47 ± 6.10) having at least two Mini‐Mental State Examination (MMSE) scores ranged from 0 to 30. Since the study subjects had varying time points of visit and MMSE records, we defined AD progression phenotypes in four ways, including differentially specified progression rates and time to pre‐defined events in genome‐wide association analyses. Genetic association analyses between single‐nucleotide variants (SNVs) and phenotypes were adjusted for baseline age, sex, year of education, baseline MMSE measures, and the first four principal components.ResultSix novel genome‐wide statistically significant associations (p<5E‐08) were observed in our study. Two associations were detected with the same SNVs on chromosomes 2 (SLC4A10/rs13036052) and 7 (chr7:58053009[Hg38] near ZNF716) with overall progression rates. One genetic variant on chromosome 6 (chr6:3127309[Hg38] near BPHL) was associated with annual progression rate. In addition, three associations were seen on chromosomes 1 (rs199560872), 14 (chr14:9600158[Hg38] near TUNAR), and 18 (rs34718969) with time‐to‐event phenotypes. All top variants were present either in introns or intergenic regions.ConclusionOur initial whole‐genome sequencing analyses have identified several independent associations with AD progression, which need to be confirmed in larger sequencing samples.