Genome-wide association analyses identify candidate loci for amyloid imaging and plasma biomarkers in adults with Down syndrome

Abstract

BACKGROUND: People with Down syndrome (DS) overproduce amyloid-beta (Aβ) due to triplication of the amyloid precursor protein (APP) gene on chromosome 21, and consequently accumulate brain amyloid load at younger ages. We conducted genome-wide association (GWA) analyses on amyloid imaging and plasma biomarkers to discern the genetic architecture of amyloid burden in DS. METHODS: GWA analyses were performed on amyloid positron emission tomography (PET) and plasma biomarkers (Aβ40, Aβ42, Aβ42/40 ratio) in participants from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) and on plasma Aβ biomarkers available in an independent DS cohort, followed by meta-analysis of plasma Aβ biomarker data. RESULTS: Meta-analysis on plasma biomarkers identified four novel loci: two for Aβ42 (PFKFB3/rs147647642, p = 2.83E-08; DLX3-PICART1/rs12952028, p = 9.31E-09) and two for Aβ40 (LINC01941-GYPC/rs78338676, p = 9.33E-09; PDE4D/rs146261781, p = 9.97E-08). Five genome-wide signals were observed for amyloid-PET in the ABC-DS cohort that need confirmation in an independent DS dataset. DISCUSSION: Despite the small sample, our findings highlight the unique genetic architecture of amyloid burden in DS. Highlights: Genetic markers for amyloid biomarkers in Down syndrome (DS) were identified. Meta-analyses identified four novel loci for plasma amyloid in two DS cohorts. Five loci associated with amyloid positron emission tomography levels were identified in the Alzheimer's Biomarker Consortium-Down Syndrome cohort. Multi-trait analysis revealed loci linking variants to amyloid biomarkers.