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

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.