Basic Science and Pathogenesis

Polygenic risk scores (PRS) are measures of an individual's aggregate genetic risk of disease and are typically calculated using common variants. Rare variants (RV), though not captured by PRS, have been shown to play an important role in AD. We utilized an AD PRS to discover associations with novel RVs.

PRS for non-Hispanic white (NHW) samples (n = 11,409; AD=6630, controls=4779) from the Alzheimer's Disease Sequencing Project (ADSP) R4 dataset were calculated using published GWAS summary statistics of NHW subjects, excluding the APOE region. Participants were classified into high (n = 5,442) and low (n = 5,967) PRS groups based on the median PRS. After quality control, 11,485,531 low frequency variants (LV) (1% < MAF < 5%) and RVs with a MAC>5 were included in the analysis. The association of each variant was evaluated in low and high PRS groups separately using a regression model including covariates for age, sex, and principal components of ancestry implemented in GENESIS.

Genome-wide significant (GWS) associations of RVs and LVs with AD were identified in both the low and high PRS groups. Risk variants were disproportionately enriched in the low group while protective ones were disproportionately enriched in the high group. Among the GWS, RVs in the coding region of NYNRIN (rs570910195) (β=4.06, p = 4.37x10^-10) and 52 kb upstream of LOC105373398 (rs572619714, β=1.67, p = 2.20x10^-8) increased AD risk in the low PRS group. A rare deletion located 27 kb downstream of SDHC (chr1:161390036) was associated with decreased AD risk (β=-2.33, p = 7.45x10^-9) and a low frequency variant 20 kb downstream of SMNDC1 (rs150913764, MAF=0.02) was associated with increased AD risk (β=0.96, p = 3.13x10^-8) in the high PRS group. These variants were not associated with AD in the other respective PRS group.

Stratifying individuals into those with lower and higher risk for AD based on aggregated effects of common variants enhanced the detection of RV and LV associations. Our results suggest that a PRS calculated from common variants may not necessarily correspond to an individual's genetic relative risk for AD. These findings also provide unique opportunities to study RVs whose effects are opposite to the risk conferred by the genetic background.