Polygenic Risk Scores for Alzheimer’s Disease and Mild Cognitive Impairment in Hispanics/Latinos in the U.S: The Study of Latinos – Investigation of Neurocognitive Aging

Abstract

IntroductionPolygenic Risk Score (PRS) are powerful summaries of genetic risk alleles that can potentially be used to predict disease outcomes and guide treatment decisions. Hispanics/Latinos suffer from higher rates of Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI) compared to non-Hispanic Whites, yet the strongest known genetic risk factor for AD, APOE-ϵ4 allele, has weak association with AD in Hispanics/Latinos. We evaluated PRS constructed based on Genome-Wide Association Studies (GWAS) of AD in predicting MCI in Hispanics/Latinos when accounting for APOE alleles and variants.MethodsWe used summary statistics from four GWAS of AD to construct PRS that predict MCI in 4,189 diverse Hispanics/Latinos (mean age 63 years, 47% males) from the Study of Latinos-Investigation of Neurocognitive Aging. We assessed the PRS associations with MCI in the combined set of people and in groups defined by genetic ancestry and Hispanic/Latino background, and when including and excluding single nucleotide polymorphisms (SNPs) from the APOE gene region.ResultsA PRS constructed based on GWAS of AD in the FINNGEN Biobank was associated with MCI (OR = 1.34, 95% CI [1.15, 1.55]), and its association was mostly driven by 158 APOE region SNPs. A PRS constructed based on a multi-ethnic AD GWAS was associated with MCI (OR=1.22, 95% CI [1.08, 1.37]) without including any APOE region SNPs. APOE-ϵ4 and APOE-ϵ2 alleles were not associated with MCI.DiscussionA combination of APOE region SNPs is associated with MCI in Hispanics/Latinos despite APOE-ϵ4 and APOE-ϵ2 alleles not being associated with MCI.

A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood

“…Another motivation behind it is that high values of PRSsum may capture individuals with either high SBP, DBP, or hypertension PRS values, or combined, meaning that their hypertension may be captured by various underlying genetic components. While PRSsum is an unweighted sum of PRS, a weighted sum (or with adaptive weights) can be constructed as well(44,45). We here used PRSsum without adaptive weights out of concern for overfitting due to a dominant PRS and dominant subgroup, for example, where the PRS based on hypertension GWAS would potentially be upweighted due toa large set of individuals with European ancestry.…”

Genetic associations between sleep traits and cognitive ageing outcomes in the Hispanic Community Health Study/Study of Latinos

“…For comparison, this estimated association is larger than the estimate association of an Alzheimer's Disease PRS with MCI in SOL-INCA (OR = 1.34, unstratified). 59 Further, when computing AUCs, measuring predictive potential of the PRS for MCI risk, sleep duration PRS increased AUC compared to a baseline model without the PRS only in short and long sleepers: from 0.60 to 0.64 (model 1, short sleepers), and from 0.62 to 0.66 (model 1, long sleepers). This interaction may explain some of the conflicting results, where higher sleep PRS values were found to be associated with both improved 21 and reduced 22 cognitive function.…”