Investigating the relationships between polygenic risk scores and dementia and cognition across and within populations of different ancestry

Background: The Cohort Studies of Memory in an International Consortium (COSMIC) studies the factors linked to cognitive decline and dementia in a diverse range of populations from around the world. COSMIC is headed by the Centre for Healthy Brain Ageing (CHeBA), University of New South Wales (UNSW), Australia (see https://cheba.unsw.edu.au/consortia/cosmic).

At present, there is limited knowledge available regarding the genetic factors associated with ageing-related complex phenotypes and diseases in non-European based cohorts, particularly in low- and middle-income countries and whether specific ancestry-based genetic association results are generalizable to populations of other ancestries.

In this study, we aim to study the genetic factors associated with dementia and related phenotypes to appraise if they can be used to predict age-related cognitive performance and decline and dementia in a wide range of diverse cohorts. We will use data collected by COSMIC Consortium studies but also from external studies wherever possible. Hence, the application to assess NIAGADS data to include as many ancestry-diverse studies as we can in this work. The data from these cohorts/studies will be analyzed by meta-analysis.

Objectives: To assess if dementia/cognitive and other polygenic risk scores (PRS) generated from different ancestries (European, non-European and trans ethnic) predicts age-related cognitive performance and decline and dementia across populations of different ancestries and including studies from low and middle-income countries.

Study Design and Analysis Plan: Participants will be adults aged 45 and above without dementia at baseline. Different PRS (constructed using different methods, eg.SBayesRC and using different GWAS p-value thresholds using PLINK) will be undertaken using available GWAS summary statistics. Cognitive data both cross-sectionally and longitudinally will be used where available, with priority given to tests of memory. PRS-cognitive analyses will be performed using appropriate mixed models. Covariates will include age, sex, years of education and any study-specific covariates (e.g. PCs for population stratification).

Most human genetic association studies have been undertaken in populations of European ancestry, despite >75% of the world’s population being of Asian or African ancestry. To date, most genetic variants for dementia have been identified using populations mainly of European ancestry and from high income countries, despite more than ~60% of dementia cases living in low and middle-income countries. In addition, many of the non-white genetic studies have had small sample sizes and lack replication. We need to increase our understanding of the genetic risk for dementia and its related traits in under-represented populations, such as the multi-ethnic cohorts of the Cohort Studies of Memory in an International Consortium (COSMIC). The current project aims to examine if polygenic risk scores for dementia, cognitive and other related phenotypes generated from populations of different ancestries predict performance and decline on cognitive tests and incident dementia in older adults from multi-ethnic populations using the COSMIC Consortium and external studies.