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. 2023 May 11;78(5):743-752.
doi: 10.1093/gerona/glad057.

Polygenic Risk Scores for Alzheimer's Disease and General Cognitive Function Are Associated With Measures of Cognition in Older South Asians

Wei Zhao  1   2 , Jennifer A Smith  1   2 , Yi Zhe Wang  1 , Manjusha Chintalapati  3   4 , Farah Ammous  1 , Miao Yu  1 , Priya Moorjani  3   4 , Andrea Ganna  5 , Alden Gross  6 , Sharmistha Dey  7 , Joyita Benerjee  8 , Prasun Chatterjee  8 , Aparajit B Dey  8 , Jinkook Lee  9 , Sharon L R Kardia  1
Affiliations

Polygenic Risk Scores for Alzheimer's Disease and General Cognitive Function Are Associated With Measures of Cognition in Older South Asians

Wei Zhao et al. J Gerontol A Biol Sci Med Sci. .

Abstract

Genome-wide association studies (GWAS) conducted in European ancestry (EA) have identified hundreds of single-nucleotide polymorphisms (SNPs) associated with general cognitive function and/or Alzheimer's disease (AD). The association between these SNPs and cognitive function has not been fully evaluated in populations with complex genetic substructure such as South Asians. This study investigated whether SNPs identified in EA GWAS, either individually or as polygenic risk scores (PRSs), were associated with general cognitive function and 5 broad cognitive domains in 932 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD). We found that SNPs identified from AD GWAS were more strongly associated with cognitive function in LASI-DAD than those from a GWAS of general cognitive function. PRSs for general cognitive function and AD explained up to 1.1% of the variability in LASI-DAD cognitive domain scores. Our study represents an important stepping stone toward better characterization of the genetic architecture of cognitive aging in the Indian/South Asian population and highlights the need for further research that may lead to the identification of new variants unique to this population.

Keywords: Dementia; Genetic risk score; India; Population structure; Single-nucleotide polymorphism.

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Conflict of interest statement

None declared.

Figures

Figure 1.
Figure 1.
Panel (A) shows the first 2 principal components (PCs) from the principal component analysis (PCA) of 932 LASI-DAD individuals from 7 Indian states or union territories with 3 reference populations including West Eurasians (Europeans [CEU], Georgians, Iranians), East Asians (Han Chinese), and Andamanese Islanders (Onge). Panel (B) shows the first 2 PCs from the PCA of 932 LASI-DAD individuals without reference populations. In both panels, PC1 is on the x-axis, and PC2 is on the y-axis for each participant. Color coding in panels (A) and (B) is according to the sampling location (state/union territory) of the participant. Panel (C) shows the Ancestral North Indian (ANI) ancestry in LASI-DAD populations. The f4ratio test was used to test the ANI ancestry proportion in LASI-DAD samples using ratio of f(YRI, Basque, test, Onge)/f(YRI, Basque, Georgian, Onge) where test = LASI-DAD samples belonging to each state/union territory in India. Standard errors were estimated using a block jackknife across genomes with 5-MB blocks across the genome. Panel (D) shows the genome-wide runs of homozygosity (ROH) in LASI-DAD. The cumulative sum of ROH per individual was estimated using PLINK for individuals from the 1000 Genomes Project (Africans [YRI], Europeans [CEU], and East Asians [CHB]) and 932 LASI-DAD samples from different states/union territories. Panels (E) and (F) show the distribution of the absolute difference in allele frequencies for 116 AD risk SNPs (E) and 130 general cognitive function SNPs (F) between quintile groups of ANI ancestry in LASI-DAD and European Ancestry (EA) GWAS samples. LASI-DAD participants were stratified into 5 groups based on quintiles of proportion of ANI (%ANI). The x-axis shows the mean %ANI of each stratified group in increasing order. Color coding is according to quintile. GWAS = genome-wide association study; LASI-DAD = Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India
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