Region-Based Analysis with Functional Annotation Identifies Genes Associated with Cognitive Function in South Asians...

Area of Science:

• Genetics
• Neuroscience
• Population Health

Background:

• High prevalence of dementia in South Asians aged 65+ in India.
• Limited understanding of genetic risk factors for dementia in this demographic.
• Need to investigate genetic underpinnings of cognitive decline in diverse populations.

Purpose of the Study:

• To identify genetic risk factors for dementia in South Asians using whole-genome sequencing.
• To explore associations between gene variants and cognitive function measures.
• To investigate novel genetic variants potentially enriched in the South Asian population.

Main Methods:

• Whole-genome sequence data from 2680 participants in the Longitudinal Aging Study of India (LASI-DAD).
• Gene-based analysis of missense/loss-of-function (LoF) and brain-specific variants in 84 Alzheimer's disease-associated genes.
• Association testing with cognitive function measures (HMSE, general cognitive function, five domains) using STAAR.

Main Results:

• Three genes (APOE, PICALM, TSPOAP1) showed significant associations with cognitive function measures (FDR q < 0.1).
• APOE variants were linked to four cognitive measures; PICALM to HMSE score; TSPOAP1 to executive function.
• A rare PICALM missense variant (rs779406084) was enriched in LASI-DAD participants compared to European Ancestry.

Conclusions:

• Missense/LoF variants in genes previously linked to Alzheimer's disease in European Ancestry populations are associated with cognitive function in Indian South Asians.
• Whole-genome sequencing facilitates the discovery of potential novel causal variants specific to South Asian populations.
• Findings highlight the importance of population-specific genetic analyses for understanding dementia risk.