Genome-wide association study of population-standardised cognitive performance phenotypes in a rural South African community

Abstract

Cognitive function is an indicator for global physical and mental health, and cognitive impairment has been associated with poorer life outcomes and earlier mortality. A standard cognition test, adapted to a rural-dwelling African community, and the Oxford Cognition Screen-Plus were used to capture cognitive performance as five continuous traits (total cognition score, verbal episodic memory, executive function, language, and visuospatial ability) for 2,246 adults in this population of South Africans. A novel common variant, rs73485231, reached genome-wide significance for association with episodic memory using data for ~14 million markers imputed from the H3Africa genotyping array data. Window-based replication of previously implicated variants and regions of interest support the discovery of African-specific associated variants despite the small population size and low allele frequency. This African genome-wide association study identifies suggestive associations with general cognition and domain-specific cognitive pathways and lays the groundwork for further genomic studies on cognition in Africa.

Fig. 1. Genome-wide and suggestive associations with verbal episodic memory.

a Manhattan plot. Genome-wide significance cut-off 5 × 10⁻⁸ is shown by red line and suggestive cut-off 5 × 10⁻⁶ is shown by blue line. b QQ-plot (λ = 0.99) for association summary statistics c Locus zoom plot for rs73485231. LD is based on a South African LD panel.

Fig. 2. Genome-wide and suggestive associations with language.

a Manhattan plot. Genome-wide significance cut-off 5 × 10⁻⁸ is shown by a red line, and suggestive cut-off 5 × 10⁻⁶ is shown by a blue line. b QQ-plot (λ = 1.00) for association summary statistics. c Locus zoom plot for rs140578927. LD values are based on a South African LD panel.

Fig. 3. Genome-wide and suggestive associations with executive function.

a Manhattan plot. No genome-wide or near genome-wide significant signals. Suggestive cut-off 5 × 10⁻⁶ shown by a blue line. b QQ-plot (λ = 1.00) for association summary statistics. c Locus zoom plot for rs3845674. LD values are based on a South African LD panel.

Fig. 4. Genome-wide and suggestive associations with visuospatial ability.

a Manhattan plot. No genome-wide or near genome-wide significant signals. Suggestive cut-off 5 × 10⁻⁶ shown by a blue line. b QQ-plot (λ = 1.00) for association summary statistics. c Locus zoom plot for rs191611493. LD values are based on a South African LD panel.

Fig. 5. Genome-wide and suggestive associations for total cognition score.

a Manhattan plot. No genome-wide or near genome-wide significant signals. Suggestive cut-off 5 × 10⁻⁶ shown by a blue line. b QQ-plot (λ = 1.00) for association summary statistics. c Locus zoom plot for rs138832740. LD values are based on a South African LD panel.

Fig. 6. Population structure and affinities of the HAALSI/AWI-Gen participants.

Principal component analysis (PCA) of individuals from the HAALSI/AWI-Gen showing PC1 and 2. a shows the absence of any major population structure after the removal of individuals outside of the 6 SD cut-off at five PCs. b shows a PCA comparison of our study participants prior to removal of outliers with African population datasets (African Caribbeans in Barbados (ACB) and Americans of African Ancestry in SW USA (ASW)), East (Luhya in Webuye, Kenya (LWK)), and West Africans (Yoruba in Ibadan, Nigeria (YRI), Gambian in Western Divisions in the Gambia (GWD), and Mende in Sierra Leone (MSL)) from the 1000 Genomes Project.