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Linkage disequilibrium and allelic heterogeneity explain variation in coronary artery disease risk at 9p21 across populations and reduced effect in Africans
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DOI：10.1016/j.ajhg.2026.06.007.png)
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Abstract
En 中文
Locus 9p21.3 was the first genome-wide significant locus for coronary artery disease (CAD) and replicates across multiple non-African populations, yet it is absent in African-ancestry cohorts. We analyzed multi-ancestry data from European, East Asian, South Asian, Middle Eastern, African, and admixed American groups. Ancestry was inferred using both global and local-ancestry inference (LAI) approaches. Within each ancestry, we performed CAD associations at 9p21.3 with common and rare variants, conditional and haplotype analyses, and pleiotropy assessments. CAD associations at 9p21.3 were robust in European, East Asian, Middle Eastern, and admixed American ancestry groups, nominal in South Asians, and absent in Africans despite similar allele frequencies for lead-associated SNPs. LAI-stratified analyses showed strong signals in African heterozygotes carrying 9p21.3 European chromosomes but not in homozygous Africans. The association is due to highly common variants; rare variants did not explain the locus signal. Linkage disequilibrium (LD) blocks were extended in non-Africans but fragmented into smaller blocks in Africans. Fine-mapping identified multiple independent signals, including an East Asian-specific haplotype absent in Europeans and Africans. Hamming-distance analyses revealed that risk alleles are dispersed across multiple haplotypes in homozygous-African groups. Phenome-wide association study (PheWAS) mirrored these ancestry-specific patterns across metabolic traits. The non-replication of 9p21.3 in African ancestry is not due to absent risk alleles, reduced power, or poorer imputation of risk alleles due to weaker LD; rather, it reflects greater haplotype diversity that disperses risk alleles across configurations, attenuating case-control contrast. These findings illustrate how ancestry-specific LD and multi-causal haplotype architecture modulate association detectability.
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