Ancestry-enriched and shared polygenic signals associated with high IQ in a Japanese extreme-phenotype cohort

Abstract Genome-wide association studies (GWAS) of cognitive traits remain concentrated in European-ancestry cohorts, limiting discovery of ancestry-enriched alleles and transfer of polygenic findings across populations. We conducted a case-control GWAS of 91 Japanese individuals meeting a prespecified high-range cognitive criterion (score ≥ 140 on the Cognitive Ability Measurement Scale [CAMS]) and 41,528 unphenotyped Japanese commercial genetic-testing controls, testing 362,797 directly genotyped autosomal variants. rs146572333, a 5′-untranslated-region variant in PPP2R1A , reached genome-wide significance ( P = 1.17 × 10 − 8 ), was 5.1-fold more frequent in cases than in controls, and was 38.7-fold more frequent in gnomAD East Asian genomes than in a pooled European proxy. The 26 retained P < 1 × 10 − 5 variants resolved to 17 East Asian linkage disequilibrium (LD)-defined loci. An LD-aware comparison with a European intelligence GWAS showed excess directional concordance among the top 500–2,000 European-ranked variants and a positive weighted signal ( Z = 3.01; P = 1.32 × 10 − 3 ). European-derived polygenic scores were associated with case status at six prespecified thresholds; the secondary optimized score yielded an OR of 1.51 per SD (95% CI, 1.23–1.85; P = 9.60 × 10 − 5 ). These findings support ancestry-enriched and shared polygenic components of high IQ and warrant independent replication.