We confirmed the association at 4q25 (PITX2) (OR 1.43; 95% CI, 1.13-1.81, p = 0.029) and 16q22 (ZFHX3) (OR 1.62; 95% CI, 1.26-2.07, p = 0.001) as risk loci for CE.
However, previously reported associations for the PITX2 and ZFHX3 gene loci with cardioembolic stroke subtype were replicated (P = 7 × 10<sup>-15</sup> and 6 × 10<sup>-3</sup> ).
Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10<sup>-19</sup>; joint OR 1·37, 1·30-1·45, p=2·79 × 10<sup>-32</sup>) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10<sup>-7</sup>; joint OR 1·17, 1·11-1·23, p=2·29 × 10<sup>-10</sup>) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10<sup>-8</sup>; joint OR 1·24, 1·15-1·33, p=4·52 × 10<sup>-9</sup>) for large artery atherosclerosis stroke.
In contrast, 3 loci from related cardiovascular GWAS studies were significant: PHACTR1 in large-vessel disease (P=2.63e(-6)), PITX2 in cardioembolic stroke (P=4.78e(-8)), and ZFHX3 in cardioembolic stroke (P=5.50e(-7)).
Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).
We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)).
We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE).