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NOTCH3 p.Arg1231Cys is Markedly Enriched in South Asians and Associated with Stroke

Rodriguez-Flores, J. L.; Khalid, S.; Parikshak, N.; Rasheed, A.; Ye, B.; Kapoor, M.; Backman, J.; Sepehrband, F.; DiGioia, S. A.; Gelfman, S.; De, T.; Banerjee, N.; Sharma, D.; Martinez, H.; Castaneda, S.; Ambrosio, D. D.; Zhang, X. A.; Xun, P.; Tsai, E.; Tsai, I.-C.; Regeneron Genetics Center, ; Jahanzaib, M.; Khan, M. Z.; Mian, M. R.; Liaqat, M. B.; Mahmood, K.; Salam, T. U.; Hussain, M.; Iqbal, J.; Aslam, F.; Cantor, M. N.; Tzoneva, G.; Overton, J.; Marchini, J.; Reid, J.; Baras, A.; Verweij, N.; Lotta, L. A.; Coppola, G.; Karalis, K.; Economides, A.; Fazio, S.; Liedtke, W.; Danesh, J.; Ka

2023-11-09 genetic and genomic medicine
10.1101/2023.10.05.23296511 medRxiv
Show abstract

The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NM_000435.3(NOTCH3):c.3691C>T, encoding the missense amino acid substitution p.Arg1231Cys, enriched in South Asians (alternate allele frequency = 0.58% compared to 0.019% in Western Europeans), and associated with subcortical hemorrhagic stroke [odds ratio (OR) = 3.39, 95% confidence interval (CI) = [2.26, 5.10], p value = 3.87x10-9), and all strokes (OR [CI] = 2.30 [1.77, 3.01], p value = 7.79x10-10). NOTCH3 p.Arg231Cys was strongly associated with white matter hyperintensity on MRI in United Kingdom Biobank (UKB) participants (effect [95% CI] in SD units = 1.1 [0.61, 1.5], p value = 3.0x10-6). The variant is attributable for approximately 2.0% of hemorrhagic strokes and 1.1% of all strokes in South Asians. These findings highlight the value of diversity in genetic studies and have major implications for genomic medicine and therapeutic development in South Asian populations.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.