RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population Sirui Zhou, Amirthagowri Ambalavanan, Daniel Rochefort, Pingxing Xie,

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RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population Sirui Zhou, Amirthagowri Ambalavanan, Daniel Rochefort, Pingxing Xie, Cynthia V. Bourassa, Pascale Hince, Alexandre Dionne- Laporte, Dan Spiegelman, Ziv Gan-Or, Cathy Mirarchi, Vessela Zaharieva, Nicolas Dupré, Hatasu Kobayashi, Toshiaki Hitomi, Kouji Harada, Akio Koizumi, Lan Xiong, Patrick A. Dion, Guy A. Rouleau The American Journal of Human Genetics Volume 99, Issue 5, Pages 1072-1085 (November 2016) DOI: 10.1016/j.ajhg.2016.09.001 Copyright © 2016 Terms and Conditions

Figure 1 Six Pedigrees with 26 IA-Affected Individuals from the Initial Cohort The American Journal of Human Genetics 2016 99, 1072-1085DOI: (10.1016/j.ajhg.2016.09.001) Copyright © 2016 Terms and Conditions

Figure 2 Matrix of Pairwise FST of RNF213 across Worldwide Populations FST was calculated for RNF213 common variants from the Omni chip (A) and functional variants from exome sequencing and (B) between each two populations. FC_CTRL and FC_IA are the FC control cohort and the IA cohort, respectively; other populations are indicated by the three-letter codes used by 1KGP. The allele distributions of RNF213 common SNPs vary among populations, suggesting the existence of genetic drift. Among others, there is a big difference in the allelic distributions of RNF213 functional variants between Asians and FC populations. The American Journal of Human Genetics 2016 99, 1072-1085DOI: (10.1016/j.ajhg.2016.09.001) Copyright © 2016 Terms and Conditions

Figure 3 ATPase Activity of the Wild-Types, Variants, and LOF Controls of the Two AAA+ Domains of RNF213 Box-and-whisker plot showing ATPase activity measured as nmol of free-phosphate release per mg protein per minute. A1WT and A2WT are the wild-types of the first and second AAA+ modules, respectively; A1M and A2M are the p.Arg2438Cys and p.Ala2826Thr variants, respectively. A1WA, A1WB, A2WA, and A2WB are four LOF controls (p. Lys2426Ala, p. Glu2488Ala, p. Lys2775Ala, and p. Glu2845Ala, respectively) located in the walker A and B domains of the first and second AAA+ modules. The results were generated by eight ATPase assays from two independent cell cultures; each sample is measured in duplicate. Boxes show the interquartile range, and whiskers show maximum and minimum measurements. The American Journal of Human Genetics 2016 99, 1072-1085DOI: (10.1016/j.ajhg.2016.09.001) Copyright © 2016 Terms and Conditions

Figure 4 Meta-analysis of Two RNF213 Studies in Different Populations Forest plot of Moteki et al.64 and the current study. Result show significantly more RNF213 mutations in FC IA-affected individuals (Cochran-Mantel-Haenszel test: p < 0.0001). Error bars represent confidence intervals, shown on the right. The American Journal of Human Genetics 2016 99, 1072-1085DOI: (10.1016/j.ajhg.2016.09.001) Copyright © 2016 Terms and Conditions

Figure 5 RNF213 Rare Functional Variants Exclusively Found in IA- and MMD-Affected Individuals Adapted from Cecchi et al.56 and Koizumi et al.66 14 variants found in the current study are marked in red, variants reported in Moteki et al.64 are marked in blue, MMD variants reported in Cecchi et al. are marked in black, and MMD variants found in other studies are marked in gray. The results show that FC IA-affected individuals harbor more deleterious mutations in the AAA+ domains than other populations do. The American Journal of Human Genetics 2016 99, 1072-1085DOI: (10.1016/j.ajhg.2016.09.001) Copyright © 2016 Terms and Conditions