Zhou Sirui, Ambalavanan Amirthagowri, Rochefort Daniel, Xie Pingxing, Bourassa Cynthia V, Hince Pascale, Dionne-Laporte Alexandre, Spiegelman Dan, Gan-Or Ziv, Mirarchi Cathy, Zaharieva Vessela, Dupré Nicolas, Kobayashi Hatasu, Hitomi Toshiaki, Harada Kouji, Koizumi Akio, Xiong Lan, Dion Patrick A, Rouleau Guy A
Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.
Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada.
Am J Hum Genet. 2016 Nov 3;99(5):1072-1085. doi: 10.1016/j.ajhg.2016.09.001. Epub 2016 Oct 13.
Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used exome sequencing to prioritize risk variants in a discovery cohort of six FC families affected by IA, and the analysis revealed an increased variation burden for ring finger protein 213 (RNF213). We resequenced RNF213 in a larger FC validation cohort, and association tests on further identified variants supported our findings (SKAT-O, p = 0.006). RNF213 belongs to the AAA+ protein family, and two variants (p.Arg2438Cys and p.Ala2826Thr) unique to affected FC individuals were found to have increased ATPase activity, which could lead to increased risk of IA by elevating angiogenic activities. Common SNPs in RNF213 were also extracted from the NeuroX SNP-chip genotype data, comprising 257 FC IA-affected and 1,988 control individuals. We discovered that the non-ancestral allele of rs6565666 was significantly associated with the affected individuals (p = 0.03), and it appeared as though the frequency of the risk allele had changed through genetic drift. Although RNF213 is a risk factor for moyamoya disease in East Asians, we demonstrated that it might also be a risk factor for IA in the FC population. It therefore appears that the function of RNF213 can be differently altered to predispose distinct populations to dissimilar neurovascular conditions, highlighting the importance of a population's background in genetic studies of heterogeneous disease.
颅内动脉瘤（IAs）是动脉壁局灶性薄弱的结果，具有复杂的基因构成。迄今为止，全基因组关联研究和测序研究在识别IA风险因素方面取得的成功有限。不同人群，如法裔加拿大人（FC）群体，IA患病率有所增加。在我们的研究中，我们使用外显子组测序对6个受IA影响的FC家族的发现队列中的风险变异进行优先级排序，分析显示环指蛋白213（RNF213）的变异负担增加。我们在更大的FC验证队列中对RNF213进行重测序，对进一步鉴定的变异进行的关联测试支持了我们的发现（SKAT-O，p = 0.006）。RNF213属于AAA+蛋白家族，发现受影响的FC个体特有的两个变异（p.Arg2438Cys和p.Ala2826Thr）具有增加的ATP酶活性，这可能通过提高血管生成活性导致IA风险增加。RNF213中的常见单核苷酸多态性（SNP）也从NeuroX SNP芯片基因型数据中提取，该数据包括257名受FC IA影响的个体和1988名对照个体。我们发现rs6565666的非祖先等位基因与受影响个体显著相关（p = 0.03），并且风险等位基因的频率似乎通过基因漂变发生了变化。尽管RNF213是东亚人烟雾病的一个风险因素，但我们证明它也可能是FC人群中IA的一个风险因素。因此，似乎RNF213的功能可以以不同方式改变，使不同人群易患不同的神经血管疾病，突出了人群背景在异质性疾病基因研究中的重要性。
