全基因組關聯分析揭示顱內動脈瘤的風險位點
作者：
小柯機器人發布時間：2020/11/17 16:10:02
荷蘭烏得勒支大學Ynte M. Ruigrok、Mark K. Bakker究組近日取得一項新成果。經過不懈努力，他們通過對顱內動脈瘤的全基因組關聯分析確定了17個風險位點和與臨床危害相關遺傳因素。這一研究成果發表在2020年11月16日的《自然-遺傳學》上。
為了發現新的風險基因座和顱內動脈瘤的遺傳結構，研究人員在10754例歐洲譜系和306882例東亞譜系的對照研究中進行了跨譜系的全基因組關聯分析。研究發現了17個風險基因座，其中11個是之前未知的。研究人員揭示了一種多基因架構，其解釋了超過一半疾病的遺傳特點。研究發現破裂和未破裂顱內動脈瘤之間存在高度的遺傳相關性。通過使用基因作圖和遺傳特徵富集研究人員還發現了內皮細胞的潛在功能。靶向藥物富集顯示顱內動脈瘤與抗癲癇藥和性激素藥物之間的多效性，這為了解顱內動脈瘤的病理生理學提供了見解。
最後，吸菸和高血壓是兩個主要的臨床風險因素，它們在顱內動脈瘤發病中起重要作用，並造成了顱內動脈瘤與其他腦血管疾病之間大部分的遺傳相關性。
據介紹，顱內動脈瘤破裂會導致蛛網膜下腔出血，這是造成嚴重中風的原因。
附：英文原文
Title: Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors
Author: Mark K. Bakker, Rick A. A. van der Spek, Wouter van Rheenen, Sandrine Morel, Romain Bourcier, Isabel C. Hostettler, Varinder S. Alg, Kristel R. van Eijk, Masaru Koido, Masato Akiyama, Chikashi Terao, Koichi Matsuda, Robin G. Walters, Kuang Lin, Liming Li, Iona Y. Millwood, Zhengming Chen, Guy A. Rouleau, Sirui Zhou, Kristiina Rannikme, Cathie L. M. Sudlow, Henry Houlden, Leonard H. van den Berg, Christian Dina, Olivier Naggara, Jean-Christophe Gentric, Eimad Shotar, Franois Eugne, Hubert Desal, Bendik S. Winsvold, Sigrid Brte, Marianne Bakke Johnsen, Ben M. Brumpton, Marie Sfteland Sandvei, Cristen J. Willer, Kristian Hveem, John-Anker Zwart, W. M. Monique Verschuren, Christoph M. Friedrich, Sven Hirsch, Sabine Schilling, Jrme Dauvillier, Olivier Martin, Gregory T. Jones, Matthew J. Bown, Nerissa U. Ko, Helen Kim, Jonathan R. I. Coleman, Gerome Breen, Jonathan G. Zaroff, Catharina J. M. Klijn, Rainer Malik, Martin Dichgans, Muralidharan Sargurupremraj, Turgut Tatlisumak, Philippe Amouyel, Stphanie Debette, Gabriel J. E. Rinkel, Bradford B. Worrall
Issue&Volume: 2020-11-16
Abstract: Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits. Cross-ancestry genome-wide association analyses in individuals of European and East Asian ancestry identify 11 new risk loci for intracranial aneurysms and highlight a polygenic architecture explaining a substantial fraction of disease heritability.
DOI: 10.1038/s41588-020-00725-7
Source: https://www.nature.com/articles/s41588-020-00725-7