Association Analysis of Chromosome X to Identify Genetic Modifiers of Huntington's Disease.
Association Analysis of Chromosome X to Identify Genetic Modifiers of Huntington's Disease.
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DOI：
10.3233/jhd-210485
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Lee JM
中科院分区：
文献类型：
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作者：
Hong EP;Chao MJ;Massey T;McAllister B;Lobanov S;Jones L;Holmans P;Kwak S;Orth M;Ciosi M;Monckton DG;Long JD;Lucente D;Wheeler VC;MacDonald ME;Gusella JF;Lee JM
亨廷顿病（HD）是由亨廷顿蛋白（HTT）中CAG三核苷酸重复扩增（>35）引起的。运动症状发作时的痉挛与遗传性CAG重复序列的大小呈负相关，由于体细胞重复序列的不稳定性，CAG重复序列在大脑区域进一步扩展。我们最近的遗传学研究集中在常染色体SNPs显示，发病年龄也受到许多基因座遗传变异的影响，其中大多数编码参与DNA维持/修复过程和重复不稳定性的基因。我们进行了互补关联分析，以确定是否在X染色体的变异修改HD。我们对约9，000名欧洲血统的HD受试者的X染色体上的SNP进行了估算，并进行了X染色体范围的关联研究（XWAS），以测试与发病年龄的关联，并对遗传性CAG重复长度进行了校正。在对所有受试者（男性和女性）进行的混合效应模型XWAS分析中，假设女性的X失活是随机的，没有发现全基因组范围内显著的起始修饰信号。然而，在没有DNA维持基因的区域中，在Xq 12（最高SNP，rs 59098970; p值，1.4E-6），靠近膜突蛋白（MSN）处检测到暗示性的显著关联信号。在其他位置的仅雄性和雌性分析中观察到不涉及DNA修复基因的其他提示性信号。虽然不是全基因组显著的，可能是由于与当前研究的功效相比效应量小，但我们的数据留下了通过非DNA修复过程修饰HD的可能性。我们的XWAS结果可在https://www.hdinhd.org/托管的更新的GEM EURO 9 K网站上公开获得，用于浏览，途径分析和数据下载。
Huntington’s disease (HD) is caused by an expanded (>35) CAG trinucleotide repeat in huntingtin (HTT). Age-at-onset of motor symptoms is inversely correlated with the size of the inherited CAG repeat, which expands further in brain regions due to somatic repeat instability. Our recent genetic investigation focusing on autosomal SNPs revealed that age-at-onset is also influenced by genetic variation at many loci, the majority of which encode genes involved in DNA maintenance/repair processes and repeat instability. We performed a complementary association analysis to determine whether variants in the X chromosome modify HD. We imputed SNPs on chromosome X for ~9,000 HD subjects of European ancestry and performed an X chromosome-wide association study (XWAS) to test for association with age-at-onset corrected for inherited CAG repeat length. In a mixed effects model XWAS analysis of all subjects (males and females), assuming random X-inactivation in females, no genome-wide significant onset modification signal was found. However, suggestive significant association signals were detected at Xq12 (top SNP, rs59098970; p-value, 1.4E-6), near moesin (MSN), in a region devoid of DNA maintenance genes. Additional suggestive signals not involving DNA repair genes were observed in male- and female-only analyses at other locations. Although not genome-wide significant, potentially due to small effect size compared to the power of the current study, our data leave open the possibility of modification of HD by a non-DNA repair process. Our XWAS results are publicly available at the updated GEM EURO 9K website hosted at https://www.hdinhd.org/ for browsing, pathway analysis, and data download.