Repeats expansions in ATXN2, NOP56, NIPA1 and ATXN1 are not associated with ALS in Africans.
Repeats expansions in ATXN2, NOP56, NIPA1 and ATXN1 are not associated with ALS in Africans.
复制标题
ATXN2、NOP 56、NIPA 1和ATXN1的重复扩增与非洲人的ALS无关。
DOI：
10.1016/j.ibneur.2021.02.002
复制
发表时间：
2021-06
影响因子：
1.5
通讯作者：
Heckmann JM
中科院分区：
文献类型：
--
作者：
Nel M;Mavundla T;Gultig K;Botha G;Mulder N;Benatar M;Wuu J;Cooley A;Myers J;Rampersaud E;Wu G;Heckmann JM
肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，其主要特征是运动神经元的进行性丧失。尽管ALS在世界各地都有发生，而且可确定的疾病遗传原因的频率和范围因人群而异，但很少有研究包括非洲受试者。除了欧洲人ALS最常见的遗传原因C9orf72中的六核苷酸重复扩增（RE）外，ATXN2、NIPA1和ATXN1中的REs与欧洲人的ALS有不同的相关性。其中一些基因（如ATXN2）的中间范围扩增已被报道为ALS的潜在危险因素或表型修饰因子。NOP56的致病性扩增可引起脊髓小脑性共济失调-36，表现为明显的运动神经元变性。在这里，我们使用全基因组测序数据比较了非洲ALS患者和人口控制人群中这些基因的REs。使用ExpansionHunter软件对105名南非（SA） ALS患者的ATXN2、NIPA1、ATXN1和NOP56中已知位点的短串联重复序列进行靶向基因分型。非洲人口对照来自南非国家统计局内部人口控制数据库（n = 25）、南非国家统计局人类基因组计划（n = 24）、西蒙斯基因组多样性计划（n = 39）和Illumina Polaris多样性队列（IPDC）数据集（n = 50）。我们发现在非洲人中，ATXN2（27-33个重复）和ATXN1（33-35个重复）的中间RE等位基因和NIPA1长等位基因（≥8个重复）很少见，且与ALS无关（p >.17）。NOP56在ALS和对照中均未发现扩增的等位基因。我们还比较了非洲和n = 50欧洲对照（来自IPDC）之间等位基因分布的差异。在非洲和欧洲对照中，ATXN1的REs分布有统计学上的显著差异（χ -检验p < 0.001）， NIPA1在欧洲人比非洲人中按比例显示更多的长等位基因（RE bb0.8） （Fisher’s p = 0.016）。在非洲和欧洲对照中，ATXN2和NOP56的RE等位基因分布相似。综上所述，ATXN2、NIPA1和ATXN1基因的重复扩增在欧洲人身上显示出与ALS相关，但在南非ALS患者身上却没有重复扩增。非洲人与ATXN2、ATXN1、NIPA1扩增突变和ALS无关联。非洲人的ATXN1和NIPA1重复扩增等位基因分布与欧洲人不同。具有不同遗传血统的ALS病例应包括在ALS基因发现研究中。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized primarily by progressive loss of motor neurons. Although ALS occurs worldwide and the frequency and spectrum of identifiable genetic causes of disease varies across populations, very few studies have included African subjects. In addition to a hexanucleotide repeat expansion (RE) in C9orf72, the most common genetic cause of ALS in Europeans, REs in ATXN2, NIPA1 and ATXN1 have shown variable associations with ALS in Europeans. Intermediate range expansions in some of these genes (e.g. ATXN2) have been reported as potential risk factors, or phenotypic modifiers, of ALS. Pathogenic expansions in NOP56 cause spinocerebellar ataxia-36, which can present with prominent motor neuron degeneration. Here we compare REs in these genes in a cohort of Africans with ALS and population controls using whole genome sequencing data. Targeting genotyping of short tandem repeats at known loci within ATXN2, NIPA1, ATXN1 and NOP56 was performed using ExpansionHunter software in 105 Southern African (SA) patients with ALS. African population controls were from an in-house SA population control database (n = 25), the SA Human Genome Program (n = 24), the Simons Genome Diversity Project (n = 39) and the Illumina Polaris Diversity Cohort (IPDC) dataset (n = 50). We found intermediate RE alleles in ATXN2 (27–33 repeats) and ATXN1 (33–35 repeats), and NIPA1 long alleles (≥8 repeats) were rare in Africans, and not associated with ALS (p > 0.17). NOP56 showed no expanded alleles in either ALS or controls. We also compared the differences in allele distributions between the African and n = 50 European controls (from the IPDC). There was a statistical significant difference in the distribution of the REs in the ATXN1 between African and European controls (Chi-test p < 0.001), and NIPA1 showed proportionately more longer alleles (RE > 8) in Europeans vs. Africans (Fisher’s p = 0.016). The distribution of RE alleles in ATXN2 and NOP56 were similar amongst African and European controls. In conclusion, repeat expansions in ATXN2, NIPA1 and ATXN1, which showed associations with ALS in Europeans, were not replicated in Southern Africans with ALS. No associations with ATXN2, ATXN1, NIPA1 expansion mutations, and ALS in Africans. Repeat expansion allele distribution in ATXN1 and NIPA1 were different in Africans compared with European populations. ALS cases with diverse genetic ancestry should included in ALS gene discovery studies.
登录
查看更多内容
影响因子：
4.2
作者：
Tazelaar GHP;Dekker AM;van Vugt JJFA;van der Spek RA;Westeneng HJ;Kool LJBG;Kenna KP;van Rheenen W;Pulit SL;McLaughlin RL;Sproviero W;Iacoangeli A;Hübers A;Brenner D;Morrison KE;Shaw PJ;Shaw CE;Panadés MP;Mora Pardina JS;Glass JD;Hardiman O;Al-Chalabi A;van Damme P;Robberecht W;Landers JE;Ludolph AC;Weishaupt JH;van den Berg LH;Veldink JH;van Es MA;Project MinE ALS Sequencing Consortium
通讯作者：
Project MinE ALS Sequencing Consortium
影响因子：
64.8
作者：
Mallick, Swapan;Li, Heng;Lipson, Mark;Mathieson, Iain;Gymrek, Melissa;Racimo, Fernando;Zhao, Mengyao;Chennagiri, Niru;Nordenfelt, Susanne;Tandon, Arti;Skoglund, Pontus;Lazaridis, Iosif;Sankararaman, Sriram;Fu, Qiaomei;Rohland, Nadin;Renaud, Gabriel;Erlich, Yaniv;Willems, Thomas;Gallo, Carla;Spence, Jeffrey P.;Song, Yun S.;Poletti, Giovanni;Balloux, Francois;van Driem, George;de Knijff, Peter;Romero, Irene Gallego;Jha, Aashish R.;Behar, Doron M.;Bravi, Claudio M.;Capelli, Cristian;Hervig, Tor;Moreno-Estrada, Andres;Posukh, Olga L.;Balanovska, Elena;Balanovsky, Oleg;Karachanak-Yankova, Sena;Sahakyan, Hovhannes;Toncheva, Draga;Yepiskoposyan, Levon;Tyler-Smith, Chris;Xue, Yali;Abdullah, M. Syafiq;Ruiz-Linares, Andres;Beall, Cynthia M.;Di Rienzo, Anna;Jeong, Choongwon;Starikovskaya, Elena B.;Metspalu, Ene;Parik, Juri;Villems, Richard;Henn, Brenna M.;Hodoglugil, Ugur;Mahley, Robert;Sajantila, Antti;Stamatoyannopoulos, George;Wee, Joseph T. S.;Khusainova, Rita;Khusnutdinova, Elza;Litvinov, Sergey;Ayodo, George;Comas, David;Hammer, Michael F.;Kivisild, Toomas;Klitz, William;Winkler, Cheryl A.;Labuda, Damian;Bamshad, Michael;Jorde, Lynn B.;Tishkoff, Sarah A.;Watkins, W. Scott;Metspalu, Mait;Dryomov, Stanislav;Sukernik, Rem;Singh, Lalji;Thangaraj, Kumarasamy;Paeaebo, Svante;Kelso, Janet;Patterson, Nick;Reich, David
通讯作者：
Reich, David
影响因子：
4.2
作者：
van Blitterswijk M;Mullen B;Heckman MG;Baker MC;DeJesus-Hernandez M;Brown PH;Murray ME;Hsiung GY;Stewart H;Karydas AM;Finger E;Kertesz A;Bigio EH;Weintraub S;Mesulam M;Hatanpaa KJ;White CL 3rd;Neumann M;Strong MJ;Beach TG;Wszolek ZK;Lippa C;Caselli R;Petrucelli L;Josephs KA;Parisi JE;Knopman DS;Petersen RC;Mackenzie IR;Seeley WW;Grinberg LT;Miller BL;Boylan KB;Graff-Radford NR;Boeve BF;Dickson DW;Rademakers R
通讯作者：
Rademakers R
影响因子：
64.8
作者：
Taylor JP;Brown RH Jr;Cleveland DW
通讯作者：
Cleveland DW
影响因子：
4.2
作者：
Lattante, Serena;Pomponi, Maria Grazia;Sabatelli, Mario
通讯作者：
Sabatelli, Mario