GRN Mutations Are Associated with Lewy Body Dementia.
GRN Mutations Are Associated with Lewy Body Dementia.
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DOI：
10.1002/mds.29144
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发表时间：
2022-09
影响因子：
8.6
通讯作者：
Scholz, Sonja W.
中科院分区：
文献类型：
--
作者：
Reho, Paolo;Koga, Shunsuke;Shah, Zalak;Chia, Ruth;Rademakers, Rosa;Dalgard, Clifton L.;Boeve, Bradley F.;Beach, Thomas G.;Dickson, Dennis W.;Ross, Owen A.;Scholz, Sonja W.
关键词：
GRN中的功能丧失突变是家族性额颞叶痴呆的一个原因，该基因中的常见变异与阿尔茨海默病和帕金森病的风险增加有关。虽然TDP-43阳性包涵体是GRN相关神经变性的特征，但在许多GRN突变携带者中也观察到路易体共同病理学。我们分析了2，591例欧洲血统路易体痴呆（LBD）病例和4，032例神经健康对照的全基因组序列数据，以确定GRN中的致病突变。我们在7名研究参与者（病例：n=6;对照：n=1）中确定了6个杂合外显子GRN突变。预测每种变体是致病性的或可能致病的。我们发现与对照组相比，LBD患者中GRN功能丧失突变显著富集（SKAT-O p值= 0.0162）。免疫组化在三个明确的LBD的情况下表现出路易体病理和TDP-43阳性神经元包涵体。我们的研究结果表明，有害的GRN突变是家族性LBD的罕见原因。
Loss-of-function mutations in GRN are a cause of familial frontotemporal dementia, and common variants within the gene have been associated with an increased risk of developing Alzheimer’s disease and Parkinson’s disease. While TDP-43-positive inclusions are characteristic of GRN-related neurodegeneration, Lewy body co-pathology has also been observed in many GRN mutation carriers. We analyzed whole-genome sequence data generated for 2,591 European-ancestry Lewy body dementia (LBD) cases and 4,032 neurologically healthy controls to identify disease-causing mutations in GRN. We identified six heterozygous exonic GRN mutations in seven study participants (cases: n=6; controls: n=1). Each variant was predicted to be pathogenic or likely pathogenic. We found significant enrichment of GRN loss-of-function mutations in LBD patients compared to controls (SKAT-O p-value = 0.0162). Immunohistochemistry in three definite LBD cases demonstrated Lewy body pathology and TDP-43-positive neuronal inclusions. Our findings suggest that deleterious GRN mutations are a rare cause of familial LBD.
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影响因子：
7
作者：
Keogh MJ;Wei W;Wilson I;Coxhead J;Ryan S;Rollinson S;Griffin H;Kurzawa-Akanbi M;Santibanez-Koref M;Talbot K;Turner MR;McKenzie CA;Troakes C;Attems J;Smith C;Al Sarraj S;Morris CM;Ansorge O;Pickering-Brown S;Ironside JW;Chinnery PF
通讯作者：
Chinnery PF
影响因子：
82.9
作者：
He, ZH;Ong, CHP;Bateman, A
通讯作者：
Bateman, A
影响因子：
30.8
作者：
Chia R;Sabir MS;Bandres-Ciga S;Saez-Atienzar S;Reynolds RH;Gustavsson E;Walton RL;Ahmed S;Viollet C;Ding J;Makarious MB;Diez-Fairen M;Portley MK;Shah Z;Abramzon Y;Hernandez DG;Blauwendraat C;Stone DJ;Eicher J;Parkkinen L;Ansorge O;Clark L;Honig LS;Marder K;Lemstra A;St George-Hyslop P;Londos E;Morgan K;Lashley T;Warner TT;Jaunmuktane Z;Galasko D;Santana I;Tienari PJ;Myllykangas L;Oinas M;Cairns NJ;Morris JC;Halliday GM;Van Deerlin VM;Trojanowski JQ;Grassano M;Calvo A;Mora G;Canosa A;Floris G;Bohannan RC;Brett F;Gan-Or Z;Geiger JT;Moore A;May P;Krüger R;Goldstein DS;Lopez G;Tayebi N;Sidransky E;American Genome Center;Norcliffe-Kaufmann L;Palma JA;Kaufmann H;Shakkottai VG;Perkins M;Newell KL;Gasser T;Schulte C;Landi F;Salvi E;Cusi D;Masliah E;Kim RC;Caraway CA;Monuki ES;Brunetti M;Dawson TM;Rosenthal LS;Albert MS;Pletnikova O;Troncoso JC;Flanagan ME;Mao Q;Bigio EH;Rodríguez-Rodríguez E;Infante J;Lage C;González-Aramburu I;Sanchez-Juan P;Ghetti B;Keith J;Black SE;Masellis M;Rogaeva E;Duyckaerts C;Brice A;Lesage S;Xiromerisiou G;Barrett MJ;Tilley BS;Gentleman S;Logroscino G;Serrano GE;Beach TG;McKeith IG;Thomas AJ;Attems J;Morris CM;Palmer L;Love S;Troakes C;Al-Sarraj S;Hodges AK;Aarsland D;Klein G;Kaiser SM;Woltjer R;Pastor P;Bekris LM;Leverenz JB;Besser LM;Kuzma A;Renton AE;Goate A;Bennett DA;Scherzer CR;Morris HR;Ferrari R;Albani D;Pickering-Brown S;Faber K;Kukull WA;Morenas-Rodriguez E;Lleó A;Fortea J;Alcolea D;Clarimon J;Nalls MA;Ferrucci L;Resnick SM;Tanaka T;Foroud TM;Graff-Radford NR;Wszolek ZK;Ferman T;Boeve BF;Hardy JA;Topol EJ;Torkamani A;Singleton AB;Ryten M;Dickson DW;Chiò A;Ross OA;Gibbs JR;Dalgard CL;Traynor BJ;Scholz SW
通讯作者：
Scholz SW
DOI：
10.1093/bioinformatics/btw079
发表时间：
2016-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Zhan X;Hu Y;Li B;Abecasis GR;Liu DJ
通讯作者：
Liu DJ
影响因子：
64.5
作者：
Lui H;Zhang J;Makinson SR;Cahill MK;Kelley KW;Huang HY;Shang Y;Oldham MC;Martens LH;Gao F;Coppola G;Sloan SA;Hsieh CL;Kim CC;Bigio EH;Weintraub S;Mesulam MM;Rademakers R;Mackenzie IR;Seeley WW;Karydas A;Miller BL;Borroni B;Ghidoni R;Farese RV Jr;Paz JT;Barres BA;Huang EJ
通讯作者：
Huang EJ