Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development.
Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development.
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全基因组测序揭示了与突触功能和神经元发育相关的基因座中新的阿尔茨海默病相关的罕见变异
DOI：
10.1002/alz.12319
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Tanzi RE
中科院分区：
文献类型：
--
作者：
Prokopenko D;Morgan SL;Mullin K;Hofmann O;Chapman B;Kirchner R;Alzheimer's Disease Neuroimaging Initiative (ADNI);Amberkar S;Wohlers I;Lange C;Hide W;Bertram L;Tanzi RE
全基因组关联研究已经导致许多与阿尔茨海默病（AD）相关的遗传位点。全基因组测序（WGS）现在允许进行全基因组分析，以确定导致AD风险的罕见变异。我们对来自605个多重AD家族的2247名受试者进行了基于家族的WGS关联研究中的罕见变异（次要等位基因频率[MAF] ≤1%）进行了基于单变量和空间聚类的检验，随后在1669名无关个体中进行了复制。我们确定了13个新的AD候选基因座，在发现和复制队列中产生一致的罕见变异信号（4个来自单变异，9个来自空间聚类），涉及这些基因：FNBP1L，SEL1L，LINC00298，PRKCH，C15ORF41，C2CD3，KIF2A，APC，LHX9，NALCN，CTNNA2，SYTL3和CLSTN2。这些新基因座的下游分析突出了突触功能，与常见的AD相关变体相反，后者涉及先天免疫和淀粉样蛋白加工。这些基因座以前与AD无关，强调了WGS识别AD相关罕见变异的能力，特别是外显子组以外的变异。
Genome‐wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole‐genome sequencing (WGS) now permits genome‐wide analyses to identify rare variants contributing to AD risk. We performed single‐variant and spatial clustering–based testing on rare variants (minor allele frequency [MAF] ≤1%) in a family‐based WGS‐based association study of 2247 subjects from 605 multiplex AD families, followed by replication in 1669 unrelated individuals. We identified 13 new AD candidate loci that yielded consistent rare‐variant signals in discovery and replication cohorts (4 from single‐variant, 9 from spatial‐clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3, and CLSTN2. Downstream analyses of these novel loci highlight synaptic function, in contrast to common AD‐associated variants, which implicate innate immunity and amyloid processing. These loci have not been associated previously with AD, emphasizing the ability of WGS to identify AD‐associated rare variants, particularly outside of the exome.
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影响因子：
2.1
作者：
Loehlein Fier H;Prokopenko D;Hecker J;Cho MH;Silverman EK;Weiss ST;Tanzi RE;Lange C
通讯作者：
Lange C
影响因子：
9.8
作者：
Allen, Mariet;Carrasquillo, Minerva M.;Funk, Cory;Heavner, Benjamin D.;Zou, Fanggeng;Younkin, Curtis S.;Burgess, Jeremy D.;Chai, High-Seng;Crook, Julia;Eddy, James A.;Li, Hongdong;Logsdon, Ben;Peters, Mette A.;Dang, Kristen K.;Wang, Xue;Serie, Daniel;Wang, Chen;Thuy Nguyen;Lincoln, Sarah;Malphrus, Kimberly;Bisceglio, Gina;Li, Ma;Golde, Todd E.;Mangravite, Lara M.;Asmann, Yan;Price, Nathan D.;Petersen, Ronald C.;Graff-Radford, Neill R.;Dickson, Dennis W.;Younkin, Steven G.;Ertekin-Taner, Nilufer
通讯作者：
Ertekin-Taner, Nilufer
影响因子：
14.9
作者：
Amlie-Wolf A;Tang M;Mlynarski EE;Kuksa PP;Valladares O;Katanic Z;Tsuang D;Brown CD;Schellenberg GD;Wang LS
通讯作者：
Wang LS
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
11
作者：
Benyamin, B.;St Pourcain, B.;Davis, O. S.;Davies, G.;Hansell, N. K.;Brion, M-J A.;Kirkpatrick, R. M.;Cents, R. A. M.;Franic, S.;Miller, M. B.;Haworth, C. M. A.;Meaburn, E.;Price, T. S.;Evans, D. M.;Timpson, N.;Kemp, J.;Ring, S.;McArdle, W.;Medland, S. E.;Yang, J.;Harris, S. E.;Liewald, D. C.;Scheet, P.;Xiao, X.;Hudziak, J. J.;de Geus, E. J. C.;Jaddoe, V. W. V.;Starr, J. M.;Verhulst, F. C.;Pennell, C.;Tiemeier, H.;Iacono, W. G.;Palmer, L. J.;Montgomery, G. W.;Martin, N. G.;Boomsma, D. I.;Posthuma, D.;McGue, M.;Wright, M. J.;Smith, G. Davey;Deary, I. J.;Plomin, R.;Visscher, P. M.
通讯作者：
Visscher, P. M.