Targeted Sequencing of Alzheimer Disease Genes in African Americans Implicates Novel Risk Variants.
Targeted Sequencing of Alzheimer Disease Genes in African Americans Implicates Novel Risk Variants.
复制标题
DOI：
10.3389/fnins.2018.00592
复制
发表时间：
2018
影响因子：
4.3
通讯作者：
Farrer LA
中科院分区：
文献类型：
--
作者：
Logue MW;Lancour D;Farrell J;Simkina I;Fallin MD;Lunetta KL;Farrer LA
非裔美国人（AAs）迟发性阿尔茨海默病（AD）的遗传结构与欧洲血统的人不同。除了APOE，AA样本中AD的全基因组关联研究（GWAS）表明ABCA 7、COBL和SLC 10A 2是AA-AD风险基因。以前，我们通过全外显子组测序确定了少量AA AD病例，随后在AD病例的大AA样本中进行了基因分型，并控制了AD风险与AKAP 9中一对罕见错义变体的关联。在这项研究中，我们对489例AD病例和472例对照的AA队列中约100个先前与AD或AD相关性状相关的基因进行了靶向深度测序（包括内含子和外显子），以发现新的AD风险变体。我们观察到与ABCA 7（rs 567222111）中的11个碱基对移码功能丧失（LOF）变异的相关性，当与来自484例病例和484例对照的复制AA队列的数据相结合时，证据得到了支持（OR = 2.42，p = 0.022）。我们还发现AD与非常接近AKAP 9转录起始位点的罕见9 bp缺失（rs371245265，OR = 10.75，p = 0.0053）相关。最显著的发现来自F5中一种罕见的保护性变异（OR = 0.053，p = 6.40 × 10-5），该基因先前与海马萎缩的脑MRI测量相关，以及KIAA 0196中的两种常见变异（OR = 1.51，p<8.6 × 10-5）。对聚集的罕见变异体进行的基于基因的测试产生了与KANSL 1、CNN 2和TRIM 35的几个名义上显著的关联。虽然没有关联通过多重检验校正，但我们的研究增加了一系列文献，证明了检查来自多个种族人群的序列数据以发现新的和有影响力的风险变体的实用性。需要更大的样本量来产生对罕见变异的有力流行病学调查，并且功能研究对于确定通过测序鉴定的变异的致病性是必不可少的。
The genetic architecture of late-onset Alzheimer disease (AD) in African Americans (AAs) differs from that in persons of European ancestry. In addition to APOE, genome-wide association studies (GWASs) of AD in AA samples have implicated ABCA7, COBL, and SLC10A2 as AA-AD risk genes. Previously, we identified by whole exome sequencing a small number of AA AD cases and subsequent genotyping in a large AA sample of AD cases and controls association of AD risk with a pair of rare missense variants in AKAP9. In this study, we performed targeted deep sequencing (including both introns and exons) of approximately 100 genes previously linked to AD or AD-related traits in an AA cohort of 489 AD cases and 472 controls to find novel AD risk variants. We observed association with an 11 base-pair frame-shift loss-of-function (LOF) variant in ABCA7 (rs567222111) for which the evidence was bolstered when combined with data from a replication AA cohort of 484 cases and 484 controls (OR = 2.42, p = 0.022). We also found association of AD with a rare 9 bp deletion (rs371245265) located very close to the AKAP9 transcription start site (rs371245265, OR = 10.75, p = 0.0053). The most significant findings were obtained with a rare protective variant in F5 (OR = 0.053, p = 6.40 × 10-5), a gene that was previously associated with a brain MRI measure of hippocampal atrophy, and two common variants in KIAA0196 (OR = 1.51, p<8.6 × 10-5). Gene-based tests of aggregated rare variants yielded several nominally significant associations with KANSL1, CNN2, and TRIM35. Although no associations passed multiple test correction, our study adds to a body of literature demonstrating the utility of examining sequence data from multiple ethnic populations for discovery of new and impactful risk variants. Larger sample sizes will be needed to generate well-powered epidemiological investigations of rare variation, and functional studies are essential for establishing the pathogenicity of variants identified by sequencing.
登录
查看更多内容
DOI：
10.1126/science.1215040
发表时间：
2012-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
MacArthur DG;Balasubramanian S;Frankish A;Huang N;Morris J;Walter K;Jostins L;Habegger L;Pickrell JK;Montgomery SB;Albers CA;Zhang ZD;Conrad DF;Lunter G;Zheng H;Ayub Q;DePristo MA;Banks E;Hu M;Handsaker RE;Rosenfeld JA;Fromer M;Jin M;Mu XJ;Khurana E;Ye K;Kay M;Saunders GI;Suner MM;Hunt T;Barnes IH;Amid C;Carvalho-Silva DR;Bignell AH;Snow C;Yngvadottir B;Bumpstead S;Cooper DN;Xue Y;Romero IG;1000 Genomes Project Consortium;Wang J;Li Y;Gibbs RA;McCarroll SA;Dermitzakis ET;Pritchard JK;Barrett JC;Harrow J;Hurles ME;Gerstein MB;Tyler-Smith C
通讯作者：
Tyler-Smith C
DOI：
10.1016/j.jalz.2017.11.006
发表时间：
2018-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Chung J;Wang X;Maruyama T;Ma Y;Zhang X;Mez J;Sherva R;Takeyama H;Alzheimer's Disease Neuroimaging Initiative;Lunetta KL;Farrer LA;Jun GR
通讯作者：
Jun GR
DOI：
10.1016/j.jalz.2016.12.012
发表时间：
2017-07
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Jun GR;Chung J;Mez J;Barber R;Beecham GW;Bennett DA;Buxbaum JD;Byrd GS;Carrasquillo MM;Crane PK;Cruchaga C;De Jager P;Ertekin-Taner N;Evans D;Fallin MD;Foroud TM;Friedland RP;Goate AM;Graff-Radford NR;Hendrie H;Hall KS;Hamilton-Nelson KL;Inzelberg R;Kamboh MI;Kauwe JSK;Kukull WA;Kunkle BW;Kuwano R;Larson EB;Logue MW;Manly JJ;Martin ER;Montine TJ;Mukherjee S;Naj A;Reiman EM;Reitz C;Sherva R;St George-Hyslop PH;Thornton T;Younkin SG;Vardarajan BN;Wang LS;Wendlund JR;Winslow AR;Alzheimer's Disease Genetics Consortium;Haines J;Mayeux R;Pericak-Vance MA;Schellenberg G;Lunetta KL;Farrer LA
通讯作者：
Farrer LA
DOI：
10.1016/j.jalz.2011.03.005
发表时间：
2011-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
McKhann GM;Knopman DS;Chertkow H;Hyman BT;Jack CR Jr;Kawas CH;Klunk WE;Koroshetz WJ;Manly JJ;Mayeux R;Mohs RC;Morris JC;Rossor MN;Scheltens P;Carrillo MC;Thies B;Weintraub S;Phelps CH
通讯作者：
Phelps CH
影响因子：
11.2
作者：
Gureje, O;Ogunniyi, A;Murrell, JR
通讯作者：
Murrell, JR