Identification of genetic modifiers of age-at-onset for familial Parkinson's disease.
Identification of genetic modifiers of age-at-onset for familial Parkinson's disease.
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DOI：
10.1093/hmg/ddw206
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发表时间：
2016-09-01
影响因子：
3.5
通讯作者：
Payami H
中科院分区：
文献类型：
--
作者：
Hill-Burns EM;Ross OA;Wissemann WT;Soto-Ortolaza AI;Zareparsi S;Siuda J;Lynch T;Wszolek ZK;Silburn PA;Mellick GD;Ritz B;Scherzer CR;Zabetian CP;Factor SA;Breheny PJ;Payami H
帕金森氏病(PD)是神经退行性运动障碍的最常见原因，也是痴呆症的第二大常见原因。基因被认为对帕金森病的发病年龄的影响比对风险的影响更大，然而在识别风险基因方面取得了惊人的成功，但没有发现发病年龄的修饰因素。我们对发病年龄进行了全基因组研究。我们分别分析了家族性和非家族性帕金森病，根据先前的证据，家族性帕金森病的发病年龄有很强的遗传效应。对来自神经遗传学研究联盟(NGRC)的431例至少有一个受累亲属(家族性帕金森病)和1544例非家族性帕金森病患者进行了GWAS检查，另有737例家族性帕金森病患者和2363例非家族性帕金森病患者用于复制。在家族性帕金森病中，有两个信号被检测到并被大量复制：一个定位于5q14.1上的LHFPL2(PNGRC = 3e-8，PReplication = 2e-5，PNGRC + Replication = 1E-11)，第二个定位于15q22.2上的TPM1(PnRc = 8e-9，PReplication = 2e-4，PNGRC + Replication = 9E-11)。与加速发病相关的变异频率较低(<；0.02)。LHFPL2基因变异与NGRC患者发病时间提前12.33[95%CI：6.2；18.45]年、重复发病时间8.03[2.95；13.11]年和合并资料中的9.79[5.88；13.70]年相关。在NGRC中，TPM1变异与发病早15.30[8.10；22.49]年，在复制中与9.29[1.79；16.79]年相关，在合并数据中与12.42[7.23；17.61]年相关。LHFPL2和TPM1与非家族性帕金森病的发病年龄无关。LHFPL2(功能未知)在脑瘤中过度表达。TPM1编码一种高度保守的蛋白质，调节肌肉收缩，是一种肿瘤抑制基因。
Parkinson’s disease (PD) is the most common cause of neurodegenerative movement disorder and the second most common cause of dementia. Genes are thought to have a stronger effect on age-at-onset of PD than on risk, yet there has been a phenomenal success in identifying risk loci but not age-at-onset modifiers. We conducted a genome-wide study for age-at-onset. We analysed familial and non-familial PD separately, per prior evidence for strong genetic effect on age-at-onset in familial PD. GWAS was conducted in 431 unrelated PD individuals with at least one affected relative (familial PD) and 1544 non-familial PD from the NeuroGenetics Research Consortium (NGRC); an additional 737 familial PD and 2363 non-familial PD were used for replication. In familial PD, two signals were detected and replicated robustly: one mapped to LHFPL2 on 5q14.1 (PNGRC = 3E-8, PReplication = 2E-5, PNGRC + Replication = 1E-11), the second mapped to TPM1 on 15q22.2 (PNGRC = 8E-9, PReplication = 2E-4, PNGRC + Replication = 9E-11). The variants that were associated with accelerated onset had low frequencies (<0.02). The LHFPL2 variant was associated with earlier onset by 12.33 [95% CI: 6.2; 18.45] years in NGRC, 8.03 [2.95; 13.11] years in replication, and 9.79 [5.88; 13.70] years in the combined data. The TPM1 variant was associated with earlier onset by 15.30 [8.10; 22.49] years in NGRC, 9.29 [1.79; 16.79] years in replication, and 12.42 [7.23; 17.61] years in the combined data. Neither LHFPL2 nor TPM1 was associated with age-at-onset in non-familial PD. LHFPL2 (function unknown) is overexpressed in brain tumours. TPM1 encodes a highly conserved protein that regulates muscle contraction, and is a tumour-suppressor gene.
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影响因子：
4.5
作者：
Do CB;Tung JY;Dorfman E;Kiefer AK;Drabant EM;Francke U;Mountain JL;Goldman SM;Tanner CM;Langston JW;Wojcicki A;Eriksson N
通讯作者：
Eriksson N
影响因子：
56.9
作者：
Bonifati, V;Rizzu, P;Heutink, P
通讯作者：
Heutink, P
影响因子：
9.9
作者：
Kay, D. M.;Stevens, C. F.;Payami, H.
通讯作者：
Payami, H.
影响因子：
5.8
作者：
Gamazon, Eric R.;Zhang, Wei;Cox, Nancy J.
通讯作者：
Cox, Nancy J.
影响因子：
2.3
作者：
Bajaj, Archna;Driver, Jane A.;Schernhammer, Eva S.
通讯作者：
Schernhammer, Eva S.