Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.
Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.
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DOI：
10.1371/journal.pgen.1002141
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发表时间：
2011-06
期刊：
影响因子：
4.5
通讯作者：
Eriksson N
中科院分区：
文献类型：
--
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
尽管帕金森病（PD）的病因被认为主要是环境因素，但近期研究表明，许多基因会影响易感性。我们利用有针对性的病例招募和在线调查工具，开展了迄今为止基于单一人群集合的规模最大的帕金森病病例对照全基因组关联研究（GWAS）（3426例病例和29624例对照）。我们发现了两个与帕金森病全新的、全基因组显著关联——位于SCARB2附近的rs6812193（[具体数值缺失]，[具体数值缺失]）以及位于SREBF1/RAI1附近的rs11868035（[具体数值缺失]，[具体数值缺失]）——两者在一个独立队列中都得到了重复验证。我们还重复验证了20个先前发现的基因关联（包括LRRK2、GBA、SNCA、MAPT、GAK和HLA区域），为我们新颖的研究设计提供了支持。依据一种最近提出的基于远亲个体之间全基因组共享估计的方法，我们估计帕金森病的遗传力至少为0.27。最后，利用稀疏回归技术，我们构建了预测模型，这些模型解释了6% - 7%的患病总方差，并表明存在超出全基因组显著性的真实关联，这通过内部和外部交叉验证都得到了证实。这些结果表明，遗传学对早发性和晚发性帕金森病易感性都有显著但绝非全部的贡献，这意味着，尽管在此处和其他地方发现了新的关联，但帕金森病的大部分遗传成分仍有待发现。
我们对帕金森病（PD）进行了一项大规模的全基因组关联研究（GWAS），有超过3400例病例和29000例对照（是迄今为止最大的单一帕金森病GWAS队列）。我们报告了两个新的基因关联，并重复验证了总共20个先前描述的关联，表明现在帕金森病背后有许多确凿的遗传因素。我们还估计遗传因素至少解释了帕金森病患病风险变异的四分之一，而目前发现的因素仅解释了一小部分（6% - 7%）。总之，这些结果扩充了迄今为止发现的遗传因素集合，并意味着还有更多关联有待发现。与传统研究不同，本研究的参与完全是在线进行的，使用的病例主要是通过帕金森病邮件列表招募的，对照来自个人基因公司23andMe的客户群。因此，我们的研究展示了基于网络的招募和数据收集方法在疾病病因研究中产生新科学见解的能力，并证明了自我报告数据在研究帕金森病遗传学方面的效力和可靠性。
Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD–rs6812193 near SCARB2 (, ) and rs11868035 near SREBF1/RAI1 (, )—both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%–7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered. We conducted a large genome-wide association study (GWAS) of Parkinson's disease (PD) with over 3,400 cases and 29,000 controls (the largest single PD GWAS cohort to date). We report two novel genetic associations and replicate a total of twenty previously described associations, showing that there are now many solid genetic factors underlying PD. We also estimate that genetic factors explain at least one-fourth of the variation in PD liability, of which currently discovered factors only explain a small fraction (6%–7%). Together, these results expand the set of genetic factors discovered to date and imply that many more associations remain to be found. Unlike traditional studies, participation in this study took place completely online, using a collection of cases recruited primarily via PD mailing lists and controls derived from the customer base of the personal genetics company 23andMe. Our study thus illustrates the ability of web-based methods for enrollment and data collection to yield new scientific insights into the etiology of disease, and it demonstrates the power and reliability of self-reported data for studying the genetics of Parkinson's disease.
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