PLoS Genetics：GWAS方法鉴定出与帕金森氏症相关两新位点

遗传检测公司23andMe联合美国帕金森研究所（Parkinson's Institute）通过全基因组关联研究（GWAS），鉴定出与帕金森氏症相关的两个新位点。该研究成果近日发表在《公共科学图书馆—遗传学》（PLoS Genetics）上。

帕金森氏症是一种慢性的中枢神经系统退化性失调，它会损害患者的动作技能、语言能力以及其他功能。历史上有许多名人曾经在晚年遭受到帕金森氏症的困扰，包括拳王阿里、杜鲁门、麦克阿瑟将军、凯瑟琳?赫本等。它的病因至今仍不明，尽管有人认为环境是帕金森氏症的主要因素，但近期的研究表明多个基因影响了疾病易感性。

该研究小组的GWAS研究包括了3426名患有帕金森氏症的个体，以及29624名未患有该病的对照个体。利用定制的Illumina HumanHap 550+ 芯片，研究人员对这些个体进行基因分型。他们不仅验证了20个过去鉴定出的关联，还检测出两个新的风险位点。这两个SNP，一个落在2型溶酶体膜蛋白编码基因SCARB2附近，另一个则在SREBF1和RAI1基因附近。

文章的第一作者，23andMe的科学家Chuong Do表示：“这些新的遗传发现不仅很重要，而且我们还表明，23andMe采集的数据支持了新关联的发现，以及已知关联的重复。这项研究是一个严格的‘原理论证’研究。”

基于目前的发现，研究小组预计至少1/4的帕金森氏症风险与遗传因素有关。下一步，他们打算开展更多研究，来进一步区分疾病的环境因素。

与传统研究不同，这项研究的参与完全是通过网络进行的。在一年半的时间内，通过定向的邮件群发，招募了帕金森氏症患者。而对照是通过23andMe 数据库招募的。他们还通过一套在线问卷来确定病例的状态。这些研究结果显示了这种基于网络的招募和数据采集方法对于了解疾病病因的能力，并证明了自我报告的数据对于研究帕金森氏症的能力和可靠性。

23andMe的总裁兼CEO Anne Wojcicki认为：“我们相信，这篇文章证明了我们将遗传信息与基于网络的数据结合来生成研究新发现的潜力。这种方法有可能应用在其他多种病例中。”

原文出处：

PLoS Genetics    doi:10.1371/journal.pgen.1002141.t001

Web-Based Genome-Wide Association Study Identifies Two Novel Loci and a Substantial Genetic Component for Parkinson's Disease

Chuong B. Do, Joyce Y. Tung, Elizabeth Dorfman, Amy K. Kiefer, Emily M. Drabant, Uta Francke1, Joanna L. Mountain, Samuel M. Goldman, Caroline M. Tanner, J. William Langston, Anne Wojcicki, Nicholas Eriksson

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. Author Summary Top 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.