Largest Study on the LRRK2 Variant Leads to Discoveries About Health, Ancestry, and History
Largest Study on the LRRK2 Variant Leads to Discoveries About Health, Ancestry, and History
Findings from 23andMe research on Parkinson's disease published in Brain
23andMe关于帕金森氏病的研究结果发表在《大脑》上
- The LRRK2 variant is strongly associated with symptoms of Parkinson's disease (PD) that are different from non-variant carriers with the disease
- The study revealed novel findings of genetic "hotspots" in people from Mexico, Cuba, Puerto Rico, and Brazil, where the founder variant has sprung up in other communities
- 23andMe has the largest LRRK2 G2019S research cohort, and launched the Parkinson's Impact Project (PIP) in 2018 to better understand which carriers are at greater risk of developing Parkinson's disease
- LRRK2 变体与帕金森氏病 (PD) 的症状密切相关,这些症状不同于该病的非变异携带者
- 该研究揭示了墨西哥、古巴、波多黎各和巴西人的遗传 “热点” 的新发现,创始变种在其他社区如雨后春笋般涌现
- 23andMe 拥有最大的 LRRK2 G2019S 研究队列,并于 2018 年启动了帕金森氏症影响项目 (PIP),以更好地了解哪些携带者患帕金森氏病的风险更大
SUNNYVALE, Calif., May 29, 2024 (GLOBE NEWSWIRE) -- 23andMe Holding Co. (Nasdaq: ME) (23andMe), a leading genetic health and biopharmaceutical company, with support from The Michael J. Fox Foundation for Parkinson's Research, conducted the world's largest study on LRRK2 G2019S and uncovered new insights into the variant. 23andMe launched the Parkinson's Impact Project (PIP) in 2018 to better understand which LRRK2 G2019S carriers' are at greatest risk of developing Parkinson's disease. The 3.5-year longitudinal study included 1,286 genotyped LRRK2 G2019S carriers and 109,154 non-carriers. Findings from the study, published today in the June 2024 issue of Brain, illustrate how DNA weaves together health, ancestry, and history.
加利福尼亚州森尼维尔,2024 年 5 月 29 日(GLOBE NEWSWIRE)— 23andMe Holding Co.纳斯达克股票代码:ME)(23andMe)是一家领先的遗传健康和生物制药公司,在迈克尔·福克斯帕金森氏症研究基金会的支持下,对 LRRK2 G2019S 进行了世界上最大规模的研究,并发现了对该变体的新见解。23andMe于2018年启动了帕金森氏症影响项目(PIP),以更好地了解哪些 LRRK2 G2019S 携带者患帕金森氏病的风险最大。这项为期3.5年的纵向研究包括1,286名基因型的 LRRK2 G2019S 携带者和109,154名非携带者。研究结果, 已出版 今天在 2024 年 6 月号中 大脑,说明了 DNA 如何将健康、祖先和历史交织在一起。
The LRRK2 G2019S variant
LRRK2 G2019S 变体
Only 10 percent of Parkinson's disease cases have a known genetic cause; the remaining 90 percent have idiopathic Parkinson's disease, where the cause is unknown. Of the 10 percent of PD cases known to be related to a high risk variant, only 5 percent have the Leucine Rich Repeat Kinase 2 Glycine to Serine variant, also known as LRRK2 G2019S. Yet, the LRRK2 G2019S variant is the most common pathogenic variant linked to Parkinson's disease. 23andMe's study showed that people with the G2019S variant are seven times more likely to develop Parkinson's than people without the variant. Yet, not everyone with this LRRK2 variant will develop Parkinson's disease.
只有10%的帕金森氏病病例有已知的遗传原因;其余90%的病例为特发性帕金森氏病,病因不明。在已知与高风险变异相关的10%的PD病例中,只有5%的病例具有富含亮氨酸的重复激酶2甘氨酸转丝氨酸变体,也称为 LRRK2 G2019S。然而,LRRK2 G2019S 变体是与帕金森氏病有关的最常见的致病变体。23andMe的研究表明,患有 G2019S 变体的人患帕金森氏症的可能性是没有该变异的人的七倍。但是,并非所有患有这种 LRRK2 变体的人都会患上帕金森氏病。
LRRK2-associated Parkinson's compared to Parkinson's without the variant
LRRK2 相关的帕金森氏症与没有变体的帕金森氏症的比较
Parkinson's disease is associated with the degeneration of nerves in the brain and body, which produces different symptoms according to the pattern of nerve death.
帕金森氏病与大脑和身体神经退化有关,根据神经死亡的模式,这种退化会产生不同的症状。
People who develop Parkinson's disease who have the LRRK2 G2019S variant have milder symptoms than those with Parkinson's who do not have the LRRK2 variant. LRRK2-associated Parkinson's tend to have a slower progression of the disease. The data also suggests that in LRRK2 Parkinson's disease, the areas outside the motor control regions are spared from the neurodegenerative process. Conversely, Parkinson's carriers without the variant report significantly higher rates of cognitive decline, memory deficits, hyposmia (decreased sense of smell), and REM sleep behavior disorder (RBD) symptoms, which occur at lower rates in Parkinson's disease patients who have the LRRK2 variant.
患有 LRRK2 G2019S 变体的帕金森氏病患者的症状比没有 LRRK2 变体的帕金森氏症患者症状较轻。与LRRK2相关的帕金森氏症的病情进展往往较慢。数据还表明,在 LRRK2 帕金森氏病中,运动控制区域以外的区域不受神经退行性过程的影响。相反,没有变异的帕金森氏症携带者报告的认知能力下降、记忆缺陷、低血症(嗅觉减退)和快速眼动睡眠行为障碍(RBD)症状的发生率明显更高,而在患有 LRRK2 变体的帕金森氏病患者中,这些症状的发生率较低。
Acting out dreams (RBD) and poor sense of smell are common symptoms that can be an early warning sign of neurodegeneration in the brain. These symptoms may indicate the onset of idiopathic Parkinson's disease, sometimes decades before the typical motor symptoms like tremor become obvious. However, people with LRRK2-associated Parkinson's are less likely to experience RBD and loss of smell.
做梦(RBD)和嗅觉不佳是常见的症状,可能是大脑神经变性的预警信号。这些症状可能表明特发性帕金森氏病的发作,有时是在震颤等典型运动症状变得明显之前的几十年前。但是,与LRRK2相关的帕金森氏症患者出现RBD和嗅觉丧失的可能性较小。
"Because people with the LRRK2 G2019S variant are less likely to have sleep and smell abnormalities, the scientific and medical communities might be underestimating the risk of Parkinson's disease in LRRK2 carriers," said Lucy Norcliffe-Kaufmann, Ph.D., Principal Scientist, Parkinson's Disease Research at 23andMe. "Existing criteria may lack sensitivity for early detection among LRRK2 carriers. If we are only looking for smell and sleep problems, which don't appear as often in the early stages of LRRK2-PD, we may be miscalculating a person's risk, because for some reason those areas of the brain are more resistant to neurodegeneration"
23andMe帕金森氏病研究首席科学家露西·诺克利夫-考夫曼博士说:“由于患有 LRRK2 G2019S 变体的人不太可能出现睡眠和气味异常,因此科学界和医学界可能低估了 LRRK2 携带者患帕金森氏病的风险。”“在 LRRK2 携带者中,现有标准可能缺乏早期发现的灵敏度。如果我们只寻找气味和睡眠问题,而这些问题在 LRRK2-PD 的早期阶段并不经常出现,那么我们可能会错误地估计一个人的风险,因为出于某种原因,大脑的这些区域对神经变性的抵抗力更强。”
LRRK2 variant unifies different populations
LRRK2 变体统一了不同的人群
The LRRK2 G2019S genetic variant originally emerged from North Africa and passed through the early Jewish settlers in that part of the world. Scientists have long been aware of high rates of the LRRK2 variant in North African and Ashkenazi Jewish populations.
LRRK2 G2019S 基因变异最初来自北非,并通过该地区的早期犹太定居者传播。科学家们早就意识到,LRRK2 变种在北非和阿什肯纳兹犹太人群中的发病率很高。
However, novel ancestry findings from 23andMe's study revealed hotspots in people from Mexico, Cuba, Puerto Rico and Brazil where the carrier rate of the LRRK2 G2019S variant was much higher than expected. The new Latin Caribbean connection historically points to migration of the Jewish population from Iberia to the Americas, after fleeing the Inquisitions. The movement of populations throughout the Mediterranean Basin brought with it the LRRK2 G2019S variant. Once the variant became established in the Jewish community, it spread to other regions of the world. In particular, it appears to have been brought to the Latin Caribbean during transatlantic voyages in the late 15th century, and there it created new founder populations. "By understanding the genetic ancestry of LRRK2 carriers, we can build community among these people," said Dr. Norcliffe-Kaufmann.
但是,23andMe研究的新血统发现显示,在来自墨西哥、古巴、波多黎各和巴西的人群中,LRRK2 G2019S 变体的携带率远高于预期。从历史上看,新的拉丁加勒比联系表明,犹太人口在逃离宗教裁判所后从伊比利亚移民到美洲。整个地中海盆地的人口流动带来了 LRRK2 G2019S 变体。一旦该变体在犹太社区确立,它就会传播到世界其他地区。特别是,它似乎是在15世纪末的跨大西洋航行中被带到拉丁加勒比海的,并在那里创造了新的创始人群。诺克利夫-考夫曼博士说:“通过了解 LRRK2 携带者的遗传血统,我们可以在这些人之间建立社区。”
23andMe's ongoing Parkinson's research
23andMe 正在进行的帕金森氏症研究
23andMe's Parkinson's Impact Project (PIP) has helped scientists better understand the progression of Parkinson's disease as well as how LRRK2 Parkinson's differs from idiopathic Parkinson's. Launched in 2018 to understand LRRK2 G2019S carriers' experience with Parkinson's disease, the 3.5-year longitudinal prospective observational study included more than 110K consented research participants (with nearly 1,300 genotyped LRRK2 G2019S carriers and more than 109K non-carriers). Ancestry composition from more than 11K additional consented research participants in 23andMe's database who have the LRRK2 G2019S variant was also included. 23andMe's cohort that participated in the LRRK2 study is three times bigger than any other study published.
23andMe 的帕金森氏症影响项目(PIP)帮助科学家更好地了解帕金森氏病的进展以及 LRRK2 帕金森氏症与特发性帕金森氏症有何不同。这项为期3.5年的纵向前瞻性观察研究于2018年启动,旨在了解 LRRK2 G2019S 携带者在帕金森氏病中的经历,其中包括超过11万名同意的研究参与者(包括近1300名基因型的 LRRK2 G2019S 携带者和超过10.9万名非携带者)。还包括23andMe数据库中超过1.1万名持有 LRRK2 G2019S 变体的经同意的研究参与者的血统构成。23andMe参与LRRK2 研究的队列比发表的任何其他研究都要大三倍。
The study participants took surveys every six months for 3.5 years. Sixty-six percent of participants completed at least one follow-up, and 42 percent of individuals with Parkinson's had at least two years of follow-up. Scientists at 23andMe built anatomic models of brain degeneration from survey answers, looked at polygenic risk scores (PRS), and evaluated genetic ancestry.
研究参与者每六个月进行一次调查,持续3.5年。66%的参与者完成了至少一次随访,42%的帕金森氏症患者接受了至少两年的随访。23andMe的科学家根据调查答案建立了脑退化的解剖学模型,研究了多基因风险评分(PRS),并评估了遗传血统。
This study is one of many aspects of 23andMe's long-standing commitment to studying Parkinson's disease. 23andMe researchers have studied the genetic underpinnings of Parkinson's since 2009. These studies have also identified almost 100 new genetic variants associated with Parkinson's. It allows 23andMe scientists and collaborators to explore what role these variants play in the progression of Parkinson's disease.
这项研究是23andMe长期致力于研究帕金森氏病的众多方面之一。自2009年以来,23andMe的研究人员一直在研究帕金森氏症的遗传基础。这些研究还发现了近100种与帕金森氏症有关的新遗传变异。它使23andMe的科学家和合作者能够探索这些变异在帕金森氏病进展中起什么作用。
The Michael J. Fox Foundation, the world's largest nonprofit funder of Parkinson's research, funded the postdoctoral program. Through the program, Matthew Kmiecik, Ph.D., a postdoctoral fellow at 23andMe, collaborated with a group of internal scientists to dive deeply into the analysis of the PIP study data. "The Michael J. Fox Foundation postdoctoral fellowship has enabled me to not only grow as a scientist, but also advance our understanding of LRRK2 Parkinson's disease," said Dr. Kmiecik.
迈克尔·福克斯基金会是世界上最大的帕金森氏症研究非营利性资助机构,为该博士后项目提供了资金。通过该项目,23andMe的博士后研究员马修·克米西克博士与一组内部科学家合作,深入研究了PIP研究数据的分析。克米西克博士说:“迈克尔·福克斯基金会的博士后奖学金不仅使我能够成长为一名科学家,而且还增进了我们对 LRRK2 帕金森氏病的理解。”
The resulting study just published in Brain is 23andMe's first paper to utilize a longitudinal prospective data collection. Read the study here.
由此产生的研究刚刚发表于 大脑 是23andMe的第一篇利用纵向前瞻性数据收集的论文。阅读研究报告 这里。
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前瞻性陈述
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