Recent genetic studies on Parkinson’s disease in Asian-ancestry individuals have demonstrated important differences in genetic risk between Asians and Europeans. Extensive collaborations across the Asia-Pacific region are needed to develop a comprehensive resource of genetic information and tissue samples that will contribute further to our understanding of the disease. This will also improve our ability to identify at-risk individuals within Asia for monitoring and early intervention. Here, we review recent developments in research on Parkinson’s disease genetics in Asia, and discuss ongoing efforts and future directions in this area.
Parkinson’s disease in Asia
Parkinson’s disease is a common age-related neurodegenerative movement disorder affecting one to two percent of the world’s population above age 65 years. A key feature of Parkinson’s disease patients is the loss of dopamine-producing cells in the midbrain that serve to regulate movement. The cause is largely unknown, although both genetic and environmental factors have been shown to play a role. It affects all populations and ethnicities, with increasing incidence worldwide as a result of the ageing population.
Asia has the world’s largest population with an estimated 60 percent residing within the continent, out of which at least a third or 1.4 billion reside in mainland China alone. Substantial genetic differences exist across populations. A recent genome sequencing study of 4,810 individuals of three ethnic groups in Singapore – Chinese, Malays and Indians, revealed that nearly half of the 98 million genetic variants identified were not seen before in sequencing studies of other ethnicities, and likely to be Asian-specific (Dou et al. Cell, 2019).
With such a large population at risk, it is important to focus research efforts on patients in Asia in understanding how inter-individual genetic variation influences who develops Parkinson’s disease and who does not. Extrapolating findings from patients of a different ancestry is likely to lead to only a partial understanding of Parkinson’s disease genetics in Asian individuals, thus leading to suboptimal healthcare in the era of precision medicine where treatment is tailored according to the genetic makeup of a patient.
Genome-wide association studies
Genome-wide association studies (GWAS) allow an unbiased survey of common (>1% of the population) genetic variation across the human genome for association with a disease. GWAS on nearly 40,000 Parkinson’s disease patients have identified about 90 genetic variants that affect one’s risk of developing the disease (Nalls et al Lancet Neurol, 2019). Nearly all these samples are of European ancestry, even though one of the earliest studies was done on Japanese samples (Satake et al Nat Genet, 2009). Indeed, a recent scientometric review of all GWAS conducted to date showed that nearly 86 percent of samples analysed are of European ancestry, and less than 10 percent are of Asian ancestry (Mills & Rahal Comm Biol, 2019).
The largest Parkinson’s disease GWAS on samples from Asia was done by the Asia Parkinson’s disease Genetics Consortium, with a total of 31,575 individuals from Singapore, Malaysia, Hong Kong, Taiwan, mainland China and South Korea. This led to the identification of two novel genetic variants that had not been previously identified in studies on samples of European ancestry (Foo et al JAMA Neurol, 2020). While findings from European-ancestry GWAS could to a certain extent predict Parkinson’s disease in Asian individuals, inclusion of genetic information from Asian-ancestry GWAS led to a significant improvement in risk prediction, highlighting the need to obtain population- or ethnic- specific genetic information.
Buried within the DNA code of the human genome are 20,000 to 30,000 functional units known as genes, which encode proteins that serve to perform most of the required functions in each cell of our body. The genetic variants analysed by GWAS tend to fall outside these genes, largely because genetic variants that occur within genes tend to have stronger effects on health, are rare and often ethnic- or population-specific.
Studies sequencing all the protein coding genes of the genome, also known as whole exome sequencing, have been done in Parkinson’s disease samples from China and Japan, and led to the discovery of CHCHD2 (Funayama et al Lancet Neurol, 2015), TMEM230 (Deng et al Nat Genet, 2016) and PSAP saposin D domain (Oji et al Brain, 2020) as novel genes important in Parkinson’s disease. Rare genetic variants in these genes segregate with Parkinson’s disease in families and are rare or never seen in unaffected individuals within the population. However, the variants reported in these studies are also uncommon in Parkinson’s disease patients of Asian- or other ancestries (Iqbal & Toft Nat Genet, 2019), highlighting the genetic heterogeneity of the disease and the need for extensive validation in large sample collections.
Studying mutations that completely knock out the function of genes, known as “loss of function” (LOF) variants provide insights into the role of the gene in humans, and the potential of its encoded protein as a drug target. Genetic variants in the gene LRRK2 has been associated with Parkinson’s disease in both European- and Asian-ancestry samples. To evaluate the effect of inhibiting the LRRK2 protein, a recent study evaluated 141,456 individuals sequenced in the Genome Aggregation Database and showed that individuals who express less or no LRRK2 protein as a result of LOF variants did not show any adverse effects on health (Whiffin et al Nat Med, 2020).
Ultimately, translation of genetic findings into understanding disease biology and development of drugs will rely on mechanistic studies in the laboratory. Given the complexity of the human brain and its potential interaction with the immune system and the gut microbiome, animal models such as the mouse, zebrafish or fly provide limited insights on disease mechanism and the availability of human cells and tissues for research studies will be critical.
The lack of brain biopsy tissue has been a major impediment for neurological disease research. Advances in stem cell research has allowed the generation of human midbrain organoids. These “mini brains” can be grown from human embryonic stem cells or induced pluripotent stem cells derived from a skin or blood sample taken from a patient, and recapitulate many features of brain cells and the development of disease that can be observed in the laboratory (Jo et al Cell Stem Cell, 2016). This platform allows mechanistic studies and drug screening to be conducted in human cells and organoids with a required genetic content, both in terms of ethnicity and disease risk.
The collection of post-mortem brain tissue has also been invaluable to understanding pathological features of Parkinson’s disease and other brain disorders. Brain banks that collect and preserve brain tissue upon death are common in Europe and the United States, but rare in Asia. To facilitate the collection of samples representative of patients in Asia, Brain Bank Singapore was launched on 27th November 2019 with the aim of recruiting clinical and community donors. In the long term, this will provide a resource of post-mortem brain tissue for research on Parkinson’s disease and other neurological diseases.
Clinical and neuroimaging studies
The clinical presentation of Parkinson’s disease is extremely heterogeneous and has overlapping features with other diseases such as essential tremor, parkinsonism and multiple system atrophy. Translation of genetic findings into clinical practice will be dependent on detailed clinical evaluation involving longitudinal follow-up of patients or high-risk individuals, even before they develop symptoms of the disease.
One such observational clinical study, the Parkinson’s Progression Markers Initiative (PPMI) aims to use advanced neuroimaging, biological samples collection and motor, cognitive and behavioural assessments to identify Parkinson’s disease progression biomarkers (Simuni et al Mov Disord, 2020). Up to 600 participants were recruited from the United States, Europe, Australia and Israel. Similar studies in more diverse ethnicities, especially in more East Asian samples will be valuable. Moreover, studies that explore detailed interactions between genetic and environmental factors such as diet, lifestyle and exposure to chemicals, will further improve our ability to identify high risk individuals for early intervention.
The need for large sample collections in genetic studies calls for strong and extensive international collaboration across different countries and regions in Asia. Efforts to assemble international consortiums are often limited by difficulties in communication across borders, language and cultural barriers as well as laws and regulations that restrict sample and data sharing to within each respective country. This has proven to be more challenging in Asia compared to other countries such as the United States and Europe.
Nonetheless, the merits of working across borders are increasingly recognised in many Asian countries, with more research groups in Asia joining international efforts in recent years. This increased participation will lead towards an improved understanding of Parkinson’s disease, and the ability to apply precision medicine and improved healthcare to the rapidly ageing population in Asia.
- Wu D, Dou J, Chai X, Bellis C, Wilm A, Shih CC, Soon WWJ, Bertin N, Lin CB, Khor CC, DeGiorgio M, Cheng S, Bao L, Karnani N, Hwang WYK, Davila S, Tan P, Shabbir A, Moh A, Tan EK, Foo JN, Goh LL, Leong KP, Foo RSY, Lam CSP, Richards AM, Cheng CY, Aung T, Wong TY, Ng HH; SG10K Consortium, Liu J, Wang C. (2019 ) Large-Scale Whole-Genome Sequencing of Three Diverse Asian Populations in Singapore. Cell. 179(3):736-749.e15. doi: 10.1016/j.cell.2019.09.019.
- Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, Tan M, Kia DA, Noyce AJ, Xue A, Bras J, Young E, von Coelln R, Simón-Sánchez J, Schulte C, Sharma M, Krohn L, Pihlstrøm L, Siitonen A, Iwaki H, Leonard H, Faghri F, Gibbs JR, Hernandez DG, Scholz SW, Botia JA, Martinez M, Corvol JC, Lesage S, Jankovic J, Shulman LM, Sutherland M, Tienari P, Majamaa K, Toft M, Andreassen OA, Bangale T, Brice A, Yang J, Gan-Or Z, Gasser T, Heutink P, Shulman JM, Wood NW, Hinds DA, Hardy JA, Morris HR, Gratten J, Visscher PM, Graham RR, Singleton AB; 23andMe Research Team; System Genomics of Parkinson's Disease Consortium; International Parkinson's Disease Genomics Consortium. (2019) Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18(12):1091-1102. doi: 10.1016/S1474-4422(19)30320-5.
- Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T. (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet. 41(12):1303-7. doi: 10.1038/ng.485.
- Mills MC, Rahal C. (2019) A scientometric review of genome-wide association studies. Commun Biol. 2:9. doi: 10.1038/s42003-018-0261-x
- Foo JN, Chew EG, Chung J, Peng R, Blauwendraat C, Nalls MA, Mok JY, IPDGC, Satake W, Toda T, Chao YX, Tan LC, Tandiono M, Lian MM, Ng EY, Prakash KM, Au WL, Meah WY, Mok SQ, Ahmad-Annuar A, Chan AY, Chen L, Chen Y, Jeon BS, Jiang L, Lim JL, Lin JJ, Liu C, Mao C, Mok V, Pei Z, Shang HF, Shi CH, Song K, Tan AH, Wu YR, Xu YM, Xu R, Yan Y, Yang J, Zhang BR, Koh WP, Lim SY, Khor CC, Liu J, Tan EK. (2020) Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study. JAMA Neurol Apr 20 online doi: 10.1001/jamaneurol.2020.0428.
- Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, Li Y, Ogaki K, Ando M, Yoshino H, Tomiyama H, Nishioka K, Hasegawa K, Saiki H, Satake W, Mogushi K, Sasaki R, Kokubo Y, Kuzuhara S, Toda T, Mizuno Y, Uchiyama Y, Ohno K, Hattori N. CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. (2015) Lancet Neurol 14(3):274-82. doi: 10.1016/S1474-4422(14)70266-2
- Deng HX, Shi Y, Yang Y, Ahmeti KB, Miller N, Huang C, Cheng L, Zhai H, Deng S, Nuytemans K, Corbett NJ, Kim MJ, Deng H, Tang B, Yang Z, Xu Y, Chan P, Huang B, Gao XP, Song Z, Liu Z, Fecto F, Siddique N, Foroud T, Jankovic J, Ghetti B, Nicholson DA, Krainc D, Melen O, Vance JM, Pericak-Vance MA, Ma YC, Rajput AH, Siddique T. (2016) Nat Genet. 48(7):733-9. doi: 10.1038/ng.3589.
- Oji Y, Hatano T, Ueno SI, Funayama M, Ishikawa KI, Okuzumi A, Noda S, Sato S, Satake W, Toda T, Li Y, Hino-Takai T, Kakuta S, Tsunemi T, Yoshino H, Nishioka K, Hattori T, Mizutani Y, Mutoh T, Yokochi F, Ichinose Y, Koh K, Shindo K, Takiyama Y, Hamaguchi T, Yamada M, Farrer MJ, Uchiyama Y, Akamatsu W, Wu YR, Matsuda J, Hattori N. (2020) Variants in saposin D domain of prosaposin gene linked to Parkinson's disease. Brain. 143(4):1190-1205. doi: 10.1093/brain/awaa064.
- Iqbal Z, Toft M (2019) TMEM230 Variants in Parkinson's Disease. Nat Genet 51(3):366. doi: 10.1038/s41588-019-0353-7.
- Whiffin N, Armean IM, Kleinman A, Marshall JL, Minikel EV, Goodrich JK, Quaife NM, Cole JB, Wang Q, Karczewski KJ, Cummings BB, Francioli L, Laricchia K, Guan A, Alipanahi B, Morrison P, Baptista MAS, Merchant KM; Genome Aggregation Database Production Team; Genome Aggregation Database Consortium, Ware JS, Havulinna AS, Iliadou B, Lee JJ, Nadkarni GN, Whiteman C; 23andMe Research Team, Daly M, Esko T, Hultman C, Loos RJF, Milani L, Palotie A, Pato C, Pato M, Saleheen D, Sullivan PF, Alföldi J, Cannon P, MacArthur DG. (2020) The effect of LRRK2 loss-of-function variants in humans. Nat Med. 26(6):869-877. doi: 10.1038/s41591-020-0893-5.
- Jo J, Xiao Y, Sun AX, Cukuroglu E, Tran HD, Göke J, Tan ZY, Saw TY, Tan CP, Lokman H, Lee Y, Kim D, Ko HS, Kim SO, Park JH, Cho NJ, Hyde TM, Kleinman JE, Shin JH, Weinberger DR, Tan EK, Je HS, Ng HH. (2016) Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons. Cell Stem Cell. 2016 19(2):248-257. doi: 10.1016/j.stem.2016.07.005.
- Simuni T, Brumm MC, Uribe L, Caspell-Garcia C, Coffey CS, Siderowf A, Alcalay RN, Trojanowski JQ, Shaw LM, Seibyl J, Singleton A, Toga AW, Galasko D, Foroud T, Nudelman K, Tosun-Turgut D, Poston K, Weintraub D, Mollenhauer B, Tanner CM, Kieburtz K, Chahine LM, Reimer A, Hutten S, Bressman S, Marek K; Parkinson's Progression Markers Initiative Investigators. (2020) Clinical and Dopamine Transporter Imaging Characteristics of Leucine Rich Repeat Kinase 2 (LRRK2) and Glucosylceramidase Beta (GBA) Parkinson's Disease Participants in the Parkinson's Progression Markers Initiative: A Cross-Sectional Study. Mov Disord. 35(5):833-844. doi: 10.1002/mds.27989.
About the Authors
Assistant Professor Foo Jia Nee, PhD,
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore
Professor Tan Eng King, MBBS, MRCP, FAMS,
FRCP, Deputy Medical Director (Academic Affairs), Research Director, Senior Consultant Neurologist, National Neuroscience Institute