Parkinson's disease is a complex neurodegenerative disorder for which both rare and common genetic variants contribute to disease risk, onset, and progression. Mutations in more than 20 genes have ...been associated with the disease, most of which are highly penetrant and often cause early onset or atypical symptoms. Although our understanding of the genetic basis of Parkinson's disease has advanced considerably, much remains to be done. Further disease-related common genetic variability remains to be identified and the work in identifying rare risk alleles has only just begun. To date, genome-wide association studies have identified 90 independent risk-associated variants. However, most of them have been identified in patients of European ancestry and we know relatively little of the genetics of Parkinson's disease in other populations. We have a limited understanding of the biological functions of the risk alleles that have been identified, although Parkinson's disease risk variants appear to be in close proximity to known Parkinson's disease genes and lysosomal-related genes. In the past decade, multiple efforts have been made to investigate the genetic architecture of Parkinson's disease, and emerging technologies, such as machine learning, single-cell RNA sequencing, and high-throughput screens, will improve our understanding of genetic risk.
Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, ...postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ‐1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high‐content, integrated datasets.
This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ‐1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high‐content, integrated datasets.
This article is part of a special issue on Parkinson disease.
This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ‐1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high‐content, integrated datasets.
This article is part of a special issue on Parkinson disease.
There has been tremendous progress toward understanding the genetic basis of Parkinson’s disease and related movement disorders. We summarize the genetic, clinical and pathological findings of ...autosomal dominant disease linked to mutations in
SNCA
,
LRRK2
,
ATXN2
,
ATXN3
,
MAPT, GCH1, DCTN1
and
VPS35
. We then discuss the identification of mutations in
PARK2
,
PARK7
,
PINK1
,
ATP13A2
,
FBXO7
,
PANK2
and
PLA2G6
genes. In particular we discuss the clinical and pathological characterization of these forms of disease, where neuropathology has been important in the likely coalescence of pathways highly relevant to typical PD. In addition to the identification of the causes of monogenic forms of PD, significant progress has been made in defining genetic risk loci for PD; we discuss these here, including both risk variants at
LRRK2
and
GBA
, in addition to discussing the results of recent genome-wide association studies and their implications for PD. Finally, we discuss the likely path of genetic discovery in PD over the coming period and the implications of these findings from a clinical and etiological perspective.
A substantial proportion of risk for Parkinson's disease (PD) is driven by genetics. Progress in understanding the genetic basis of PD has been significant. So far, highly-penetrant rare genetic ...alterations in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1 and GBA have been linked with typical familial PD and common genetic variability at 90 loci have been linked to risk for PD. In this review, we outline the journey thus far of PD genetics, highlighting how significant advances have improved our knowledge of the genetic basis of PD risk, onset and progression. Despite remarkable progress, our field has yet to unravel how genetic risk variants disrupt biological pathways and molecular networks underlying the pathobiology of the disease. We highlight that currently identified genetic risk factors only represent a fraction of the likely genetic risk for PD. Identifying the remaining genetic risk will require us to diversify our efforts, performing genetic studies across different ancestral groups. This work will inform us on the varied genetic basis of disease across populations and also aid in fine mapping discovered loci. If we are able to take this course, we foresee that genetic discoveries in PD will directly influence our ability to predict disease and aid in defining etiological subtypes, critical steps for the implementation of precision medicine for PD.
•A total of 90 risk loci have been associated with PD representing 16–36% of the heritable component of the disease.•The validation of novel genes linked to familial and early onset PD remains extremely challenging.•Increasing diversity will promote discoveries of the missing pieces of PD genetics.
Summary Background Much basic research into disease mechanisms has made use of genetic findings to model and understand aetiology. Broad success has been achieved in finding disease-linked mutations ...with traditional positional cloning approaches; however, because of the requirements of this method, these successes have been limited by the availability of large, well characterised families. Because of these and other restrictions the genetic basis of many diseases, and diseases in many families, remains unknown. Recent developments Exome sequencing uses DNA-enrichment methods and massively parallel nucleotide sequencing to comprehensively identify and type protein-coding variants throughout the genome. Coupled with growing databases that contain known variants, exome sequencing makes identification of genetic mutations and risk factors possible in families and samples that were deemed insufficiently informative for previous genetic studies. Not only does exome sequencing enable identification of mutations in families that were undetectable with linkage and positional cloning methods, but compared with these methods, it is also much quicker and cheaper. Use of exome sequencing has so far been successful in many rare diseases. Where next? Exome sequencing is being adopted widely and we can expect an abundance of mutation discovery, similar to the deluge of genome-wide-association findings reported over the past 5 years; it is expected to enable the discovery of not only rare causal variants, but also protein-coding risk variants. This method will have application in both the research and clinical arenas and sets the scene for the use of whole-genome sequencing.
Common variant genome-wide association studies (GWASs) have, to date, identified >24 risk loci for Parkinson's disease (PD). To discover additional loci, we carried out a GWAS comparing 6,476 PD ...cases with 302,042 controls, followed by a meta-analysis with a recent study of over 13,000 PD cases and 95,000 controls at 9,830 overlapping variants. We then tested 35 loci (P < 1 × 10
) in a replication cohort of 5,851 cases and 5,866 controls. We identified 17 novel risk loci (P < 5 × 10
) in a joint analysis of 26,035 cases and 403,190 controls. We used a neurocentric strategy to assign candidate risk genes to the loci. We identified protein-altering or cis-expression quantitative trait locus (cis-eQTL) variants in linkage disequilibrium with the index variant in 29 of the 41 PD loci. These results indicate a key role for autophagy and lysosomal biology in PD risk, and suggest potential new drug targets for PD.
Menopause accelerates biological aging Levine, Morgan E.; Lu, Ake T.; Chen, Brian H. ...
Proceedings of the National Academy of Sciences - PNAS,
08/2016, Letnik:
113, Številka:
33
Journal Article
Recenzirano
Odprti dostop
Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate ...epigenetic biomarker of age (known as the “epigenetic clock”), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women’s Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson’s disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further.
A fundamental challenge in the post-genome era is to understand and annotate the consequences of genetic variation, particularly within the context of human tissues. We present a set of integrated ...experiments that investigate the effects of common genetic variability on DNA methylation and mRNA expression in four human brain regions each from 150 individuals (600 samples total). We find an abundance of genetic cis regulation of mRNA expression and show for the first time abundant quantitative trait loci for DNA CpG methylation across the genome. We show peak enrichment for cis expression QTLs to be approximately 68,000 bp away from individual transcription start sites; however, the peak enrichment for cis CpG methylation QTLs is located much closer, only 45 bp from the CpG site in question. We observe that the largest magnitude quantitative trait loci occur across distinct brain tissues. Our analyses reveal that CpG methylation quantitative trait loci are more likely to occur for CpG sites outside of islands. Lastly, we show that while we can observe individual QTLs that appear to affect both the level of a transcript and a physically close CpG methylation site, these are quite rare. We believe these data, which we have made publicly available, will provide a critical step toward understanding the biological effects of genetic variation.
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