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Article: Discovering genetic mechanisms underlying the co-occurrence of Parkinson's disease and non-motor traits.

Gokuladhas, Sreemol / Fadason, Tayaza / Farrow, Sophie / Cooper, Antony / O'Sullivan, Justin M

2024 Volume 10, Issue 1, Page(s) 27

Abstract: Understanding the biological mechanisms that underlie the non-motor symptoms of Parkinson's disease (PD) requires comprehensive frameworks that unravel the complex interplay of genetic risk factors. Here, we used a disease-agnostic brain cortex gene ... ...

Abstract	Understanding the biological mechanisms that underlie the non-motor symptoms of Parkinson's disease (PD) requires comprehensive frameworks that unravel the complex interplay of genetic risk factors. Here, we used a disease-agnostic brain cortex gene regulatory network integrated with Mendelian Randomization analyses that identified 19 genes whose changes in expression were causally linked to PD. We further used the network to identify genes that are regulated by PD-associated genome-wide association study (GWAS) SNPs. Extended protein interaction networks derived from PD-risk genes and PD-associated SNPs identified convergent impacts on biological pathways and phenotypes, connecting PD with established co-occurring traits, including non-motor symptoms. These findings hold promise for therapeutic development. In conclusion, while distinct sets of genes likely influence PD risk and outcomes, the existence of genes in common and intersecting pathways associated with other traits suggests that they may contribute to both increased PD risk and symptom heterogeneity observed in people with Parkinson's.
Language	English
Publishing date	2024-01-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2819218-7
ISSN	2373-8057
ISSN	2373-8057
DOI	10.1038/s41531-024-00638-w
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Identification of 27 allele-specific regulatory variants in Parkinson's disease using a massively parallel reporter assay.

Farrow, Sophie L / Gokuladhas, Sreemol / Schierding, William / Pudjihartono, Michael / Perry, Jo K / Cooper, Antony A / O'Sullivan, Justin M

NPJ Parkinson's disease

2024 Volume 10, Issue 1, Page(s) 44

Abstract: Genome wide association studies (GWAS) have identified a number of genomic loci that are associated with Parkinson's disease (PD) risk. However, the majority of these variants lie in non-coding regions, and thus the mechanisms by which they influence ... ...

Abstract	Genome wide association studies (GWAS) have identified a number of genomic loci that are associated with Parkinson's disease (PD) risk. However, the majority of these variants lie in non-coding regions, and thus the mechanisms by which they influence disease development, and/or potential subtypes, remain largely elusive. To address this, we used a massively parallel reporter assay (MPRA) to screen the regulatory function of 5254 variants that have a known or putative connection to PD. We identified 138 loci with enhancer activity, of which 27 exhibited allele-specific regulatory activity in HEK293 cells. The identified regulatory variant(s) typically did not match the original tag variant within the PD associated locus, supporting the need for deeper exploration of these loci. The existence of allele specific transcriptional impacts within HEK293 cells, confirms that at least a subset of the PD associated regions mark functional gene regulatory elements. Future functional studies that confirm the putative targets of the empirically verified regulatory variants will be crucial for gaining a greater understanding of how gene regulatory network(s) modulate PD risk.
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2819218-7
ISSN	2373-8057
ISSN	2373-8057
DOI	10.1038/s41531-024-00659-5
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Article: Integrating Multimorbidity into a Whole-Body Understanding of Disease Using Spatial Genomics.

Gokuladhas, Sreemol / Zaied, Roan E / Schierding, William / Farrow, Sophie / Fadason, Tayaza / O'Sullivan, Justin M

Results and problems in cell differentiation

2022 Volume 70, Page(s) 157–187

Abstract: Multimorbidity is characterized by multidimensional complexity emerging from interactions between multiple diseases across levels of biological (including genetic) and environmental determinants and the complex array of interactions between and within ... ...

Abstract	Multimorbidity is characterized by multidimensional complexity emerging from interactions between multiple diseases across levels of biological (including genetic) and environmental determinants and the complex array of interactions between and within cells, tissues and organ systems. Advances in spatial genomic research have led to an unprecedented expansion in our ability to link alterations in genome folding with changes that are associated with human disease. Studying disease-associated genetic variants in the context of the spatial genome has enabled the discovery of transcriptional regulatory programmes that potentially link dysregulated genes to disease development. However, the approaches that have been used have typically been applied to uncover pathological molecular mechanisms occurring in a specific disease-relevant tissue. These forms of reductionist, targeted investigations are not appropriate for the molecular dissection of multimorbidity that typically involves contributions from multiple tissues. In this perspective, we emphasize the importance of a whole-body understanding of multimorbidity and discuss how spatial genomics, when integrated with additional omic datasets, could provide novel insights into the molecular underpinnings of multimorbidity.
MeSH term(s)	Humans ; Multimorbidity ; Genomics/methods ; Gene Expression Regulation
Language	English
Publishing date	2022-11-08
Publishing country	Germany
Document type	Journal Article
ISSN	0080-1844
ISSN	0080-1844
DOI	10.1007/978-3-031-06573-6_5
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Article ; Online: Unravelling the Shared Genetic Mechanisms Underlying 18 Autoimmune Diseases Using a Systems Approach.

Gokuladhas, Sreemol / Schierding, William / Golovina, Evgeniia / Fadason, Tayaza / O'Sullivan, Justin

Frontiers in immunology

2021 Volume 12, Page(s) 693142

Abstract: Autoimmune diseases (AiDs) are complex heterogeneous diseases characterized by hyperactive immune responses against self. Genome-wide association studies have identified thousands of single nucleotide polymorphisms (SNPs) associated with several AiDs. ... ...

Abstract	Autoimmune diseases (AiDs) are complex heterogeneous diseases characterized by hyperactive immune responses against self. Genome-wide association studies have identified thousands of single nucleotide polymorphisms (SNPs) associated with several AiDs. While these studies have identified a handful of pleiotropic loci that confer risk to multiple AiDs, they lack the power to detect shared genetic factors residing outside of these loci. Here, we integrated chromatin contact, expression quantitative trait loci and protein-protein interaction (PPI) data to identify genes that are regulated by both pleiotropic and non-pleiotropic SNPs. The PPI analysis revealed complex interactions between the shared and disease-specific genes. Furthermore, pathway enrichment analysis demonstrated that the shared genes co-occur with disease-specific genes within the same biological pathways. In conclusion, our results are consistent with the hypothesis that genetic risk loci associated with multiple AiDs converge on a core set of biological processes that potentially contribute to the emergence of polyautoimmunity.
MeSH term(s)	Autoimmune Diseases/diagnosis ; Autoimmune Diseases/genetics ; Autoimmune Diseases/immunology ; Autoimmunity/genetics ; Databases, Genetic ; Gene Regulatory Networks ; Genetic Predisposition to Disease ; Genomics ; Humans ; Phenotype ; Polymorphism, Single Nucleotide ; Protein Interaction Maps ; Quantitative Trait Loci ; Systems Biology
Language	English
Publishing date	2021-08-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.693142
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Article ; Online: Establishing gene regulatory networks from Parkinson's disease risk loci.

Farrow, Sophie L / Schierding, William / Gokuladhas, Sreemol / Golovina, Evgeniia / Fadason, Tayaza / Cooper, Antony A / O'Sullivan, Justin M

Brain : a journal of neurology

2022 Volume 145, Issue 7, Page(s) 2422–2435

Abstract: The latest meta-analysis of genome-wide association studies identified 90 independent variants across 78 genomic regions associated with Parkinson's disease, yet the mechanisms by which these variants influence the development of the disease remains ... ...

Abstract	The latest meta-analysis of genome-wide association studies identified 90 independent variants across 78 genomic regions associated with Parkinson's disease, yet the mechanisms by which these variants influence the development of the disease remains largely elusive. To establish the functional gene regulatory networks associated with Parkinson's disease risk variants, we utilized an approach combining spatial (chromosomal conformation capture) and functional (expression quantitative trait loci) data. We identified 518 genes subject to regulation by 76 Parkinson's variants across 49 tissues, whicih encompass 36 peripheral and 13 CNS tissues. Notably, one-third of these genes were regulated via trans-acting mechanisms (distal; risk locus-gene separated by >1 Mb, or on different chromosomes). Of particular interest is the identification of a novel trans-expression quantitative trait loci-gene connection between rs10847864 and SYNJ1 in the adult brain cortex, highlighting a convergence between familial studies and Parkinson's disease genome-wide association studies loci for SYNJ1 (PARK20) for the first time. Furthermore, we identified 16 neurodevelopment-specific expression quantitative trait loci-gene regulatory connections within the foetal cortex, consistent with hypotheses suggesting a neurodevelopmental involvement in the pathogenesis of Parkinson's disease. Through utilizing Louvain clustering we extracted nine significant and highly intraconnected clusters within the entire gene regulatory network. The nine clusters are enriched for specific biological processes and pathways, some of which have not previously been associated with Parkinson's disease. Together, our results not only contribute to an overall understanding of the mechanisms and impact of specific combinations of Parkinson's disease variants, but also highlight the potential impact gene regulatory networks may have when elucidating aetiological subtypes of Parkinson's disease.
MeSH term(s)	Adult ; Gene Regulatory Networks/genetics ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Genomics ; Humans ; Parkinson Disease/genetics
Language	English
Publishing date	2022-02-10
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awac022
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Article ; Online: Assigning function to SNPs: Considerations when interpreting genetic variation.

Fadason, Tayaza / Farrow, Sophie / Gokuladhas, Sreemol / Golovina, Evgeniia / Nyaga, Denis / O'Sullivan, Justin M / Schierding, William

Seminars in cell & developmental biology

2021 Volume 121, Page(s) 135–142

Abstract: Assigning function to single nucleotide polymorphisms (SNPs) to understand the mechanisms that link genetic and phenotypic variation and disease is an area of intensive research that is necessary to contribute to the continuing development of precision ... ...

Abstract	Assigning function to single nucleotide polymorphisms (SNPs) to understand the mechanisms that link genetic and phenotypic variation and disease is an area of intensive research that is necessary to contribute to the continuing development of precision medicine. However, despite the apparent simplicity that is captured in the name SNP - 'single nucleotide' changes are not easy to functionally characterize. This complexity arises from multiple features of the genome including the fact that function is development and environment specific. As such, we are often fooled by our terminology and underlying assumptions that there is a single function for a SNP. Here we discuss some of what is known about SNPs, their functions and how we can go about characterizing them.
MeSH term(s)	Genetic Variation/genetics ; Humans ; Machine Learning/standards ; Polymorphism, Single Nucleotide/genetics ; Precision Medicine/methods
Language	English
Publishing date	2021-08-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2021.08.008
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Article: Shared Regulatory Pathways Reveal Novel Genetic Correlations Between Grip Strength and Neuromuscular Disorders.

Gokuladhas, Sreemol / Schierding, William / Cameron-Smith, David / Wake, Melissa / Scotter, Emma L / O'Sullivan, Justin

Frontiers in genetics

2020 Volume 11, Page(s) 393

Abstract: Muscle weakness is a common consequence of both aging (sarcopenia) and neuromuscular disorders (NMD). Whilst genome-wide association (GWA) studies have identified genetic variants associated with grip strength (GS; measure of muscle strength/weakness) ... ...

Abstract	Muscle weakness is a common consequence of both aging (sarcopenia) and neuromuscular disorders (NMD). Whilst genome-wide association (GWA) studies have identified genetic variants associated with grip strength (GS; measure of muscle strength/weakness) and NMDs, including multiple sclerosis (MS), myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS), it is not known whether there are common mechanisms between these phenotypes. To examine this, we have integrated GS and NMD associated genetic variants (single nucleotide polymorphisms; SNPs) in a multimorbid analysis that leverages high-throughput chromatin interaction (Hi-C) data and expression quantitative trait loci data to identify target genes (i.e., SNP-mediated gene regulation). Biological pathways enriched by these genes were then identified using next-generation pathway enrichment analysis. Lastly, druggable genes were identified using drug gene interaction (DGI) database. We identified gene regulatory mechanisms associated with GS, MG, MS, and ALS. The SNPs associated with GS regulate a subset of genes that are also regulated by the SNPs of MS, MG, and ALS. Yet, we did not find any genes commonly regulated by all four phenotype associated SNPs. By contrast, we identified significant enrichment in three pathways (mTOR signaling, axon guidance, and alcoholism) that are commonly affected by the gene regulatory mechanisms associated with all four phenotypes. 13% of the genes we identified were known drug targets, and GS shares at least one druggable gene and pathway with each of the NMD phenotypes. We have identified significant biological overlaps between GS and NMD, demonstrating the potential for spatial genetic analysis to identify common mechanisms between potential multimorbid phenotypes. Collectively, our results form the foundation for a shift from a gene to a pathway-based approach to the rationale design of therapeutic interventions and treatments for NMD.
Language	English
Publishing date	2020-04-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2020.00393
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Article ; Online: A transcription regulatory network within the ACE2 locus may promote a pro-viral environment for SARS-CoV-2 by modulating expression of host factors

Fadason, Tayaza / Gokuladhas, Sreemol / Golovina, Evgeniia / Ho, Daniel / Farrow, Sophie / Nyaga, Denis / Pan, Hong / Karnani, Neerja / Wong, Conroy / Cooper, Antony / Schierding, William / O’Sullivan, Justin M.

bioRxiv

Abstract: Introduction A novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was recently identified as the pathogen responsible for the COVID-19 outbreak. SARS-CoV-2 triggers severe pneumonia, which leads to acute respiratory distress syndrome and ... ...

Abstract	Introduction A novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was recently identified as the pathogen responsible for the COVID-19 outbreak. SARS-CoV-2 triggers severe pneumonia, which leads to acute respiratory distress syndrome and death in severe cases. As reported, SARS-CoV-2 is 80% genetically identical to the 2003 SARS-CoV virus. Angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for entry of both SARS-CoV and SARS-CoV-2 into human cells. ACE2 is normally expressed in cardiovascular and lung type II alveolar epithelial cells, where it positively modulates the RAS system that regulates blood flow, pressure, and fluid homeostasis. Thus, virus-induced reduction of ACE2 gene expression is considered to make a significant contribution to severe acute respiratory failure. Chromatin remodeling plays a significant role in the regulation of ACE2 gene expression and the activity of regulatory elements within the genome. Methods Here, we integrated data on physical chromatin interactions within the genome organization (captured by Hi-C) with tissue-specific gene expression data to identify spatial expression quantitative trait loci (eQTLs) and thus regulatory elements located within the ACE2 gene. Results We identified regulatory elements within ACE2 that control the expression of PIR, CA5B, and VPS13C in the lung. The gene products of these genes are involved in inflammatory responses, de novo pyrimidine and polyamine synthesis, and the endoplasmic reticulum, respectively. Conclusion Our study, although limited by the fact that the identification of the regulatory interactions is putative until proven by targeted experiments, supports the hypothesis that viral silencing of ACE2 alters the activity of gene regulatory regions and promotes an intra-cellular environment suitable for viral replication.
Keywords	covid19
Publisher	BioRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.04.14.042002
Database	COVID19

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Article ; Online: A transcription regulatory network within the ACE2 locus may promote a pro-viral environment for SARS-CoV-2 by modulating expression of host factors

bioRxiv

Abstract: Introduction: A novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was recently identified as the pathogen responsible for the COVID-19 outbreak. SARS-CoV-2 triggers severe pneumonia, which leads to acute respiratory distress syndrome and ...

Abstract	Introduction: A novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was recently identified as the pathogen responsible for the COVID-19 outbreak. SARS-CoV-2 triggers severe pneumonia, which leads to acute respiratory distress syndrome and death in severe cases. As reported, SARS-CoV-2 is 80% genetically identical to the 2003 SARS-CoV virus. Angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for entry of both SARS-CoV and SARS-CoV-2 into human cells. ACE2 is normally expressed in cardiovascular and lung type II alveolar epithelial cells, where it positively modulates the RAS system that regulates blood flow, pressure, and fluid homeostasis. Thus, virus-induced reduction of ACE2 gene expression is considered to make a significant contribution to severe acute respiratory failure. Chromatin remodelling plays a significant role in the regulation of ACE2 gene expression and the activity of regulatory elements within the genome. Methods: Here, we integrated data on physical chromatin interactions within the genome organization (captured by Hi-C) with tissue-specific gene expression data to identify spatial expression quantitative trait loci (eQTLs) and thus regulatory elements located within the ACE2 gene. Results: We identified regulatory elements within ACE2 that control the expression of PIR, CA5B, and VSP13C in the lung. The gene products of these genes are involved in inflammatory responses, de novo pyrimidine and polyamine synthesis, and the endoplasmic reticulum, respectively. Conclusion: Our study, although limited by the fact that the identification of the regulatory interactions is putative until proven by targeted experiments, supports the hypothesis that viral silencing of ACE2 alters the activity of gene regulatory regions and promotes an intra-cellular environment suitable for viral replication.
Keywords	covid19
Language	English
Publishing date	2020-04-15
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.04.14.042002
Database	COVID19

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Article: Discovering genetic mechanisms underlying the co-occurrence of Parkinson's disease and non-motor traits.

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Article: Identification of 27 allele-specific regulatory variants in Parkinson's disease using a massively parallel reporter assay.

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Article: Integrating Multimorbidity into a Whole-Body Understanding of Disease Using Spatial Genomics.

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Article ; Online: Unravelling the Shared Genetic Mechanisms Underlying 18 Autoimmune Diseases Using a Systems Approach.

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Article ; Online: Establishing gene regulatory networks from Parkinson's disease risk loci.

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Article ; Online: Assigning function to SNPs: Considerations when interpreting genetic variation.

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Article: Shared Regulatory Pathways Reveal Novel Genetic Correlations Between Grip Strength and Neuromuscular Disorders.

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Article ; Online: A transcription regulatory network within the ACE2 locus may promote a pro-viral environment for SARS-CoV-2 by modulating expression of host factors

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Article ; Online: A transcription regulatory network within the ACE2 locus may promote a pro-viral environment for SARS-CoV-2 by modulating expression of host factors

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