Decision: From genetic variation to precision medicine — R0/PR5 DOI Creative Commons

Panagiotis I. Sergouniotis,

Tomas Fitzgerald, Ewan Birney

et al.

Published: Oct. 21, 2022

Genetics has been an important tool for discovering new aspects of biology across life. In humans, there is growing momentum behind the application this knowledge to drive innovation in clinical care, most notably through developments precision medicine. Nowhere impact genetics on practice more striking than field rare disorders. For these conditions, individual disease susceptibility influenced by DNA sequence variation a single or small number genes. contrast, common disorders are multifactorial and caused complex interplay multiple genetic, environmental stochastic factors. The longstanding division human into components obscured continuum traits echoes century-old debate between Mendelian biometric views genetics. article, we discuss differences data concepts Opportunities unify two areas noted importance adopting holistic perspective that integrates diverse genetic factors discussed.

Language: Английский

The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource DOI Creative Commons
Elliot Sollis, Abayomi Mosaku, Ala Abid

et al.

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 51(D1), P. D977 - D985

Published: Oct. 20, 2022

Abstract The NHGRI-EBI GWAS Catalog (www.ebi.ac.uk/gwas) is a FAIR knowledgebase providing detailed, structured, standardised and interoperable genome-wide association study (GWAS) data to >200 000 users per year from academic research, healthcare industry. contains variant-trait associations supporting metadata for >45 published across >5000 human traits, >40 full P-value summary statistics datasets. Content curated publications or acquired via author submission of prepublication through new portal validation tool. volume has vastly increased in recent years. We have updated our software meet this scaling challenge enable rapid release submitted statistics. scope the repository expanded include additional types high interest community, including sequencing-based GWAS, gene-based analyses copy number variation analyses. Community outreach shared datasets under-represented e.g. cancer, we continue contribute awareness lack population diversity GWAS. Interoperability been enhanced links other resources Polygenic Score International Mouse Phenotyping Consortium, refinements trait annotation, development standard format data.

Language: Английский

Citations

1026
From genetic variation to precision medicine DOI Creative Commons

Panagiotis I. Sergouniotis,

Tomas Fitzgerald, Ewan Birney

et al.

Cambridge Prisms Precision Medicine, Journal Year: 2023, Volume and Issue: 1

Published: Jan. 1, 2023

Abstract Genetics has been an important tool for discovering new aspects of biology across life. In humans, there is growing momentum behind the application this knowledge to drive innovation in clinical care, most notably through developments precision medicine. Nowhere impact genetics on practice more striking than field rare disorders. For these conditions, individual disease susceptibility influenced by DNA sequence variation a single or small number genes. contrast, common disorders are multifactorial and caused complex interplay multiple genetic, environmental stochastic factors. The longstanding division human into components obscured continuum traits echoes century-old debate between Mendelian biometric views genetics. article, we discuss differences data concepts Opportunities unify two areas noted importance adopting holistic perspective that integrates diverse genetic factors discussed.

Language: Английский

Citations

16
Citrus genomic resources unravel putative genetic determinants of Huanglongbing pathogenicity DOI Creative Commons
Yuxia Gao, Jin Xu, Zhilong Li

et al.

iScience, Journal Year: 2023, Volume and Issue: 26(2), P. 106024 - 106024

Published: Jan. 23, 2023

Citrus HLB caused by Candidatus Liberibacter asiaticus is a pathogen-triggered immune disease. Here, we identified putative genetic determinants of pathogenicity integrating citrus genomic resources to characterize the pan-genome accessions that differ in their response HLB. Genome-wide association mapping and analysis allele-specific expression between susceptible, tolerant, resistant further refined candidates underlying We first developed phased diploid assembly sinensis 'Newhall' genome produced resequencing data for 91 These were combined with previous from 356 genome-wide response. Genes associated host response, ROS production, antioxidants. Overall, this study has provided significant resource candidate genes be explored understand pathogenicity.

Language: Английский

Citations

15
Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease DOI Creative Commons
Laura Xicota, Stephanie Cosentino, Badri N. Vardarajan

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(4), P. 2670 - 2679

Published: Feb. 21, 2024

Late-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering unique opportunity to investigate LOAD genetics.

Language: Английский

Citations

5
Workshop proceedings: GWAS summary statistics standards and sharing DOI Creative Commons
Jacqueline MacArthur, Annalisa Buniello, Laura W. Harris

et al.

Cell Genomics, Journal Year: 2021, Volume and Issue: 1(1), P. 100004 - 100004

Published: Oct. 1, 2021

Genome-wide association studies (GWASs) have enabled robust mapping of complex traits in humans. The open sharing GWAS summary statistics (SumStats) is essential facilitating the larger meta-analyses needed for increased power resolving genetic basis disease. However, most SumStats are not readily accessible because limited and a lack defined standards. With aim increasing availability, quality, utility SumStats, National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Catalog organized community workshop to address standards, infrastructure, incentives required promote enable sharing. We evaluated barriers sharing, both technological sociological, developed an action plan those challenges ensure that study metadata findable, accessible, interoperable, reusable (FAIR). encourage early deposition datasets as recognized central repository. recommend standard requirements reporting elements formats accompanying guidelines standards submission Catalog. Finally, we provide recommendations enable, promote, incentivize broader data FAIRness order advance genomic medicine.

Language: Английский

Citations

31
Opportunities and challenges for the use of common controls in sequencing studies DOI
Genevieve L. Wojcik, Jessica I. Murphy, Jacob Edelson

et al.

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(11), P. 665 - 679

Published: May 17, 2022

Language: Английский

Citations

21
The Genetic Side of the Mood: A Scientometric Review of the Genetic Basis of Mood Disorders DOI Open Access
Giovanni Bonacina, Alessandro Carollo, Gianluca Esposito

et al.

Genes, Journal Year: 2023, Volume and Issue: 14(2), P. 352 - 352

Published: Jan. 30, 2023

Mood disorders are highly heritable psychiatric disorders. Over the years, many genetic polymorphisms have been identified to pose a higher risk for development of mood To overview literature on genetics disorders, scientometric analysis was performed sample 5342 documents downloaded from Scopus. The most active countries and impactful in field were identified. Furthermore, total 13 main thematic clusters emerged literature. From qualitative inspection clusters, it that research interest moved monogenic polygenic framework. Researchers study single genes early 1990s conducting genome-wide association studies around 2015. In this way, overlaps between other conditions too. 2010s, interaction environmental factors as pivotal understanding provides valuable insight into past recent trends sheds light onto future lines research.

Language: Английский

Citations

12
Editorial: Advancements and prospects of genome-wide association studies DOI Creative Commons
Ayo P. Doumatey, Yafang Li, Juan Carlos Fernández-López

et al.

Frontiers in Genetics, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 19, 2025

Since the very first Genome-Wide association study was published in 2005 followed by pivotal manuscript Wellcome Trust Case Control Consortium (WTCCC) 2007 (Klein et al., 2005;Wellcome Control, 2007), several thousands of studies (GWAS) have been conducted (>45 000) and yielded a myriad loci associated with diverse human phenotypic traits or diseases (>5000) (Sollis 2023). These not only shed light on involvement common variants but also discovered important insights into biology (Uffelmann, 2021) The field GWAS has seen tremendous advances both technologically methodologically. For example, facilitated single nucleotide polymorphisms (SNPs)-arrays containing couple thousand hundred to 2 million SNPs (Visscher 2017). ability impute untyped increased marker density, improved statistical power GWAS, enabled large-scale metaanalyses across populations, aided fine-mapping regions interest genetic (Cahoon 2024;Zhihui Zhang, 2022). Additionally, sequencing technologies drop cost, latest follow-up sequence-based allowed for assessment low-frequency rare (Acar 2023;McMahon 2021;Pan Despite all Genomics, global populations are evenly represented GWAS. mainly limited European descent could exacerbate existing health disparities implementation precision medicine (Doumatey push genomic equity representation biomedical research led initiatives such as the1000 Genomes, Human Heredity& Health (H3Africa), Trans-omics Precision Medicine (TOPMed), All Us recent years (Auton 2015;Investigators, 2024;Peprah 2017;Taliun 2021). Some these imputation references, 1000 genomes TOPMed (Kowalski 2019). Others, H3Africa, helped develop population-specific genotype arrays, thus improving discovery populations. In this topic, Brandenburg, JT al. used custom array enriched African variants, H3A genotyping array, largest urinary albumin-to-creatinine ratio (UACR), biomarker kidney disease, Sub Saharan Africans living different continent non-resident individuals ancestry (UK BioBank) American cohorts (CKD-Gen Ancestry). authors identified two novel UACR (BMP6, HBB), they replicated three out 60 known UACR-associated previously multiancestry studies. performed polygenic score (PGS) comparison analyses evaluate transferability PGS derived from non-African multi-ancestry https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1372042/full).A comprehensive review Bruner, S.W. al, topic underscored need account population-biased findings various ancestral which should, turn, address replication challenges especially highlighted advancements methods techniques available resources conduct functional annotations mechanistic "variant-to-function They described (e.g. epigenetic annotations, pathway network analyses, quantitative trait loci) validations (reporter assays, genome editing, animal models) approaches characterize effector genes. https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1375481/full. were included topic. Abbas, M ancestries, leveraged expression locus (eQTL) understand mechanisms connecting phenotypes (ref. Abbas Brandenburg al.) using strategies. al subsequently carried annotation lead (SNP) relevant tissue profile (glomerular tubulointerstitial tissues) cis-eQTL analysis. contrast, differential analysis identify mRNAs that differentially expressed between Low-Density Lipoproteins, LDL groups (low tertile vs upper tertile), then extracted SNP cis region each mRNA perform an eQTL eQTLs significantly overlapped catalogue database. further decipher relationships transcriptomics, genomics, phenotype. Noteworthy, African-specific TTC38 Americans. upregulated elevated LDL. https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2024.1345541/full.Animal models proposed variant-to-function method discovery. can take many effectively underpinnings humans. one studies, Fowler S heterogeneous stock (HS) intraocular pressure (IOP). indicated few advantages conducting rats like IOP: 1) control environmental variables affect IOP humans, 2) humans share similar anatomical developmental characteristics eyes aqueous outflow pathway), ideal model pathophysiology ophthalmologic disorders, 3) tissues phenotyping gene be easily collected. combination ~1800 HS 5 candidate genes, (Ctsc2 Plekhf2-never reported studies); concluded use resulted new provide molecular basis IOP. https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.1029058/full linked trait/disease, cannot always establish causality. Thus, epidemiology-based Mendelian randomization (MR) causality instrumental variables, risk factors lifestyle (Benn & Nordestgaard, 2018). Lin, X strategy causal relationship reproductive age at menopause, menarche, live birth) bone density. Their suggest early menopause late childbirth may

Language: Английский

Citations

0
Genetic Diversity and Crop Genome‐wide Association Studies to Identify Biofortified Traits for Micronutrients DOI

R Praviinkumar

Published: Feb. 27, 2025

Language: Английский

Citations

0
CREB3 gain of function variants protect against ALS DOI Creative Commons
Salim Megat,

Christine Marques,

Marina Hernán-Godoy

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 26, 2025

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly evolving neurodegenerative disease arising from the loss of glutamatergic corticospinal neurons (CSN) cholinergic motoneurons (MN). Here, we performed comparative cross-species transcriptomics CSN using published snRNA-seq data motor cortex ALS control postmortem tissues, longitudinal RNA-seq on purified male Sod1G86R mice. We report that undergo ER stress altered mRNA translation, identify transcription factor CREB3 its regulatory network as resilience marker ALS, not only amongst vulnerable neuronal populations, but across all populations well other cell types. Using genetic epidemiologic analyses further rare variant CREB3R119G (rs11538707) positive modifier in ALS. Through gain function, decreases risk developing progression rate patients. Cross-species unravels markers Genetics epidemiology protective CREB3R119G.

Language: Английский

Citations

0