Update on genetics of amyotrophic lateral sclerosis DOI
Dávid Brenner, Axel Freischmidt

Current Opinion in Neurology, Journal Year: 2022, Volume and Issue: 35(5), P. 672 - 677

Published: Aug. 8, 2022

Purpose of review ALS genetics are highly dynamic and great interest for the research community. Each year, by using ever-growing datasets cutting-edge methodology, an array novel ALS-associated genes downstream pathomechanisms discovered. The increasing plenty complexity insights warrants regular summary by-reviews. Recent findings Most recent disease gene discoveries constitute candidate risk SPTLC1 , KANK1 CAV1 HTT WDR7 as well seven loci. Cell type functional enrichment analyses enlighten genetic basis selective motor neuron vulnerability in demonstrating high expression cortical neurons highlight pathogenic significance cell-autonomous processes. Major pathomechanistic have been gained regarding known genes/proteins, specifically C9orf72 TDP43, ANXA11 KIF5A . first ASO-based gene-specific therapy trials familial forms yielded equivocal results stressing re-evaluation linked to SOD1 mutations. Summary molecular is increasingly examined on single-cell resolution. In past 2 years, understanding mechanisms several TDP-43 proteinopathy has considerably extended. These will result specific approaches sporadic subtypes.

Language: Английский

Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation DOI Open Access
Richard J. Mead,

Ning Shan,

H. Joseph Reiser

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 22(3), P. 185 - 212

Published: Dec. 21, 2022

Language: Английский

Citations

250
Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases DOI Creative Commons
Niek de Klein, Ellen Tsai, Martijn Vochteloo

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(3), P. 377 - 388

Published: Feb. 23, 2023

Identification of therapeutic targets from genome-wide association studies (GWAS) requires insights into downstream functional consequences. We harmonized 8,613 RNA-sequencing samples 14 brain datasets to create the MetaBrain resource and performed cis- trans-expression quantitative trait locus (eQTL) meta-analyses in multiple region- ancestry-specific (n ≤ 2,759). Many 16,169 cortex cis-eQTLs were tissue-dependent when compared with blood cis-eQTLs. inferred cell types for 3,549 by interaction analysis. prioritized 186 31 brain-related traits using Mendelian randomization co-localization including 40 an type, such as a neuron-specific cis-eQTL (CYP24A1) sclerosis. further describe 737 trans-eQTLs 526 unique variants 108 genes. used brain-specific gene-co-regulation networks link GWAS loci prioritize additional genes five central nervous system diseases. This study represents valuable post-GWAS research on

Language: Английский

Citations

143
Locus for severity implicates CNS resilience in progression of multiple sclerosis DOI
Adil Harroud, Pernilla Stridh, Jacob L. McCauley

et al.

Nature, Journal Year: 2023, Volume and Issue: 619(7969), P. 323 - 331

Published: June 28, 2023

Language: Английский

Citations

123
iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders DOI Creative Commons
Hideyuki Okano, Satoru Morimoto

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(2), P. 189 - 208

Published: Feb. 1, 2022

Language: Английский

Citations

120
Genetic control of RNA splicing and its distinct role in complex trait variation DOI Creative Commons
Ting Qi, Yang Wu,

Hailing Fang

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(9), P. 1355 - 1363

Published: Aug. 18, 2022

Abstract Most genetic variants identified from genome-wide association studies (GWAS) in humans are noncoding, indicating their role gene regulation. Previous have shown considerable links of GWAS signals to expression quantitative trait loci (eQTLs) but the other regulatory mechanisms, such as splicing QTLs (sQTLs), underexplored. Here, we introduce an sQTL mapping method,  t esting for h eterogeneity between is oform-eQ TL e ffects (THISTLE), with improved power over competing methods. Applying THISTLE together a complementary strategy brain transcriptomic ( n = 2,865) and genotype data, 12,794 genes cis -sQTLs at P < 5 × 10 −8 , approximately 61% which were distinct eQTLs. Integrating data into 12 brain-related complex traits (including diseases), 244 associated through -sQTLs, could not be discovered using corresponding eQTL data. Our study demonstrates most sQTLs regulation transcription variation.

Language: Английский

Citations

120
Amyotrophic lateral sclerosis: translating genetic discoveries into therapies DOI
Fulya Akçimen, Elia R. Lopez, John E. Landers

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(9), P. 642 - 658

Published: April 6, 2023

Language: Английский

Citations

108
Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis DOI Creative Commons
Sai Zhang, Johnathan Cooper‐Knock, Annika K. Weimer

et al.

Neuron, Journal Year: 2022, Volume and Issue: 110(6), P. 992 - 1008.e11

Published: Jan. 18, 2022

Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes represent 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, rare variant analyses demonstrated the significance candidate healthy diseased brain tissues. Genetic convergence between common variation highlighted KANK1 as new ALS gene. Reproducing patient mutations human led neurotoxicity TDP-43 mislocalization, hallmark pathology ALS, downstream axonal dysfunction. can be readily applied other diseases.

Language: Английский

Citations

97
Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy DOI Creative Commons
Naoki Suzuki, Ayumi Nishiyama, Hitoshi Warita

et al.

Journal of Human Genetics, Journal Year: 2022, Volume and Issue: 68(3), P. 131 - 152

Published: June 13, 2022

Abstract Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS motor neurons. success antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a neuron disease, has triggered paradigm shift developing therapies. causative genes and disease-modifying genes, including those sporadic ALS, have been identified one after another. Thus, the freedom target choice for gene expanded by ASO strategy, new avenues therapeutic development. Tofersen superoxide dismutase 1 (SOD1) was pioneer ALS. Improving protocols devising early interventions are vital. In this review, we updated knowledge We summarized genetic mutations familial their clinical features, focusing on SOD1 , fused sarcoma (FUS) transacting response DNA-binding protein. frequency C9ORF72 mutation low Japan, unlike Europe United States, while FUS more common, indicating vary ethnicity. A genome-wide association study revealed which could be novel therapy. current status prospects development were discussed, ethical issues. Furthermore, discussed potential axonal pathology as targets from perspective intervention, intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired transport, aberrant cytoskeleton, axon branching. simultaneously discuss important pathological states cell bodies: persistent stress granules, disrupted nucleocytoplasmic cryptic splicing. based elucidation intervention molecular expected become strategy

Language: Английский

Citations

92
GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture DOI Creative Commons
Remi Stevelink, Ciarán Campbell, Siwei Chen

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(9), P. 1471 - 1482

Published: Aug. 31, 2023

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes epilepsy, 52,538 controls. We identify 26 significant loci, 19 specific genetic generalized epilepsy (GGE). implicate 29 likely causal genes underlying these loci. SNP-based heritability analyses show that common variants explain between 39.6% 90% risk for GGE its subtypes. Subtype analysis revealed markedly different architectures focal epilepsies. Gene-set signals synaptic processes in both excitatory inhibitory neurons the brain. Prioritized candidate overlap with monogenic targets antiseizure medications. Finally, leverage our results alternate drugs predicted efficacy if repurposed treatment.

Language: Английский

Citations

84
Integrative transcriptomic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes DOI
Jack Humphrey, Sanan Venkatesh,

Rahat Hasan

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 26(1), P. 150 - 162

Published: Dec. 8, 2022

Language: Английский

Citations

76