Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Cirulli, Elizabeth T.; Lasseigne, Brittany N.; Petrovski, Slavé; Sapp, Peter C.; Dion, Patrick A.; Leblond, Claire S.; Couthouis, Julien; Lu, Yifan; Wang, Quanli; Krueger, Brian J.; Ren, Zhongfa; Keebler, Jonathan E. M.; Han, Yujun; Levy, Shawn; Boone, Braden; Wimbish, Jack R.; Waite, Lindsay L.; Jones, Lindsay Waite; Carulli, John P.; Williams, Kelly L.; Staropoli, John F.; Xin, Winnie; Chesi, Alessandra; Raphael, Alya R.; McKenna‐Yasek, Diane; Cady, Janet; Jong, J.M.B.V. de; Kenna, Kevin P.; Smith, Bradley N.; Topp, Simon; Miller, Jack W.; Gkazi, Athina Soragia; Al‐Chalabi, Ammar; Berg, Leonard H van den; Veldink, Jan H.; Silani, Vincenzo; Ticozzi, Nicola; Shaw, Christopher E.; Baloh, Robert H.; Appel, Stanley H.; Simpson, Ericka; Lagier‐Tourenne, Clotilde; Pulst, Stefan M.; Gibson, Summer; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Grossman, Murray; Shneider, Neil A.; Chung, Wendy K.; Ravits, John; Glass, Jonathan D.; Sims, Katherine B.; Deerlin, Vivianna M. Van; Maniatis, Tom; Hayes, Sebastian; Ordureau, Alban; Swarup, Sharan; Landers, John E.; Baas, Frank; Allen, Andrew S.; Bedlack, Richard; Harper, J. Wade; Gitler, Aaron D.; Rouleau, Guy A.; Brown, Robert H.; Harms, Matthew B.; Cooper, Gregory M.; Harris, Tim; Myers, R; Goldstein, David B.

doi:10.1126/science.aaa3650

Cited by 849 publications

(790 citation statements)

References 61 publications

(82 reference statements)

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“…From an empirical perspective, our findings suggest that re-sequencing in large samples is likely the best way forward in the face of the allelic heterogeneity imposed by the presence of rare alleles of large effect. Resequencing of candidate genes [77][78][79][80] and exomes [40,[81][82][83][84][85][86] in case-control panels have observed an abundance of rare variants associated with case status. Here we show that under a model of mutation-selection balance on the genic level, neither current single-marker nor popular multi-marker tests are especially powerful at detecting large genomic regions harboring multiple risk variants (Fig 3).…”

Section: Resultsmentioning

confidence: 99%

A model of compound heterozygous, loss-of-function alleles is broadly consistent with observations from complex-disease GWAS datasets

Sanjak

Long

Thornton

2016

Preprint

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The genetic component of complex disease risk in humans remains largely unexplained. A corollary is that the allelic spectrum of genetic variants contributing to complex disease risk is unknown. Theoretical models that relate population genetic processes to the maintenance of genetic variation for quantitative traits may suggest profitable avenues for future experimental design. Here we use forward simulation to model a genomic region evolving under a balance between recurrent deleterious mutation and Gaussian stabilizing selection. We consider multiple genetic and demographic models, and several different methods for identifying genomic regions harboring variants associated with complex disease risk. We demonstrate that the model of gene action, relating genotype to phenotype, has a qualitative effect on several relevant aspects of the population genetic architecture of a complex trait. In particular, the genetic model impacts genetic variance component partitioning across the allele frequency spectrum and the power of statistical tests. Models with partial recessivity closely match the minor allele frequency distribution of significant hits from empirical genome-wide association studies without requiring homozygous effect sizes to be small. We highlight a particular gene-based model of incomplete recessivity that is appealing from first principles. Under that model, deleterious mutations in a genomic region partially fail to complement one another. This model of gene-based recessivity predicts the empirically observed inconsistency between twin and SNP based estimated of dominance heritability. Furthermore, this model predicts considerable levels of unexplained variance associated with intralocus epistasis. Our results suggest a need for improved statistical tools for region based genetic association and heritability estimation. Author SummaryGene action determines how mutations affect phenotype. When placed in an evolutionary context, the details of the genotype-to-phenotype model can impact the maintenance of genetic variation for complex traits. Likewise, non-equilibrium demographic history may affect patterns of genetic variation. Here, we explore the impact of genetic model and population growth on distribution of genetic variance across the allele frequency spectrum underlying risk for a complex disease. Using forward-in-time population genetic simulations, we show that the genetic model has important impacts on the composition of variation for complex disease risk in a population. We explicitly simulate genome-wide association studies (GWAS) and perform heritability estimation on population samples. A particular model of gene-based partial recessivity, based on allelic non-complementation, aligns well with empirical results. This model is congruent with the dominance variance estimates from both SNPs and twins, and the minor allele frequency distribution of GWAS hits.

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Section: Resultsmentioning

confidence: 99%

A model of compound heterozygous, loss-of-function alleles is broadly consistent with observations from complex-disease GWAS datasets

Sanjak

Long

Thornton

2016

Preprint

View full text Add to dashboard Cite

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“…In addition to its roles of degradating foreign pathogens (xenophagy) (Wild et al, 2011) and binding to protein aggregates (Korac et al, 2013), OPTN1 is found in neuronal inclusions of patients affected by ALS and other neurodegenerative diseases (Schwab et al, 2012;Mori et al, 2012). The role of OPTN1 in ALS has been further elucidated by the recent discovery of loss of function mutations in TBK1 gene in familial ALS cases (Cirulli et al, 2015). The interaction between TBK1 and OPTN1 is a key factor in autophagy and inflammation (Maruyama et al, 2010;Maruyama and Kawakami, 2013;Thomas et al, 2013;Kachaner et al, 2012).…”

Section: Accumulation Of Als Pathogenetic Proteins and Autophagymentioning

confidence: 99%

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mis

Brajkovic

Frattini

et al. 2016

Molecular and Cellular Neuroscience

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a b s t r a c tAutophagy is a lysosome-dependant intracellular degradation process that eliminates long-lived proteins as well as damaged organelles from the cytoplasm. An increasing body of evidence suggests that dysregulation of this system plays a pivotal role in the etiology and/or progression of neurodegenerative diseases including motor neuron disorders. Herein, we review the latest findings that highlight the involvement of autophagy in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the potential role of this pathway as a target of therapeutic purposes. Autophagy promotes the removal of toxic, cytoplasmic aggregate-prone pathogenetic proteins, enhances cell survival, and modulates inflammation. The existence of several drugs targeting this pathway can facilitate the translation of basic research to clinical trials for ALS and other motor neuron diseases..

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“…Because intracellular components released during necroptosis stimulate inflammation and immune responses, it is thought that necroptosis contributes to the development/progression of neurodegenerative diseases. Recently, Cirulli et al [33] compared the whole exome sequences between ALS and control, and found that the non-canonical IκB kinase family TANK-binding kinase 1 (TBK1) was a gene associated with ALS by interacting with ALS-related proteins, optineurin (OPTN) and p62. Furthermore, Ito et al [34] demonstrated that OPTN inhibited dysmyelination and axonal degeneration through suppressing receptorinteracting kinase 1 (RIPK1) and the downstream subsets are preferentially elicited in ALS has been elusive.…”

Section: Necroptosis and Its Implications In Alsmentioning

confidence: 99%

How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis?

Liu¹,

Zheng²,

Xin³

et al. 2017

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How to cite this article: Liu JF, Zheng OX, Xin JG, Chen HH, Xin JJ. How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis ? Neuroimmunol Neuroinflammation 2017;4:109-16. Abnormal immune response/inflammation is present in patients of amyotrophic lateral sclerosis (ALS). Autoimmune-related inflammation has been thought to be involved in the pathogenesis of ALS. However, how the abnormal immune responses are initiated, what specific immune cells and how these immune cells are involved in this disease have not been well understood. This is partly owing to two facts of ALS: late diagnosis and chronic nature. The late diagnosis makes it difficult to conclude whether the abnormal immune responses/inflammation is the cause or result of the disease. The chronic nature makes it difficult to determine the best timing for the detection of such autoimmune responses. To resolve these two challenges for research, the authors introduced motor nerve injury (facial nerve axotomy, FNA) into a pre-symptomatic mouse ALS model (8-week-old SOD1 G93A mice), which induces a readily detectable immune response in a predictable time period (3-14 days). The authors found that pre-symptomatic SOD1 G93A mice showed a higher basal level of T cell activation and Th17 cells than WT mice, which can be further increased by FNA. However, why these pro-inflammatory Th lymphocyte MinireviewThis is an open access article distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Cited by 849 publications

References 61 publications

A model of compound heterozygous, loss-of-function alleles is broadly consistent with observations from complex-disease GWAS datasets

A model of compound heterozygous, loss-of-function alleles is broadly consistent with observations from complex-disease GWAS datasets

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis?

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