Rare Variant Burden Analysis within Enhancers Identifies  &lt;i&gt;CAV1&lt;/i&gt; as a New ALS Risk Gene

Cooper‐Knock, Johnathan; Zhang, Sai; Kenna, Kevin P.; Moll, Tobias; Franklin, John; Allen, Samantha; Nezhad, Helia Ghahremani; Eitan, Chen; Hornstein, Eran; Elhaik, Eran; Celadova, Petra; Bose, Daniel; Farhan, Sali M.K.; Fishilevich, Simon; Lancet, Doron; Morrison, Karen E.; Shaw, Christopher E.; Al‐Chalabi, Ammar; Veldink, Jan H.; Kirby, Janine; Snyder, M; Shaw, Pamela J.

doi:10.2139/ssrn.3606796

Cited by 4 publications

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“…As an additional rare variant validation of the total set of RefMap ALS genes, we examined rare deleterious variation within enhancer regions. Enhancer regions were defined as previously described (Fishilevich et al, 2017;Cooper-Knock et al, 2020). Significant variants were identified based on evolutionary conservation, functional annotations, and population frequency (Ritchie et al, 2014;Huang et al, 2017;Rentzsch et al, 2019;Karczewski et al, 2020) (STAR Methods).…”

Section: Rare Variant Analysis Validates Refmap Genesmentioning

confidence: 99%

“…ALS GWASs to date have lost power by considering genetic variants in isolation, whereas in reality, a biological system is the product of a large number of interacting partners (Wang et al, 2011;Li et al, 2019). Moreover, noncoding regulatory regions of the genome have been relatively neglected in efforts to pinpoint the genetic basis of ALS, despite their functional synergy with the coding sequence (Wang et al, 2018;Cooper-Knock et al, 2020). ALS GWAS have demonstrated that missing heritability is distributed throughout noncoding chromosomal regions (van Rheenen et al, 2016;Nicolas et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Zhang

Cooper‐Knock

Weimer

et al. 2022

Neuron

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Genome-wide identification of the genetic basis of amyotrophic lateral sclerosisHighlights d Machine learning method identifies risk genes by integrating GWASs and epigenetic data d Discovered ALS risk genes lead to a 5-fold increase in recovered heritability d Genetic and experimental support for initiation of ALS pathogenesis in the distal axon d Convergent genetic and experimental data establish KANK1 as a new ALS gene

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Section: Rare Variant Analysis Validates Refmap Genesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Zhang

Cooper‐Knock

Weimer

et al. 2022

Neuron

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“…We filtered for rare, deleterious variants within KANK1 enhancer, promoter and coding regions based on evolutionary conservation, functional annotations and population frequency 33,44–46 ( Methods ). Enhancer and promoter regions for KANK1 were defined as previously described 8,47 . Enhancer and promoter regions were independently enriched with ALS-associated rare deleterious variants (P<0.05, SKAT 48,49 ; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…, (8) in which the rectified Gaussian distribution is defined via a dumb variable. Specifically, we first define v -1 and v +1 by ,…”

Section: Model Design and Inference Of Refmapmentioning

confidence: 99%

“…ALS GWAS studies to date have lost power by considering genetic variants in isolation, whereas in reality, a biological system is the product of a large number of interacting partners 6,7 . Moreover, noncoding regulatory regions of the genome have been relatively neglected in efforts to pinpoint the genetic basis of ALS, despite their functional synergy with the coding sequence 8,9 . Indeed, GWAS studies have suggested that a significant proportion of missing heritability in ALS is distributed throughout noncoding chromosomal regions 4,5 .…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis

Zhang

Cooper‐Knock

Weimer

et al. 2020

Preprint

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Amyotrophic lateral sclerosis (ALS) is an archetypal complex disease centered on progressive death of motor neurons. Despite heritability estimates of 52%, GWAS studies have discovered only seven genome-wide significant hits, which are relevant to <10% of ALS patients. To increase the power of gene discovery, we integrated motor neuron functional genomics with ALS genetics in a hierarchical Bayesian model called RefMap. Comprehensive transcriptomic and epigenetic profiling of iPSC-derived motor neurons enabled RefMap to systematically fine-map genes and pathways associated with ALS. As a significant extension of the known genetic architecture of ALS, we identified a group of 690 candidate ALS genes, which is enriched with previously discovered risk genes. Extensive conservation, transcriptome and network analyses demonstrated the functional significance of these candidate genes in motor neurons and disease progression. In particular, we observed a genetic convergence on the distal axon, which supports the prevailing view of ALS as a distal axonopathy. Of the new ALS genes we discovered, we further characterized KANK1 that is enriched with coding and noncoding, common and rare ALS-associated genetic variation. Modelling patient mutations in human neurons reduced KANK1 expression and produced neurotoxicity with disruption of the distal axon. RefMap can be applied broadly to increase the discovery power in genetic association studies of human complex traits and diseases.

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Genome-Wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis

et al. 2020

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Rare Variant Burden Analysis within Enhancers Identifies <i>CAV1</i> as a New ALS Risk Gene

Cited by 4 publications

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Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis

Genome-wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis

Genome-Wide Identification of the Genetic Basis of Amyotrophic Lateral Sclerosis

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