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

Abstract

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.

Common and rare variant analyses combined with single-cell multiomics reveal cell-type-specific molecular mechanisms of COVID-19 severity

“…With RefMap, we can scan the genome for functional regions in which disease-associated genetic variation is significantly shifted from the null distribution. The power of the RefMap model for gene discovery and recovery of missing heritability has been demonstrated in our recent work 32 . Here, to achieve cell-type-specific resolution within multicellular tissue, we modified RefMap to integrate single-cell multiomic profiling of human lungs with COVID-19 GWAS data ( Fig.…”

“…The copyright holder for this preprint this version posted June 21, 2021. ; https://doi.org/10.1101/2021.06.15.21258703 doi: medRxiv preprint integrate common variants with epigenetic profiles 32 , and PULSE for rare variant discovery by prediction. The evolution of clinical COVID-19 involves the interaction of multiple viral and host factors in what is likely to be a nonlinear system; our work supports this proposal and suggests that traditional methods may be inadequate given current sample sizes.…”

“…Our study of common and rare genetic variation associated with severe COVID-19 converges on common biology, despite non-overlapping datasets and orthogonal analytical methods. We have achieved this because we have developed effective machine learning methods which offer advantages over traditional methods: RefMap to integrate common variants with epigenetic profiles 32 , and PULSE for rare variant discovery by prediction. The evolution of clinical COVID-19 involves the interaction of multiple viral and host factors in what is likely to be a nonlinear system; our work supports this proposal and suggests that traditional methods may be inadequate given current sample sizes.…”

“…(1) to (18), we are interested in calculating the posterior probability p ( T | Z , S ), where the mean-field variational inference (MFVI) 73 was adopted to solve the intractability. More technical details, including a coordinate ascent-based inference algorithm, can be found in our previous work 32 .…”

Membrane lipid raft homeostasis is directly linked to neurodegeneration

“…We have recently developed a novel machine learning model called RefMap to increase the power of gene discovery by integrating motor neuron functional genomics with ALS genetics [ 105 ]. We examined the 690 candidate genes identified by RefMap to see which are linked with MLR homeostasis and SMase/PL function in particular.…”