Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

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The effects of temperature on parameters of motor nerve excitability were investigated in 10 healthy human subjects. The median nerve was stimulated at the wrist and compound muscle action potentials were recorded from the abductor pollicis brevis. Multiple excitability measures were recorded: stimulus-response curves, the strength-duration time constant (tauSD), threshold electrotonus, a current-threshold relationship and the recovery of excitability following supramaximal activation. Recordings were made at wrist temperatures of 35, 32 and 29 degrees C by immersing the arm proximal to the wrist in a water-bath. Cooling increased the relative refractory period by 7.8% per degree C (P < 0.0001), slowed the accommodation to depolarizing currents by 4.0% per degree C (P < 0.0001) and increased tauSD by 2.6% per degree C (P < 0.01), but most other excitability parameters were not affected significantly. The effects of temperature on threshold electrotonus were investigated further in separate studies on two subjects over the range 28-36 degrees C and found to be complex. Whereas the rate of accommodation to depolarizing current was closely related to instantaneous temperature, the threshold increase induced by hyperpolarizing current was most sensitive to changes in temperature, probably because warming the nerve causes a transient hyperpolarization by accelerating the electrogenic sodium pump. Consequently, it may be preferable to make allowances for differences in skin temperature when testing patients for abnormal excitability parameters, rather than to change the temperature to a standard value. For most excitability parameters, however, temperature control is not as important as it is for conduction velocity measurements.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.