Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

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. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

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. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. 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

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

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.peer-reviewe

Brain mapping

Cartography of the brain ("brain mapping") aims to represent the complexities of the working brain in an understandable and usable way. There are four crucial steps in brain mapping: (1) acquiring data about brain structure and function, (2) transformation of data into a common reference, (3) visualization and interpretation of results, and (4) databasing and archiving. Electrophysiological and functional imaging methods provide information about function of the human brain. A prerequisite for multisubject, multidimensional and multimodal mapping is transformation of individual images to match a standard brain template. To produce brain maps, color, contours, and other visual cues are used to differentiate metabolic rates, electrical field potentials, receptor densities, and other attributes of structure or function. Databases are used to organize and archive data records. By relating the maps to cognitive functions and psychological models, brain mapping offers a prerequisite for the understanding of organizational principles of the human brain

Speech system of the brain: Insight via functional imaging methods

The study of neural correlates of language has always lagged behind the study of other aspects of behavior and cognition due to the lack of an animal model. Clinical data led to the idea that language perception is localized in the posterior superior temporal lobe (Wernicke's area) and functions related to speech production are localized in the lateral frontal lobe (Broca's area) of the dominant hemisphere. Recent data from electrophysiological and functional neuroimaging investigations shows that the roles of Wernicke's and Broca's areas are not as clear as they appeared. A variety of cortical and subcortical regions have been found to be critically important for language processing. Functional magnetic resonance imaging (fMRI) can be used to study language system of the brain. When planning certain neurosurgical interventions, it is important to determine hemispheric language dominance and localization of language functions in order to avoid damaging these areas. Some fMRI language paradigms promise a completely noninvasive way of localizing language functions in an individual patient – a possible substitute for the tests currently in use. In our lab, we have recently started to use fMRI for localization of cortical language areas in healthy individuals and in neurological patients

Spatial and verbal working memory: A functional magnetic resonance imaging study

According to numerous studies, working memory is not a unitary system. Baddeley's model of working memory includes besides central executive also two separate systems for verbal and visuo-spatial information processing. A modality- and process-specific specialization presumably exists in working memory system of the frontal lobes. In our preliminary study, we have used functional magnetic resonance imaging to study the pattern of cortical activation during spatial and verbal n-back task in six healthy subjects. A bilateral fronto-parietal cortical network was activated in both tasks. There was larger activation of right parietal and bilateral occipital areas in spatial than in vebal task. Activation of left sensorimotor area was larger in verbal compared to spatial task. No task-specific differences were found in the prefrontal cortex. Our results support the assumption that modality-specific processes exist within the working-memory system

Electroencephalographic (eeg) coherence between visual and motor areas of the left and the right brain hemisphere while performing visuomotor task with the right and the left hand

Background: Unilateral limb movements are based on the activation of contralateral primary motor cortex and the bilateral activation of premotor cortices. Performance of a visuomotor task requires a visuomotor integration between motor and visual cortical areas. The functional integration (»binding«) of different brain areas, is probably mediated by the synchronous neuronal oscillatory activity, which can be determined by electroencephalographic (EEG) coherence analysis. We introduced a new method of coherence analysis and compared coherence and power spectra in the left and right hemisphere for the right vs. left hand visuomotor task, hypothesizing that the increase in coherence and decrease in power spectra while performing the task would be greater in the contralateral hemisphere.Methods: We analyzed 6 healthy subjects and recorded their electroencephalogram during visuomotor task with the right or the left hand. For data analysis, a special Matlab computer programme was designed. The results were statistically analysed by a two-way analysis of variance, one-way analysis of variance and post-hoc t-tests with Bonferroni correction.Results: We demonstrated a significant increase in coherence (p &lt; 0.05) for the visuomotor task compared to control tasks in alpha (8–13 Hz) in beta 1 (13–20 Hz) frequency bands between visual and motor electrodes. There were no significant differences in coherence nor power spectra depending on the hand used. The changes of coherence and power spectra between both hemispheres were symmetrical.Conclusions: In previous studies, a specific increase of coherence and decrease of power spectra for the visuomotor task was found, but we found no conclusive asymmetries when performing the task with right vs. left hand. This could be explained in a way that increases in coherence and decreases of power spectra reflect symmetrical activation and cooperation between more complex visual and motor brain areas.</p