Ramirez, A. | bioRxiv Science

bioRxiv2018

Gene-Based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes For Alzheimer’s Disease

A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimers Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates.\n\nThree novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423. The ZNF423 gene resides in an Alzheimers disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.

genetics↗

bioRxiv2017

Population-scale organization of cerebellar granule neuron signaling during a visuomotor behavior

Granule cells at the input layer of the cerebellum comprise over half the neurons in the human brain and are thought to be critical for learning. However, little is known about granule neuron signaling at the population scale during behavior. We used calcium imaging in awake zebrafish during optokinetic behavior to record transgenically identified granule neurons throughout a cerebellar population. A significant fraction of the population was responsive at any given time. In contrast to core precerebellar populations, granule neuron responses were relatively heterogeneous, with variation in the degree of rectification and the balance of excitation versus inhibition. Functional correlations were strongest for nearby cells, with weak spatial gradients in the degree of rectification and excitation. These data open a new window upon cerebellar function and suggest granule layer signals represent elementary building blocks underrepresented in core sensorimotor pathways, thereby enabling the construction of novel patterns of activity for learning.\n\nSIGNIFICANCE STATEMENTCerebellar processing is important for a variety of fine motor tasks and sensorimotor adaptations, and a growing body of evidence indicates a prominent role in cognitive control. However, it has been challenging to understand cerebellar function during behavior because of difficulties in recording from cerebellar granule neurons, the most populous neuron type in the brain. We use population-scale optical imaging in the larval zebrafish to compare precerebellar activity to granule cell signaling. Our results suggest a behaviorally relevant expansion of precerebellar signaling representations at the granule layer of the cerebellum.

neuroscience↗