Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Introduction: Gastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. Methods: To ascertain the genetic risk factors for gastroparesis, we conducted the largest thus far whole-genome sequencing study of gastroparesis. We investigated the frequency and effect of rare loss-of-function variants in patients with both idiopathic and diabetic gastroparesis enrolled in a clinical study of gastroparesis. Results: Among rare loss-of-function variants, we reported an increased frequency of a frameshift mutation p.Leu202ArgfsTer105, within the motilin receptor gene, variant rs562138828 (odds ratio 4.9). We currently replicated this finding in an independent large cohort of gastroparesis samples obtained from patients participating in the ongoing phase III gastroparesis clinical study. Discussion: Motilin receptor is an important therapeutic target for the treatment of hypomotility disorders. The identified genetic variants may be important risk factors for disease as well as may inform treatments, especially those targeting motilin receptor.

Mosaic loss of the Y chromosome (LOY) is a somatic, age-related event that has been previously associated with a variety of diseases of aging. A prior study of European cohorts demonstrated an association between LOY and Alzheimer's Disease and more recent molecular studies have shown that LOY can also occur within microglia, suggesting a potential functional role in AD pathogenesis. In this study, we further validate the association between LOY and AD via prospective analyses of 1,447 males, and perform Mendelian Randomization analysis on 10,013 males across 26 US cohorts. Significant results from these analyses provide further evidence for a role of LOY in the development of Alzheimer's Disease.

Gastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. An innate immune dysregulation and injury to the interstitial cells of Cajal and other components of the enteric nervous system are likely central to the pathogenesis of gastroparesis. Thus far, little is known about the underlying genetic risk factors for gastroparesis. To ascertain these genetic risk factors for gastroparesis we conducted the first large whole-genome sequencing genome-wide association study (GWAS) analysis of gastroparesis patients. The GWAS focused on idiopathic and diabetic gastroparesis cases as compared to matched controls as well as compared idiopathic versus diabetic cases. Amongst the top variants, we report a novel genetic risk variant for idiopathic gastroparesis - genetic association of the Solute Carrier Family 15 (SLC15) locus. This signal is driven by multiple variants with top missense variant SLC15A4:NM145648:exon2:c.T716C:p.V239A, rs33990080. SLC15A4 was shown to mediate M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress. The risk variant carriers have a significantly higher nausea score at baseline. We also delineated a number of statistically significant loci including novel ones as well as previously known loci such as HLA-DQB1 - rs9273363, variant associated with Type 1 diabetes. The GWAS picture that is emerging implicates the role of the machinery of M1 to M2 macrophage polarization in the etiology of idiopathic gastroparesis. We suggest that macrophage polarization fate could lead to the destruction of the interstitial cells of Cajal which effectively leads to abnormal gastric emptying.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels generate electrical rhythmicity in various tissues although primarily heart, retina and brain. The HCN channel blocker compound, Ivabradine (Corlanor), is approved by the US Food and Drug Administration (FDA) as a medication to lower heart rate by blocking hyperpolarization activated inward current in the sinoatrial node. In addition, a growing body of evidence suggests a role for HCN channels in regulation of sleep/wake behavior. Zebrafish larvae are ideal model organisms for high throughput drug screening, drug repurposing and behavioral phenotyping studies. We leveraged this model system to investigate effects of three HCN channel blockers (Ivabradine, Zatebradine Hydrochloride and ZD7288) at multiple doses on sleep/wake behavior in wild type zebrafish. Results of interest included shorter latency to sleep at 0.1 μM dose of Ivabradine (ANOVA, p:0.02), moderate reductions in average activity at 30 μM dose of Zatebradine Hydrochloride (ANOVA, p:0.024), and increased sleep at 4.5 μM dose of ZD7288 (ANOVA, p:0.036). These differences support the hypothesis that compounds blocking HCN channels can decrease wakefulness.