Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10 −3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drugrepurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.

While cutaneous leishmaniasis is characterized by lesions proximal to the site of the sandfl y bite, visceral leishmaniasis is associated with immunopathology in the liver and spleen of the infected host. This chapter offers a brief overview of the immune responses generated during infections with cutaneous and visceral leishmaniasis. Insights on how the immune responses generated during cutaneous and visceral leishmaniasis coupled with other host-and pathogen-derived factors determine the clinical pathology and outcome of the disease are also discussed.

We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genomewide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93-1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53-1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population. Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal multisystem neurodegenerative disease, leading to substantial public health threat although it is relatively rare worldwide. However, the cause and pathogenesis underlying ALS mostly remains unknown, with few replicable and definitive risk factors and scarce drugs available 1-4. The number of ALS cases is predicted to increase dramatically due to population aging in the coming years 5 , which would further aggravate the ALS-associated social and economic burden. Therefore, the identification of its risk factors can provide better understanding of ALS and has the potential to pave the way for therapeutic intervention. In the past few years the role of telomere in various complex diseases has attracted much attention 6. Progressive telomere shortening occurs in all dividing normal cells due to incomplete synthesis of DNA lagging-strand, oxidative damage and other factors, which ultimately leads to cellular growth arrest or apoptosis that is thought to be an initial proliferative barrier to tumor development in humans 7. Indeed, recent studies suggested that leukocyte telomere length (LTL) was widely relevant to age-related diseases and disorders (e.g. many types of cancer and coronary heart disease) 8-11. In particular, it was demonstrated that shorter LTL was associated with various neurodegenerative disorders. For example, a latest study showed LTL at baseline and 18 months was shorter in patients of Parkinson's disease (PD) compared to healthy controls 12 , although prior studies found nonsignificant association between LTL and PD (Table 1). In addition, telomere shortening was recognized as an indicator of progression for Alzheimer's disease (AD) (Table 1). However, the knowledge about the relationship between LTL and ALS is very limited. Previous studies proposed th...