African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.

The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer’s Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.

While protein-DNA interactions are crucial for a wide range of cellular functions, only a small fraction of these interactions was annotated to date. One solution to close this annotation gap is to employ computational methods that accurately predict protein-DNA interactions from widely available protein sequences. We present and empirically test first-of-its-kind predictor of DNA-binding residues in local segments of protein sequences that relies on the Fuzzy Cognitive Map (FCM) model. The FCM model uses information about putative solvent accessibility, evolutionary conservation and relative propensities of amino acid to interact with DNA to generate putative DNA-binding residues. Empirical tests on a benchmark dataset reveal that the FCM model secures AUC = 0.72 and outperforms recently released hybridNAP predictor and several popular machine learning methods including Support Vector Machines, Nave Bayes and k-Nearest Neighbor. The improvements in the predictive performance result from an intrinsic feature of FCMs that incorporate relations between the input features, besides the relations between the inputs and output that are modelled by other algorithms. We also empirically demonstrate that use of a short sliding window results in further improvements in the predictive quality. The funDNApred webserver that implements the FCM predictor is available at http://biomine.cs.vcu.edu/servers/funDNApred/.